Third Annual Rutgers Brain Health Institute Symposium Friday, December 1st, 2017

Raritan Valley Community College

Branchburg, NJ 08876

8.00 AM – 8.30 AM Registration, Breakfast and Welcome

8.30 AM – 9.00 AM Dr. Gary Aston-Jones: BHI Overview & Updates

9.00 AM - 9.10 AM

Dr. Kelvin Kwan

“A Bio-Inspired Transcription Factor for Spiral Ganglion Neuron

Regeneration”

9.15 AM –9.25 AM

Dr. Teresa Wood

“Delineating Oligodendrocyte Progenitor Subtypes and their Roles in

CNS Remyelination”

9.30 AM – 9.40 AM

Dr. Morgan James

“Designer Receptors: A Novel Potential Therapeutic for

Management of Trigeminal Neuropathic Pain”

9.45 AM – 9.55 AM

Dr. Viji Santhakumar

“Developmental Inhibitory Dysregulation in a Mouse Model of

Autism-Epilepsy Syndrome”

10.00 AM – 10.10 AM

Dr. Madhuvika Murugan

“Mechanisms Underlying Epileptogenesis Following Blast-induced

Traumatic Brain Injury in a Rat Model”

10.15 AM – 10.25 AM

Dr. Neha Sinha

“Neurocognitive and Brain imaging Biomarkers that Track the

Progression of Striatal Neurodegeneration in Early Prodromal

Huntington’s Disease”

10.30 AM – 10.45 AM Refreshment Break

10.45 AM – 10.55 AM

Dr. Nicholas Minar

“Intersenory Integration in Typically Developing and Children At-

Risk for Autism Spectrum Disorder”

11.00 AM – 11.10 AM

Dr. Tracey Shors

“Learning to Recover from Sexual Trauma with Mental and Physical

(MAP) Training”

11.15 AM – 11.25 AM

Dr. Kevin Beck

“Establishing a Model for Sex Specific Enhanced Avoidance Learning

in Opioid-dependent Individuals”

11.30 AM – 12.30 PM

Keynote: Dr. Regina M. Carelli, PhD, Stephen B. Baxter Distinguished

Professor, University of North Carolina at Chapel Hill.

“Unraveling Mechanisms of Impaired Learning & Decision-making in

Addiction”

12.30 PM – 2.00 PM Buffet Lunch

2.00 PM – 2.20 PM

RUCDR and Rutgers Human Genetics Institute of NJ Mini Talks

Dr. Jay A. Tischfield: “Identifying Genes for Tourette disorder and

Deciphering their Molecular Pathology”

2.25 PM – 2.35 PM Dr. Ronald Hart: “Human iPSC Models of Neurological Disorders”

2.40 PM – 2.50 PM Dr. Jennifer Moore: “RUCDR Infinite Biologics: Providing

Biospecimen Services and Resources for the Global Community”

3.00 PM – 4.30 PM Post-doc and Student Poster Session

4.30 PM – 5.30 PM Wine & Cheese Reception and Best Poster Awards

Mission Statement

The goal of the Brain Health Institute (BHI) is to develop neuroscience at Rutgers to become a highly

translational and internationally preeminent research enterprise. New tools are transforming neuroscience, and

these afford an unprecedented opportunity to create new treatments for central nervous system disorders.

Neuroscience has been identified by Rutgers University as one of five signature areas for future focus and

development. As part of this strategic plan, the BHI was established to become an internationally recognized

center for basic, translational, and clinical research into the biological bases of human brain function and

dysfunction. The BHI is the home for the overall Rutgers neuroscience initiative, and is a growing

interdisciplinary institute consisting of more than 250 principal investigators with neuroscience laboratories

across various campuses of Rutgers University and Rutgers Biomedical and Health Sciences. By supporting and

coordinating neuroscience across all campuses, the BHI will unite Rutgers University’s dynamic and diverse

neuroscience community toward common goals:

To create research programs focused on the biological underpinnings of the central nervous system’s

function and dysfunction.

To develop treatments for these disorders using novel neuroscience tools.

To establish a rich neuroscience resource in New Jersey that educates the public, clinicians, faculty, and

students, as well as state, national, and international health officials.

BHI Strategic Plan

Initial focus for development of neuroscience via the BHI at Rutgers will be on four areas and associated

disorders: Neurodevelopment, Neurodegeneration and Injury, Cognitive and Sensory Neuroscience, and

Motivational and Affective Neuroscience. The selection of the focus areas was based on an analysis of strengths

at Rutgers currently, as well as the recognition of prevalent nervous system disorders with a large need for novel

treatments. A major goal will be to identify potential teams within these areas of focus, where targeted

recruitments would have a significant impact on multi-investigator translational research.

A further area of focus for the Brain Health Institute will be to utilize new techniques in basic neuroscience to

develop novel therapies for brain and spinal disorders. Over the past 7 years, developments in viral vector

neurotransduction, optogenetics, and chemogenetics (designer receptors), among other areas, are

revolutionizing neuroscience. These new methods have proven effective in altering brain function and

dysfunction in highly specific ways in animal models, indicating that such methods may lead to a new generation

of neurotherapeutics. Indeed, viral vectors are already being used in clinical trials to treat Alzheimer’s and

Parkinson’s diseases by expressing growth factors to halt degeneration of neurons in the basal forebrain and

midbrain. Similar viral vectors can be used to express opsins or designer receptors in a cell type-specific manner

to allow control of selective populations of brain or spinal neurons with unprecedented specificity. This will allow

new therapies, based upon knowledge from basic neuroscience research, with many fewer side effects

compared to almost any current treatment. By studying different disorders in parallel, we can identify

commonalities for the underpinnings of disease. The goal is to identify the genetic, environmental, and other

aspects related to neuropathology and repair so that effective strategies can be developed for prevention and

treatment.

Director: Gary Aston-Jones, PhD: gsa35@ca.rutgers.edu

Associate Director: Robin Davis, PhD: Rldavis@dls.rutgers.edu

Managing Director: Eldo Kuzhikandathil, PhD: kuzhikev@ca.rutgers.edu

Administrative Services Manager: Lena Fullem, CRA: fullem@ca.rutgers.edu

Secretary: Louise Petrone: lp544@ca.rutgers.edu

Brain Health Institute

683 Hoes Lane West, Office 259A

Piscataway, NJ 08854

Phone: 732-235-4767; e-mail: bhi@ca.rutgers.edu; Web site: https://brainhealthinstitute.rutgers.edu/

SPEAKER ABSTRACTS

Keynote Speaker

Regina M. Carelli, Ph.D. Stephen B. Baxter Distinguished Professor, University of North Carolina at Chapel Hill

“Unraveling mechanisms of impaired learning & decision-making in addiction”

To secure resources necessary for survival, animals must acquire basic associative learning (cue-

outcome associations), and use that information to guide goal-directed behaviors. To do this effectively,

the costs and benefits of behaviors must be evaluated, including how hard one must work for reward,

the probability of acquiring valuable assets, as well as the magnitude of reward and the delay to its

procurement. To add to this complexity, specific elements of value-based decision making are

separable into related but distinct components involving outcome-based features (e.g., reward

magnitude), as well as subjective components that may be more variable across individuals (e.g.,

willingness to wait for reward). Research in the Carelli lab takes a multidisciplinary approach in rodent

models to examine how the brain processes information about reward learning and decision making,

and how these processes are altered in addiction. At the core of this work is the development of

sophisticated behavioral tasks we then combine with various methods (e.g., electrophysiology,

electrochemistry and optogenetics) to examine these processes. In this talk, I will present preclinical

data from our lab showing that the nucleus accumbens and its dopamine input play unique roles in

associative learning and discrete aspects of value-based decision making. I will also present work

showing that a history of cocaine self-administration interferes with associative learning and the ability

to process value that in turn can influence decision-making strategies. Finally, I will present ongoing

studies that build upon these circuit dynamics to include prefrontal cortical regions, and studies

examining if cocaine-induced deficits can be restored by optogenetically strengthening discrete

elements of circuit function. This later research direction is clinically relevant since strengthening

prefrontal-subcortical circuits that are ‘offline’ in addicts (i.e., hypofrontality) holds great promise in

restoring compromised cognitive function in addicts, and form the basis of innovative brain stimulation

treatment strategies for substance use disorders.

Dr. Carelli is the Stephen B. Baxter Distinguished Professor and Associate Chair of the Department of

Psychology at UNC-Chapel Hill. She obtained her BA, MS and PhD from the Behavioral Neuroscience

program, in the Department of Psychology at Rutgers. Her research examines how the brain processes

information about rewards, and how that information is used to guide goal-directed actions. Dr. Carelli

has won numerous awards, including the Presidential Early Career Award for Scientists and Engineers.

She serves on several national and international committees, editorial boards and NIH, NSF and DOD

review panels.

Kelvin Kwan, PhD Assistant Professor Department of Cell Biology & Neuroscience Rutgers-School of Arts and Sciences, New Brunswick

A Bio-Inspired Transcription Factor for Spiral Ganglion Neuron

Regeneration Kelvin Kwan1, KiBum Lee2, Mary Ying3 1Cell Biology & Neuroscience, Rutgers-SAS, New Brunswick, NJ 2Chemistry & Chemical Biology, Rutgers-SAS, New Brunswick, NJ. 3Otolaryngology, RBHS-NJMS, Newark, NJ

Loss of spiral ganglion neurons (SGNs) in the cochlea results in hearing loss. Currently, there is no treatment

for SGN loss. Directed differentiation of Schwann cells that reside adjacent to SGNs is a potential replacement

therapy to treat hearing loss. Ascl1 is a transcription factor that can promote differentiation of fibroblasts and

pluripotent stem cells into neurons. Delivery of Ascl1 into Schwann cells may promote neuronal differentiation.

Although delivery of single genes is feasible, future requirements to deliver multiple genes for generating

different neuronal subtypes will require more efficient delivery methods. The goal of the proposal is to efficiently

deliver a nanoparticle based Ascl1 synthetic transcription factor to direct neuronal differentiation of Schwann

cells. We have developed Ascl1-NanoScript by conjugating small molecules to an inert paramagnetic

nanoparticle. Ascl1-NanoScript enhances transcription activity in vitro when using a reporter plasmid containing

Ascl1 binding sites. We are currently employing methods for cell type specific delivery of Ascl1-NanoScript into

Schwann cells.

Teresa Wood, PhD Professor, Rena Warshow Endowed Chair in Multiple Sclerosis Department of Pharmacology, Physiology & Neuroscience Rutgers-New Jersey Medical School

Delineating Oligodendrocyte Progenitor Subtypes and their Roles

in CNS Remyelination M. Jeffries, I. Ornelas, Y. Huang, M. Isaac, Y. Song, A. Patel, W.G. Mcauliffe,

C.F. Dreyfus2, S.W. Levison1, S. Dhib-Jalbut3, T.L. Wood1 1Pharmacology, Physiology & Neuroscience, RBHS-NJMS, Newark, NJ 2Neuroscience & Cell Biology, RBHS-RWJMS, New Brunswick, NJ 3Neurology, RBHS-NJMS/RWJMS.

A central issue in multiple sclerosis (MS) is how to enhance remyelination of demyelinated axons.

Remyelination failure in MS is multifactorial and not completely understood, but there is evidence for decreased

efficiency of both recruitment and differentiation of oligodendrocyte progenitor cells (OPCs). Recent and

emerging studies support the hypothesis that OPC heterogeneity may play a role in differential remyelination

capacities in MS. For example, lesions in different areas of the brain in MS patients are repopulated with

unequal proportions of oligodendrocytes recruited from different sources such as the subventricular zone (SVZ)

and surrounding parenchyma. The goal of our studies is to provide new insights into the properties of different

OPCs and their capacities to promote remyelination. Towards this goal, we are defining 1) heterogeneity of

OPCs produced from the SVZ, and 2) the types of oligodendrocytes that participate in remyelinating the brain.

To test oligodendrocyte heterogeneity in remyelination in rodents, we are investigating how IGF/mTOR and

TrkB/Erk signaling pathways coordinately regulate remyelination. Based on published data and our preliminary

data, we have determined that neither the IGF/mTOR nor the TrkB/Erk pathways are solely responsible for CNS

myelination and remyelination and that loss of one pathway in oligodendroglia induces expression of the

alternate pathway. Our initial studies are focused on the cuprizone model that allows us to determine the

function of the mTOR and TrkB pathways specifically in the process of demyelination and remyelination in the

absence of adaptive immune mediated inflammation in the brain.

Morgan H. James, PhD Post-Doctoral Fellow (Gary Aston-Jones lab) Rutgers Brain Health Institute

Designer Receptors: A novel potential therapeutic for

management of trigeminal neuropathic pain Morgan H James1, Olga Korczeniewska2, Gary Aston-Jones1 & Rafael

Benoliel2 1Brain Health Institute, 2Diagnostic Sciences, Rutgers-SDM

Neuropathic pain often results from a lesion or disease affecting the somatosensory system, including the

trigeminal system. Current management of painful traumatic trigeminal neuropathies relies on pharmacologic

agents with severe side effects and low success rates. DREADDs (designer receptors exclusively activated by

designer drugs) are a new class of synthetic receptors that allow for localized suppression of neuronal

excitability via viral expression of a Gi-coupled designer receptor, referred to as hM4Di. The hM4Di receptor is

activated by the otherwise inert ligand clozapine N-oxide (CNO). We have previously shown that inhibition of

trigeminal ganglion (TG) neuronal activity using hM4Di under a general synapsin promotor successfully

produces analgesia in an acute formalin pain model in rat. However, owing to the general synapsin promoter

system, this approach was also associated with a reduction in non-pain reduced sensation. Here, we describe

experiments in which we sought to develop a novel vector to selectively drive hM4Di expression in TG

tachykinin/Substance P neurons, which are known to be primarily involved in pain sensation. We show that

using this approach, CNO-induced inhibition of TG tachykinin/Substance P neurons was associated with

analgesia on a rat model of chronic trigeminal neuropathic pain, without affecting non-pain sensation. We will

also discuss how this approach modulates activity of pain-related brainstem nuclei. Together, our data highlight

a potentially transformative approach for the management of trigeminal neuropathic pain. This approach may

also be relevant and applicable to a variety of other painful neuropathies and neuralgias.

Viji Santhakumar, PhD Associate Professor Department of Pharmacology, Physiology & Neuroscience

Rutgers-New Jersey Medical School

Developmental Inhibitory Dysregulation in a Mouse Model of

Autism-Epilepsy Syndrome Milad Afrasibai1, Carol Eisenberg2, Víctor Danelon2, Tracy Tran2, Viji

Santhakumar1 1Pharmacology, Physiology & Neuroscience, RBHS-NJMS, Newark, NJ 2Biology, RU-Newark, Newark, NJ;

Autism and childhood epilepsies are a complex disorders which can occur alongside devastating intellectual

disability and mental disorders. It has been proposed that developmental deficits in inhibitory neuron function

may lead to changes in neuronal circuit connections and function and underlie both disorders. Repulsive

interactions between the receptor Neuropilin2 (Nrp2) and the secreted class 3 semaphorin, Sema3F are

essential for regulating cellular morphology and cortical migration of specific inhibitory neuron subtypes. Nrp2

polymorphism is associated with autism in a cohort of patients and global Nrp2 deletion leads to autistic and

epileptic phenotype. Using transgenic mice with global and selective developmental deletion of Nrp2 as our

model, we are examining the role of inhibitory circuit dysfunction and interneuron migrational and behavioral

deficits in the mutants. Global Nrp2 knockout reduced hippocampal expression of inhibitory neurons expressing

parvalbumin. Although pyramidal neuron intrinsic physiology was not altered, CA1 neurons in Nrp2 knockout

mice showed altered synaptic inhibitory currents. Effects of selective early life disruption of Nrp2 are currently

under investigation. These studies will develop mechanistic insights into cellular, molecular, genetic and

systems-level changes in interneuron circuits underlying childhood epilepsy-autism comorbidity and enable

subsequent targeted therapeutics.

Madhuvika Murugan, PhD Post-Doctoral Fellow (Namas Chandra’s lab) Department of Biomedical Engineering NJIT

Mechanisms underlying epileptogenesis following blast induced

traumatic brain injury in rat model Madhuvika Murugan1, Bogumila Swietek2, Vijayalakshmi Santhakumar2,

Namas Chandra1 1Biomedical Engineering, Center for Injury Biomechanics, Materials and Medicine, New Jersey Institute of

Technology, NJ; 2Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, NJ.

Blast-related traumatic brain injury (bTBI) is the signature injury of combat troops in recent conflicts and leads to

acute and chronic physical, cognitive and behavioral dysfunctions. bTBI is defined here as an injury due to pure

shock wave exposure and impact TBI (iTBI) as injury due to blunt body impact or inertia. Although iTBI is known

to contribute to the development of post traumatic epilepsy (PTE), the risk for PTE following bTBI is not known.

Hence, the primary aim of this study was to investigate the effect of bTBI on epileptogenesis in a military-

relevant rat model of bTBI. bTBI can be classified as mild, moderate or severe based on the magnitude of blast

overpressure. In this work, we found that rats subject to mild bTBI developed abnormal EEG patterns and

demonstrated behavioral seizures earlier than controls following kainic acid administration. Post-injury induced

neuronal death and neuronal excitability changes in the dentate gyrus corresponded with the epileptogenic

phenotype seen in bTBI rats. We further compared our results from bTBI model with a known model of iTBI-

induced seizures (lateral fluid percussion injury- LFPI), in order to evaluate the effect of biomechanical

differences in determining the neurological outcomes. Our results suggests that similar to the LFPI model, bTBI

causes an axonal and ischemic pathology that enhance hippocampal dentate excitability and contribute to

epileptogenesis. This study will further our understanding of the mechanisms underlying bTBI-induced seizures

and help identify targets for improved therapeutic solutions.

Neha Sinha, PhD Post-Doctoral Fellow (Mark Gluck’s lab) CMBN, Rutgers- Newark

Neurocognitive and brain imaging biomarkers that track the

progression of striatal neurodegeneration in early prodromal

Huntington’s Disease. Neha Sinha1, Mark A. Gluck1; Daniel Schneider2 1CMBN, RU-Newark; 2Neurology, RBHS-RWJMS, New Brunswick, NJ

Huntington’s disease (HD) is a hereditary, progressive neurodegenerative disease, caused by an expanded tri-

nucleotide CAG sequence in the HD gene. There are currently no effective treatments or interventions to slow or

reverse the progression of this disease. The development of interventions, however, depends both on the ability

to predict the time course of future disease onset, and, the assessment of subtle pathologic changes in the

prodromal trajectory before clinical manifestation. In the current study, we combined behavioral experiments and

brain imaging to study the neurobiological and cognitive processes underlying prodromal cognitive and

neurocognitive changes in HD gene carriers many years before symptom onset. Subjects underwent brain

imaging while performing a learning task that differentiates positive from negative feedback. Patients with

prodromal HD (gene carriers), early-stage HD patients, and, age/education matched non-gene carriers

underwent brain imaging, while engaging in a reward/punishment associative learning task, known to depend on

the striatum, the brain region identified as a key structure for the neuropathology of HD. While still in its early

stages, this research has the potential to provide a sensitive measure of cognitive and neurological changes in

HD patients, and may lead to important translational benefits for future HD drug discovery and treatment

evaluation efforts.

Nicholas Minar, PhD Post-Doctoral Fellow (Michael Lewi’s lab) Department of Pediatrics RBHS-RWJMS

Intersenory integration in typically developing and children at-risk

for autism spectrum disorder Nicholas Minar1, Alan Leslie2, & Michael Lewis1 1Pediatrics, RBHS-RWJMS, New Brunswick, NJ; 2Psychology, RU-New Brunswick

Talking faces are the most important multisensory objects in an infant’s world because they are crucial for both

social exchange and for language development. Audiovisual synchrony cues are perceived in talking faces

because infants concurrently see visual lip movements and hear audible speech. This audiovisual synchrony

allows children to perceive the face and voice as a coherent whole rather than two disjointed events. Because

children learn to integrate faces and voices prior to language production, it is believed this ability acts as a

precursor to language development. We used social and non-social stimuli, such as talking faces or bouncing

balls and their sounds on impact, to investigate the intersensory integration abilities of infants under 24 months

of age who were either typically developing (TD) or at-risk for Autism (ASD). At-risk children were less sensitive

to audiovisual synchrony relations when viewing talking faces as well as bouncing balls. In a second study, we

examined the relation between sensitivity to audiovisual synchrony and subsequent language production 8

months later. We found that greater sensitivity to audiovisual synchrony was related to better language

production, in particular for face and voice integration. This was not the case for bouncing balls. These results

indicate that it is not sensitivity to audiovisual synchrony relations per se that is related to language production,

but rather sensitivity to synchrony relations between lip movements and audible speech that is important in the

development of language skills.

Tracey Shors, PhD Distinguished Professor Department of Psychology Rutgers- SAS, Piscataway

Learning to recover from sexual trauma with mental and physical

(MAP) training. Tracey J. Shors, Emma M. Millon, Han Yan M. Chang

Psychology, Rutgers–SAS, New Brunswick

Memories for traumatic life events are obviously generated by the brain but often felt in the body. MAP Training

is a novel clinical intervention that combines mental training of the brain with physical training of the body (Shors

et al., 2014). Each training session begins with 20-min of mental training with sitting meditation, followed by 10-

min of slow-walking meditation, ending with 30-min of physical training with aerobic exercise (see

MAPTRAINMYBRAIN.com). In previous studies, we reported that eight weeks of MAP training significantly

reduced symptoms of depression and ruminative thoughts while enhancing synchronized brain activity in

individuals with and without depression (Shors et al., 2014; Alderman et al., 2016; Shors et al., 2017). Recently,

we provided MAP Training to a large group of women (n>100), many of whom had a history of sexual trauma.

Before training, symptoms of depression, anxiety, and trauma-related cognitions were significantly elevated in

women with sexual trauma history (Millon, Chang Shors, under review). Groups were then trained with 1) MAP

Training or 2) aerobic exercise alone or 3) meditation alone. Aerobic exercise alone and meditation alone

reduced depressive symptoms. Aerobic exercise alone was effective in reducing anxiety symptoms whereas

meditation alone was effective in reducing trauma-related cognitions. Overall, these data suggest MAP Training

is preferable to either training practice alone because the combination targets more types of mental health

symptoms. As a consequence, more people benefit, including but not limited to women with sexual trauma

history.

Kevin Beck, PhD

Associate Professor, Associate Chief of Staff/R&D - VA New Jersey Health Care System Department of Pharmacology, Physiology & Neuroscience Rutgers-New Jersey Medical School

Establishing a model for sex specific enhanced avoidance

learning in opioid-dependent individuals Kevin Beck1, 2 & Mark West3 1Pharmacology, Physiology & Neuroscience, RBHS-NJMS, Newark; 2Neurobehavioral Research Laboratory,

VA New Jersey Health Care System, East Orange; 3Psychology, RU-SAS, Piscataway.

Male patients in an opioid-maintenance therapy program were found to acquire a novel avoidance behavior

more rapidly and to a higher asymptotic level compared to females in the same program and to male and

female controls. The question is whether addiction to opioids enhances avoidance learning, selectively in

males, or is an enhanced susceptibility to acquire avoidance a risk factor for developing opioid addiction in

males. Controlled studies are needed to answer this question. To address the first part of the question, male

and female Sprague Dawley rats are trained to self-administer fentanyl at the West lab at Rutgers University.

Once addictive behavior is well-established, the rats are transferred to the Rutgers University affiliated East

Orange VA Medical Center. Once there, the rats receive daily methadone maintenance treatments and be

trained in avoidance learning. Subsequent research will reverse the order of experimentation to determine if

avoidance susceptibility is predictive of opioid addiction vulnerability, selectively in male rats. Since

avoidance susceptibility is associated with anxiety disorders, this research could establish a unique animal

model to study sex-specific neurobehavioral connections between anxiety disorder vulnerability and risk for

opioid addiction.

Jay A. Tischfield, PhD, FFACMG

Duncan and Nancy MacMillan Distinguished Professor of Genetics

Professor of Pediatrics and Psychiatry, RBHS-RWJMS

Scientific Director and CEO, RUCDR Infinite Biologics

Executive Director, Human Genetics Institute of New Jersey, Piscataway.

Identifying genes for Tourette disorder and deciphering their

molecular pathology. Jay A. Tischfield and Gary A. Heiman, The Human Genetics Institute of New

Jersey and the Department of Genetics, Rutgers University New Brunswick.

Gene discovery by identifying recurrent de novo variants with whole-exome sequencing (WES) has proven

effective in neurodevelopmental disorders like autism, epilepsy, and intellectual disability. We have completed

WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a

replication sample of 186 trios (511 total). We observe strong and consistent evidence for the contribution of de

novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging

variants (LGD and probably damaging missense) are over-represented in probands (RR 1.37, p = 0.003). We

identify one risk gene with high certainty, CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), and

three likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2

domain containing 1), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo

damaging variants in approximately 400 genes contribute risk in 12-15% of clinical cases. In addition, we are

pursuing functional genetic studies of TD genes using induced pluripotent stem cell-derived neurons and

CRISPR mouse models. For example, we identified a rare heterozygous nonsense mutation in PNKD as the

likely TD gene in a three generation family with multiple affected members. Neurons were derived from iPSCs

and biochemical assays were conducted to evaluate possible molecular differences between affected and

unaffected. Transcript and protein levels of the PNKD long (neuronal) isoform were reduced in neurons derived

from the individuals with TD due to nonsense-mediated mRNA decay. We demonstrated that the PNKD long

isoform monomer oligomerizes with itself as well as interacts with the synaptic active zone protein RIMS1α, and

that this complex was reduced in concentration in TD subjects, suggesting a possible disease mechanism in this

multiplex family.

Ronald Hart, PhD Professor, Director, Stem Cell Program, Human Genetics Institute of New Jersey Department of Cell Biology and Neuroscience Rutgers-SAS, Piscataway

Human iPSC models of neurological disorders Human neurological disorders have been difficult to investigate at the level of molecular mechanisms in culture.

Using iPSC to prepare selected neuronal subtypes or brain organoids, HGINJ research groups have addressed

drug and alcohol abuse as well as neurodegenerative and developmental disorders. For example, excitatory

neuron cultures prepared from individuals carrying a nicotinic receptor variant (CHRNA4 D398N) were found to

have enhanced response to nicotine and rapid desensitization (Oni et al., 2016). Inhibitory neurons from

OPRM1 variants (encoding MOR N40D), linked with alcohol abuse, exhibit reduced agonist sensitivity following

chronic treatment (Halikere et al., in prep.). Neural precursors from Tuberous sclerosis subjects (TSC2+/-) have

a reduced rate of differentiation linked with attenuated Akt signaling (Zucco et al., in prep.). iPSC prepared from

Ataxia telangiectasia subjects with ATM mutations have been shown to spontaneously revert in culture (Lin et

al., 2015). Three-dimensional (3D) cultures of cerebral organoids and neuronal mouse chimeras reveal OLIG2-

dependent overproduction of GABAergic neurons in Down Syndrome (Xu et al., in prep.). This broad range of

studies demonstrates the utility of iPSC-derived human neurons for investigating genetic variants and neuronal

phenotypes.

Jennifer Moore, PhD Associate Director, Stem Cell Stem Cell and Lymphocyte Laboratories, RUCDR-Infinite Biologics Department of Genetics Rutgers-SAS, Piscataway

RUCDR Infinite Biologics: providing bio-specimen services and resources for the global community Established in 1998, RUCDR Infinite Biologics (RUCDR, www.rucdr.org) is the world’s largest university-based

integrated cell and DNA repository, assisting researchers throughout the world by providing the highest quality

biomaterials, technical consultation, and logistical support. Its services include sample collection and

bioprocessing (i.e., blood fractionation, nucleic-acid extraction, cell-line creation, etc.) and analytical services

such as gene expression, sequencing, and genotyping. RUCDR offers comprehensive stem cell culture

services that include the reprogramming of source cells such as skin fibroblasts and blood cells to yield induced

pluripotent cells (iPSC) and genome editing using CRISPR/CAS technology. In addition, RUCDR performs a

complete range of assays to characterize iPSCs to assess their quality, pluripotency, germline potential and

genomic stability, and distributes a cGMP grade iPSC line.

RUCDR has been awarded grants from the NINDS and NIMH to establish stem cell repositories that provide

high quality patient and control iPSCs and somatic cells from a wide range of disorders. The NINDS Human Cell

and Data Repository (NHCDR) has 170 fibroblast and 128 induced pluripotent stem cell (iPSC) lines for

Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Ataxia-telangiectasia, Frontotemporal Lobar

Degeneration (FTD), Huntington’s Disease (HD), Parkinson’s Disease (PD), and healthy controls.

The NIMH Stem Cell Center has 443 fibroblast and 169 induced pluripotent stem cell (iPSC) lines in support of

investigators engaged in stem cell-based research relevant to mental disorders, including but not limited to

anxiety disorders, attention deficit hyperactivity disorder, autism spectrum disorders, bipolar disorder ,

depression, eating disorders, obsessive-compulsive disorder, post-traumatic stress disorder, and schizophrenia.

Funded by grants from NINDS (5U24NS095914-02) and NIMH (4U24MH068457-14).

POSTER ABSTRACTS

Poster #1 Sex Differences in Ethanol Consumption, Persistent Negative Affects and Neuronal Activity in Rats Withdrawn from Intermittent Access to Ethanol

Authors Jing Li, Pei Chen, Wanhong Zuo, Jiang Hong Ye

PI Name: Jiang Hong Ye

Background: Although significant sex differences in alcohol drinking patterns have been noted, it remains

unknown whether there are sex differences in ethanol-related behaviors after prolonged abstinence.

Methods: Adult Sprague-Dawley rats had intermittent access to 20% ethanol for two months. After a 4-weeks

of abstinence, their ethanol-withdrawal related behaviors were measured. Cellular activities of several relevant

brain regions were quantified using Fos immunostaining.

Results: Females drank more alcohol and had higher blood ethanol concentrations than the males. No

difference in ethanol consumption was found among different menstrual phases of female rats. Compared with

sex-matched ethanol-naïve controls, after a 4-week abstinence, ethanol-withdrawn rats of both sexes displayed

depressive-like behaviors, and the females had higher anxiety levels, and the males displayed mechanical

allodynia. Upon resuming drinking, ethanol intake of the females but not the males was significantly elevated.

Furthermore, activities of neurons of abstinence rats changed in a sex- and time-dependent manner. Specifically,

at 24 h withdrawal, Fos-positive nuclei were increased in the prefrontal cortex, nucleus accumbens, amygdala,

and paraventricular nucleus of the females, but increase was only found in the amygdala, and lateral habenula

of the males. Conversely, after a 4-weeks abstinence, Fos-positive nuclei were decreased in the prefrontal

cortex, and nucleus accumbens of the females, but in the lateral habenula, and nucleus accumbens of the males.

Conclusion: Negative psychiatry disorders persistently presented in a sex-dependent manner in rats with a

history of chronic intermittent voluntary drinking. These behaviors may be regulated by different thalamo-cortical

circuits in different sexes.

This work was supported by NIH-NIAAA AA021657, AA022292, and a grant from NJ Health Foundation.

Poster #2 Changes to PSD-95 and cypin suggest that mild and moderate TBI act via distinct pathways

Authors Sara McEwan, Przemyslaw Swiatkowski, Nicholas Cuccolo, Bonnie L. Firestein

PI Name: Bonnie L. Firestein, Ph.D.

Traumatic brain injury (TBI) affects 1.7 million people every year in the United States. Although damage occurs quickly due to primary mechanical injury, secondary injury due to release of excess glutamate occurs hours to days after the initial insult. For this reason, rapid therapeutic intervention during the secondary injury phase is crucial for recovery. Cytosolic PSD-95 interactor (cypin) is a guanine deaminase, which we reported to play a neuroprotective role in an in vitro model of secondary injury of TBI. Thus, it is possible that cypin protein expression is altered after TBI. In the present study, mice were given hippocampal injections of compounds we identified to increase guanine deaminase activity of cypin or a compound that has no effect on this activity. Mice were then subjected to varying levels of CCI injury or sham surgery, contra- and ipsilateral cortices and hippocampi were dissected at select timepoints after CCI, and these brain regions were analyzed for cypin and PSD-95 protein by Western blot analysis. We found that cypin is elevated in the cortex at 1 day post-mild CCI and that PSD-95 is elevated in the hippocampus 1 day post-moderate CCI. Cortices from animals treated with cypin activator H9 showed elevated PSD-95 compared to control cortices at 1 day post-moderate CCI. Collectively, our data suggest that mild and moderate CCI act via distinct mechanisms and that cypin induction at specific time points may be part of a response system that could be advantageous for modulation of activity with small molecule compounds.

This work is funded in part by New Jersey Commission on Brain Injury Research grant #CBIR14IRG019 (to BLF). American Academy of Neurology Medical Student Summer Research Scholarship (to Nick Cuccolo).

Poster#3 The glucose sensitivity of lateral hypothalamic area (LHA) orexin glucose-inhibited (GI) neurons may influence reward-based feeding via modulation of ventral tegmental area (VTA) dopamine (DA) neurons.

Authors Suraj B. Teegala*, Zhenyu Sheng, Usman Khan, Miloni Dalal, Mark. P. Thomas, Vanessa. H. Routh

PI Name: Vanessa. H. Routh

One of the leading predictors for obesity is non-homeostatic or reward-based feeding which occurs when signals of energy homeostasis are overridden. Lateral hypothalamus (LH) orexin neurons play a role in food and drug reward by enhancing glutamate transmission onto ventral tegmental area (VTA) dopamine neurons. Orexin neurons are inhibited by glucose (GI neurons). We previously showed that fasting enhances activation of orexin GI neurons in low glucose. We hypothesized that activation of LHA orexin-GI neurons in low glucose persistently enhances glutamate neurotransmission onto VTA dopamine neurons and reinforces reward-based feeding behavior. We measured spontaneous NMDA and AMPA receptor mediated postsynaptic currents on VTA dopamine neurons using whole cell voltage clamp recording. Lowering glucose increased NMDA current amplitude (n=8; P<0.05). This was blocked by an orexin antagonist suggesting that activation of orexin-GI neurons mediated the effect of low glucose. Fasting increased the AMPA/NMDA current amplitude ratio, a measure of in vivo glutamate plasticity (n=7, P=0.03). Next, rats were food restricted to 85% of their body weight, bilaterally implanted with microdialysis guide cannula aimed 1mm above the LHA and trained for standard conditioned place preference (CPP) using chocolate. We dialyzed the LHA with brain glucose concentrations ranging from fasting to hyperglycemia to determine whether glucose dialysis reversed CPP. There was a significant negative correlation between glucose concentration and CPP score (P<0.05, R2=0.286, n= 15). Our data suggest that the glucose sensitivity of LHA orexin-GI neuron may link metabolic status to reward based-feeding by altering glutamate plasticity on VTA DA neurons.

NIH 1R01DK103676 and AHA

Poster#4

Calcium-dependent Erk1/2 MAPK activation following mechanical stretch injury induces myelin loss in

oligodendrocytes

Authors

Jihyun Kim, Pradeepa Gokina, Bryan J. Pfister and Haesun Kim

PI Name: Haesun Kim

Traumatic brain injury (TBI) is caused by mechanical force to the brain. Oligodendrocyte (OL) pathology

following TBI includes demyelination and cell death accompanied with axon degeneration. Since myelin is

crucial for neuronal functions and survival, loss of myelin is likely to result in axonal degeneration. While axon

pathology associated with TBI has been actively studied, the molecular mechanisms understanding the OL

response and the consequences on the myelin are not fully understood.

In this study, we investigated the effect of mechanical injury on OL. To elucidate the OL autonomous

response to mechanical injury, we have established OL monocultures on deformable silicone membranes,

which are rapidly stretched to initiate OL injury response in vitro. Stretch injury induced Erk1/2 activation and

MBP loss in OLs without cell death. Also, the stretch injury induced efflux of calcium in OLs. Increasing

intracellular calcium with a calcium ionophore was sufficient to activate Erk1/2 resulting in MBP loss. In

contrast, chelating intracellular calcium during the injury inhibited Erk1/2 activation. The Erk1/2 inhibitor

treatment prevented the MBP loss following injury. In vivo, we also validated TBI-induced Erk1/2 activation in

OLs within white matter accompanied by loss of myelin.

Altogether, our data show that the mechanical injury in OL initiates activation of intracellular signaling that

disrupts the myelin maintenance. The process is mediated by calcium-dependent Erk1/2 activation. Results

from this study provide insights into signaling pathways that are associated with myelin loss following TBI,

suggesting a therapeutic target that may attenuate myelin loss following brain injury.

This work was supported by grants from New Jersey Commission on Brain Injury Research (CBIR11PJT012) and Rutgers Initiative for Multidisciplinary Research Team (IMRT) Award to H.A.K.

Poster #5 The effect of neuroglia on acute mild traumatic insult Authors Bogumila Swietek, Magou, GC., Pfister, BJ., Berlin, JR.

PI Name: Joshua R. Berlin

Injuries sustained after an acute traumatic brain injury (TBI), such as a fall or motor vehicle accident, can lead

to long-term neurological and cognitive impairments. The injury sequelae following include mechanical injury

to neuronal cells which undergo uniaxial shear forces that stretch and compress axonal fibers. Unlike

moderate to severe TBI cases, acute TBI is absent of these microscopic anatomical changes despite

alteration in neuronal function. The molecular cascades, glutamate excitotoxicity, inflammation, ischemia and

oxidative stress, which ensue are secondary in nature but the mechanism initiating these cascades and its

effect on neuronal function is unknown. Therefore, to examine neuronal function in real time, an in vitro model

replicating the neuronal injury phenomenon will be used to assess the role of glial cells on neuronal function

after an acute traumatic insult. Using a stretch injury device, neurons will be stretched at controlled strain and

strain rate simulating an acute TBI. Intrinsic membrane and action potential properties will be examined in

neuronal-glial cultures at time points up to a day after injury to determine glial effect on neuronal function in

the injury milieu.

Supported by BHI-RUN-NJIT Pilot grant

Poster# 6 Inhibiting orexin-1 receptor signaling in ventral pallidum decreases demand for the opioid remifentanil

Authors Aida Mohammadkhani, Caroline B. Pantazis, Hannah B. Bowrey, Morgan H. James, Gary Aston-Jones

PI Name : Gary Aston-Jones

The orexin/hypocretin system has been implicated in motivation for drug reward and relapse. Orexin neurons of the hypothalamus send widespread axonal efferents to many reward-associated regions of the brain such as ventral pallidum (VP). Several studies have investigated the involvement of orexin signaling in motivation for cocaine, but little is known about the role of orexin signaling in motivation for opioids. Previously our lab showed that systemic blockade of orexin-1 receptors (Ox1Rs) decreases motivation for the potent and short-acting opioid remifentanil (Porter-Stransky et al., 2015). Previous studies also found that VP is an important site for the reinforcing effect of opiates and cocaine self-administration, as well as for reinstatement of drug seeking (Hubner and Koob, 1990; Mahler et al., 2014). However, it is unclear if orexin signaling in VP contributes to remifentanil demand. This study sought to determine whether intra-VP orexin signaling contributes to remifentanil demand and cue-induced reinstatement. We used a within-session behavioral economic (BE) paradigm in which remifentanil price (responses/μg iv remifentanil) was sequentially increased throughout the session. Rats were implanted with bilateral cannulae into VP, through which microinjections of SB334867 (SB; Ox1R antagonist) were given prior to BE testing. Rats were then extinguished and subjected to cue-induced reinstatement following intra-VP SB microinjection. We found that inhibition of OxR1 signaling in VP reduced motivation (increased demand elasticity) and cue induced reinstatement for remifentanil without affecting baseline consumption, or general locomotor activity. These effects were not observed with aCSF injections into VP or SB injections 2 mm dorsal to VP (controls). These behavioral results provide evidence for orexin signaling in VP in motivation for the opioid remifentanil.

Supported by R01DA006214 from NIDA

Poster#7 Protein phosphatase 2A is dysregulated in tauopathies of progressive supranuclear palsy and Alzheimer’s disease

Authors Hye-Jin Park, Kang-Woo Lee, Stephanie Oh, Run Yan, Jie Zhang, Thomas G. Beach, Charles H. Adler, Michael Voronkov, Steven P. Braithwaite, Jeffry B. Stock, M. Maral Mouradian

PI Name: M. Maral Mouradian

Abnormal aggregates of hyper-phosphorylated tau are a characteristic feature of several neurodegenerative disorders including Progressive Supranuclear Palsy (PSP) and Alzheimer’s disease (AD), but factors contributing to this pathologic tau phosphorylation are not well understood. In the present investigation, we studied the regulation of the phosphatase responsible for dephosphorylating tau in the brains of patients with PSP and AD. The assembly and activity of this PP2A isoform are regulated by reversible carboxyl methylation of its catalytic C subunit, while the B subunit confers substrate specificity. We sought to address whether the decreases in PP2A methylation and its methylating enzyme, leucine carboxyl methyltransferase (LCMT-1), reported in AD relate to tau pathology or to concomitant amyloid pathology by comparing them in the relatively pure tauopathy PSP. Immunohistochemical stains of frontal cortices showed that methyl-PP2A is reduced while demethyl-PP2A is increased, with no changes in total PP2A or B55α subunit, resulting in a reduction in the methyl/demethyl PP2A ratio of 63% in PSP and 75% in AD compared to controls. Similar findings were observed using Western blot analyses that showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains compared to controls. This is associated with a significant decrease in LCMT-1, as well as an increase in the demethylating enzyme, protein phosphatase methylesterase (PME-1), in both diseases. These findings suggest that PP2A dysregulation in tauopathies may contribute to the accumulation of hyper-phosphorylated tau and to neurodegeneration. Supported by the Michael J. Fox Foundation for Parkinson’s Research

Poster#8 Synergistic protective effect of sub-therapeutic doses of eicosanoyl-5-hydroxytryptamide and caffeine in α-synuclein transgenic mice Authors Run Yan, Chelsea Bautista, Jie Zhang, Eunsu Park, Hye Jin Park, Stephanie Oh, Jean Baum, M. Maral Mouradian PI Name: M. Maral Mouradian

Parkinson’s disease (PD) is characterized by the accumulation of aggregated α-synuclein (α-Syn) in Lewy-bodies and Lewy-neurites, and the progressive loss of dopaminergic neurons in the midbrain. Thy-1 promoter driven α-Syn transgenic mice were studied extensively as a disease model to understand PD. In the brains of these mice, abundant phosphorylated α-Syn (p-α-Syn) accumulation, neuroinflammation and impaired motor and cognitive functions were observed which parallels the hallmark of PD pathology. In our previous studies, we have shown that α-Syn-transgenic mice treated with a diet supplemented with eicosanoyl-5-hydroxytryptamide (EHT), a natural component present in coffee that enhances PP2A activity, has anti-inflammatory and anti-oxidant properties, exhibited decreased α-Syn phosphorylation and aggregation, improved neuronal integrity, reduced neuroinflammation, and better behavioral performance. Caffeine, another component of coffee, has also exhibited antioxidant, anti-inflammatory and anti-apoptotic properties and showed neuroprotective effects in MPTP and 6-OHDA models of PD. In fact, epidemiological studies have already revealed the association between coffee consumption and decreased incidence of PD. In this study, we tried to examine if combined treatments of sub-therapeutic concentration of EHT and caffeine could mitigate the phenotype and toxicity induced by α-Syn over-expression. Wild type or α-Syn transgenic mice were administered orally in mouse chow containing EHT and/or water containing caffeine upon weaning. Behavior tests showed that co-treatment of EHT and caffeine prevented 70% of the behavioral declines. Moreover, brain samples from mice under co-treatment showed reduced neuroinflammation and phosphorylation of α-Syn and increased c-fos immunoreactivity. Taken together, these findings suggest combined protective effect of EHT and caffeine treatment against α-Syn pathology and ameliorates PD related behavior deficits, which hints the active antiparkinsonian components of coffee drinking. Supported by NIH grant AT006868

Poster #9 Role of mu opioid receptor A112G SNP in the mesolimbic neurocircuitry

Authors Popova Dina, Nidhi Desai, Julie A. Blendy, Zhiping Pang

PI Name: Zhiping Pang

Mu opioid receptors (MORs) are highly enriched in the reward circuitry and can be activated by endogenous ligands as well as drugs of abuse. Individuals with the A118G single nucleotide polymorphism (SNP) in OPRM1 exhibit increased risk for drug addiction and require higher morphine doses to achieve adequate analgesia. Genetically engineered mice carrying A112G SNPs (homologous to human A118G) display less total MOR mRNA and protein expression and reduced analgesic response to morphine. In this study, we are investigating how A112G in MOR affects opioid regulation of synaptic transmission in the ventral tegmental (VTA). Previously, it has been proposed that opioids excite dopamine (DA) neurons in the VTA through inhibition of local interneurons; however, recent reports show significant diversity in DA neurons response to MOR. We addressed role of A118G polymorphism in MOR considering VTA heterogeneity, focusing on the mesolimbic pathway. Using slice electrophysiology, we found that both inhibitory and excitatory inputs to VTA DA neurons projecting to the nucleus accumbens medial shell (mAcb sh) were highly inhibited by application of MOR agonist DAMGO, leading to a moderate increase of DA neurons firing. Interestingly, mice carrying minor allele (i.e. GG112) exhibited no change in synaptic transmission compared to their littermate major allele controls (i.e. AA112), but had overall lower DAMGO sensitivity. Additionally, no significant differences in DA neurons firing were found between genotypes. Our current focus is to study the underlying molecular and cellular mechanisms of the A118G SNP which contribute to altered sensitivity of VTA DA neurons to opioids.

This study was supported by NIH grant 1R01AA023797

Poster #10 Reduced temporal and spatial cocaine-related coding in IL-NAc neurons is associated with increased motivation for cocaine Authors Courtney M. Cameron, Malavika Murugan, Jonathan W. Pillow, Ilana Witten

PI Name: Ilana Witten

Heightened risk of relapse during extended drug-free periods is a major obstacle in the treatment of cocaine addiction. The descending projection from the infralimbic cortex to the nucleus accumbens shell (IL-NAc) is thought to inhibit cocaine seeking. However, it remains unclear what information this projection carries to support cocaine-seeking behavior or how encoding of this behavior is altered by a drug-free period. To answer these questions, we combined cellular resolution calcium imaging and a Cre-dependent GCaMP virus to record projection-defined neurons in rats during a test of cocaine-seeking, either immediately after self-administration training (D1; n=188 neurons, 9 rats) or following a 15 day drug-free period (D15; n=197 neurons, 11 rats). We found that a subset of IL-NAc neurons (n=23 (12%), D1; n=16 (8%), D15) displayed sequential activity in relation to cocaine seeking, with the vast majority of this activity occurring after the action previously associated with drug delivery. These neuronal responses correlated on a trial-by-trial basis with animals’ latency to drug seek on subsequent trials; however, this correlation was reduced in animals that underwent a drug-free period. Additionally, other neurons were active selectively in specific spatial locations within the cocaine-associated context, and this pattern of activity was also reduced by a drug-free period (53% D1 vs. 35% D15). To determine if the observed activity in IL-NAc neurons acutely impacts cocaine-seeking behavior, we used optogenetics to control IL-NAc projection neurons. On stimulation trials, activity in this projection significantly decreased active lever presses (F(1,34)=19.06, p<0.0001) and increased inactive lever presses (F(1,34)=8.45, p<0.01) in both the D1 and D15 groups. While stimulation had no significant effect on response selection on the next trial (F(1,34)=1.76, p>0.05, active lever; F(1,34)=0.59, p>0.05, inactive lever), it did significantly increase the latency to respond on trials after stimulation (F(1,34)=8.52, p<0.01). These optogenetic findings provide further evidence that activity in IL-NAc neurons normally serves to decrease drug-seeking behavior and, taken together with the imaging results, suggest that the decreased neural encoding of temporal and spatial cocaine-associated information observed in this work may be one mechanism by which cocaine motivation is enhanced during drug-free periods. Supported by F32DA042515 awarded to CMC

Poster #11 An fMRI Study to Examine Cerebral Blood Flow in Non-treatment Seeking Cocaine Users

Authors Suchismita Ray, Keerthana Karunakaran. and Bharat B. Biswal

PI Name: Suchismita Ray

Background: Long-term cocaine use has been associated with cerebrovascular events such as infarction and hemorrhage in humans. Animal studies have shown a decrease in cerebral blood flow (CBF) velocities in small vessels due to chronic cocaine use. One human brain imaging study (Volkow, 1988) showed decreased CBF in the prefrontal cortex of cocaine users (vs. controls) using positron emission tomography (PET) technique. This human functional magnetic resonance imaging (fMRI) study examined CBF in non-treatment seeking cocaine smokers and healthy control participants. Methods: Ten cocaine users (3F; 47 years) and ten controls (2F; 47 years) were scanned using an arterial spin labeling (ASL) technique to compare mean CBF differences. ASL images were preprocessed using SPM before entering into ASL toolbox based on MATLAB to quantify CBF for each participant. Sequential odd and even number (tag and control) images from ASL data were subtracted to obtain voxel wise estimate of CBF. Results: Mean CBF images from each group were entered into a two sample t-test using FSL’s randomize method. The resulting p-maps were thresholded at uncorrected p < 0.01 with monte-carlo cluster threshold of 85 voxels. Cocaine users (vs. controls) showed significantly lower mean CBF in ten brain regions including frontal gyrus, basal ganglia, amygdala, caudate, pallidum and temporo-parietal cortex. Mean CBF in these regions was negatively correlated with cocaine use duration. Conclusions: Future research will determine whether cerebrovascular resistance in cocaine users can be enhanced by drug abstinence, pharmacological manipulations and whether enhanced blood flow relates to improved treatment outcome.

Supported by National Institute on Drug Abuse (K01DA029047)

Poster #12 Inhibition of Eph/Ephrin Signaling Promotes Recovery Following Traumatic Brain Injury

Authors Shavonne Teng, Alicia Palmieri, Juyeon Park, Renping Zhou, Janet Alder, Smita Thakker-Varia.

PI Name: Janet Alder and Smita Thakker-Varia

Traumatic Brain Injury (TBI) is a serious clinical problem with limited treatment strategies available to date.

Molecules of the Eph/Ephrin family are known process outgrowth inhibitors and blocking Eph function or

expression has been shown to enhance recovery after spinal cord injury. The effect of inhibition of Eph

receptors in TBI has yet to be investigated. EphA6 receptor is upregulated after the lateral fluid percussion

(LFP) model of TBI. Uninjured EphA6 knockout (KO) mice exhibit increase in dendrites with abnormally

exuberant processes, indicating EphA6’s inhibitory role on neuronal growth. Here we show that EphA6 KO

mice exhibit decreased neuronal cell death and glial scarring compared to wildtype (WT) mice after LFP

injury. Moreover, visualization of axons from injured EphA6 mutant mice crossed with transgenic Thy1-YFP

mice demonstrated enhanced regeneration in the cortex. Soluble EphA6-Fc fusion proteins administered to

injured WT mice, decreased cell death and neurodegeneration 7 days post injury (dpi) and improved motor

function on the Rotarod test at 21 dpi. EphrinA5, a ligand of the EphA6 receptor, is highly expressed in the

hippocampus and cortex of adult mice. Soluble clustered EphrinA5-fc fusion protein, an agonist to the EphA6

receptor, administered to injured mice, caused exacerbated levels of cell death and neurodegeneration

whereas, protein phosphotyrosine phosphatase inhibitor, sodium orthovandate, administration improved

cellular changes at 7 dpi. Together, these findings provide insight into the role of Eph/Ephrin pathways in

injury and demonstrate the therapeutic potential of intervention of EphA6 signaling via Fc fusion proteins and

pharmacological agents for the treatment of TBI.

Supported by NJ Commission of Brain Injury Research and American Academy of Neurology.

Poster #13 Next Generation Models of Dementia

Authors Marc Tambini, Wen Yao, David Briley, Radoslaw Dobrowolski and Luciano D’Adamio

PI Name: Luciano D’Adamio

Alzheimer’s Disease (AD) has a shattering impact on affected individuals, family members and society at large. Unfortunately, there is no disease-modifying drug available indicating an inadequate understanding of the pathogenic mechanisms underlying AD. ~5% of AD cases are familial (FAD) while ~95% of patients develop sporadic AD (SAD). APP is cleaved by β-secretase and γ-secretase. Mutations in either APP or the γ-secretase-components PSEN1 and PSEN2 cause FAD. Moreover, a rare APP variant -APPP- which is a poor β-secretase substrate- protects humans from SAD. These data point to a role for APP processing in both FAD and SAD pathogenesis. Model organisms of human diseases are helpful to dissect disease mechanisms, identify therapeutic targets and test therapeutic strategies. A critical features of animal models of AD is the ability to analyze learning-memory. The rat has been the organism of choice for cognitive research because the rat is an intelligent and quick learner. However, its popularity has diminished as techniques for genetic manipulation in rats have lagged behind that of mice. Recent developments in gene-editing technologies have erased this gene-editing gap. Hence, we have generated rats carrying pathogenic APP and PSEN1 mutations knocked in the endogenous genes. These animals are genetic copies of FAD in an unsurpassed model organism. We have also generated rats carrying the protective APP variant APPP. Assessing whether APPP prevents FAD caused by APP and PSEN1 mutations would determine if SAD and FAD share pathogenic mechanisms. The initial validation of these KI rats as model organisms of AD will be presented.

Supported by NIH/NIA

Poster #14 The role of dentate gyrus activin signaling in antidepressant treatment response

Authors: Mark M. Gergues, Christine Yohn, Marjorie R. Levinstein, Rene Hen, Benjamin A. Samuels

PI Name: Benjamin A. Samuels

Approximately 32-35 million adults in the US population (16%) experience an episode of major depression in their lifetime, and commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients (~33%) achieves remission with initial treatment. The reasons why some individuals remit to antidepressant treatments while others do not are unknown. Our overall research program addresses this question by assessing antidepressant treatment resistance in mice. Proper assessment of the antidepressant response in mice first requires manipulations that will yield behaviors associated with negative valence constructs that can then be reversed by antidepressant treatment. Chronic treatment of mice with corticosterone (CORT) effectively induces multiple changes in behavior associated with enhanced responses to potential harm and sustained threats (David et al 2009). Subsequent chronic treatment with antidepressants such as fluoxetine (FLX) reverses these behavioral changes in some, but not all, of the mice, permitting stratification into responders and non-responders to FLX. We looked for changes in gene expression in dentate gyrus, a region that we recently reported is critical for the beneficial behavioral, neurogenic, and neuroendocrine effects of FLX (Samuels et al 2015). We found several significant differences inexpression of Activin signaling-related genes between responders and non-responders to FLX in the dentate gyrus. Furthermore, modulating Activin signaling in the dentate gyrus can convert behavioral non-responders to FLX into responders

Poster #15 Synaptic and Behavioral Phenotypes Associated with Cyfip1 and Fmr1 interaction

Authors Azadeh Kamali Tafreshi, Thrishna Kumar, Salma Abdalmaged, Georgia Barbayannis, Kristen L. Szabla, Deanna L. Benson, Ozlem Bozdagi-Gunal

PI Name: Ozlem Bozdagi-Gunal

Cytoplasmic FMRP-interacting protein 1 (Cyfip1) increases the risk for autism and other neuropsychiatric disorders that are characterized by cognitive, social, and emotional dysfunction. In order to test the effects of

genetic interaction between Cyfip1 and Fmr1, Cyfip1+/-, Fmr1-/y, crossed Cyfip1+/-/ Fmr1-/y mice were tested for synaptic, cognitive and emotional phenotypes. Single and crossed mutants showed similar excessive

mGluR- LTD phenotype. The Cyfip1+/-/ Fmr1-/y double mutant mice showed significantly reduced LTP and decreased NMDA receptor-dependent LTD, phenotypes which were not observed in either single mutant. We next asked whether NMDA receptor composition is altered in single or double mutants. Our data showed that in the crossed mice both GluN2A and GluN2B levels were higher than WT in both total and synaptosome fractions and the effect on GluN2B appears to be additive. To test the social and cognitive deficits that are relevant to autism, the three-chamber sociability task and the inhibitory avoidance test were used. In the three- chamber task, all three groups of mutant mice showed less social interaction with the

novel mouse, only Fmr1-/y mice displayed a significant difference in social interaction compared to WT. The inhibitory avoidance task showed a statistically significant difference between the long-term memory of the

Fmr1-/y and WT group, after 24-hours, and between Cyfip1+/- and WT mice, after 48 hours. The results demonstrate that Cyfip1 has an interactive effect with Fmrp in the regulation of postsynaptic function in mature synapses.

This research was supported by NIMH MH103455

Poster #16 Recognizing the Task-Specific Dynamic Structure of the Brain Function through EEG.

Authors Ali Haddad and Laleh Najafizadeh

PI Name: Laleh Najafizadeh

We propose a novel framework for developing an atlas for the dynamic functional networks that are specific to a given task, using data measured through electroencephalography (EEG). Our framework, first, examines the temporal structure of the EEG data in the sensor space (the scalp) to determine the intervals during which functional networks sustain their connectivity and spatial distribution in the cortex. This is achieved by using our previously proposed source-informed segmentation algorithm. Prior to identifying the spatial location of these functional networks, the EEG data needs to be transformed into the source space (the cortex). Without loss of generality, here, we use the standardized low-resolution brain electromagnetic tomography (sLORETA), a linear source localization algorithm, to estimate the underlying activity on a vast array of points covering the entire surface of the brain. Rather than pairwise connectivity measures and following our previous work, we use singular value decomposition (SVD) to detect active functional networks during each segment. These networks are located as the groups of cortical points sharing common time-courses and are represented as vectors of Boolean values, indicating whether each point in the cortex is involved in the given functional network. To identify and locate the most consistent and recurrent dynamic functional networks throughout the recorded data, a Boolean matrix factorization (BMF) algorithm, here the Asso algorithm, is applied to the Boolean matrix comprising all the concatenated networks. This factorization also provides us with the dynamics of the identified functional networks for the given task.

This Project is supported by DARPA grant W911NF-16-1-0096

Poster #17 Childhood exposure to violence predicts altered neural circuitry for emotion regulation in adulthood

Authors Samantha R. Mattheiss, Hillary L. Levinson, Nadine Aboukaff, William W. Graves

PI Name: William W. Graves

It is often suggested that early experiences of adversity, such as exposure to violence, alter how people process reward and threat. Previous studies of the neural basis of acute and chronic stress have shown alterations in connectivity between frontal and subcortical regions, corresponding to differential reward and threat processing. However, no studies to our knowledge have examined the particular effects of high exposure to community violence during childhood on resting state functional connectivity, a measure of the organization and communication among neural regions. The current study aims to elucidate such effects by conducting a between-group resting state functional connectivity analysis comparing individuals reporting high compared to low exposure to violence during the ages of 3 to 14 years. We predicted decreased connectivity between frontal and, and subcortical regions implicated in threat and reward processing, for individuals exposed to high compared to low levels of violence during childhood. Results supported our predictions, with individuals reporting high compared to low levels of exposure to violence demonstrating negative connectivity with vmPFC and the left amygdala, implicated in threat processing, as well as the bilateral parahippocampal gyrus. These results suggest that exposure to violence during the ages of 3 to 14 may alter functional connectivity of a neural circuit involved in the regulation of emotional responses. Further, this study offers evidence supporting the claim that students in urban academic settings, where neighborhood crime rates are high, may benefit from interventions designed specifically to capitalize on such altered neural circuitry.

This work was supported by NIH Grant R00 HD065839.

Poster #18 Cortical networks supporting semantics and social cognition as distinguished in autism.

Authors Hillary Levinson, Miriam Rosenberg-Lee, William Graves

PI Name: William Graves

Autism spectrum disorder (ASD) affects roughly 1 in 68 US children. While primary language impairment is not always present, even high-functioning individuals with ASD have difficulty with abstract semantics and pragmatic language. It remains unknown whether these difficulties arise from social deficits or from difficulty with semantic abstraction. In neurotypicals (NTs), cortical networks supporting semantics (word meanings) and social cognition largely overlap, notably in the left inferior parietal lobe. Recent evidence suggests these networks may be distinguished by connectivity from distinct but adjacent regions: angular gyrus (AG) for semantics, and temporoparietal junction (TPJ) for social cognition. We tested whether social cognitive abilities were related to connectivity in the social or semantic networks across a sample of 26 ASD and 26 NT individuals. We correlated resting state functional connectivity of the AG and TPJ with the social cognition subscale of the social responsiveness scale (SRS-Cog, higher scores = poorer social cognitive abilities). While SRS-Cog scores differed significantly between the groups (MASD=68.5; MNT=44.27), there were no group differences in AG or TPJ connectivity. Rather, SRS-Cog scores were negatively correlated with connectivity between left AG and posterior cingulate, and positively correlated with AG to middle frontal gyrus (MFG) connectivity. These results suggest that difficulties with social cognition in individuals with autism may be related to aberrant connectivity within the semantic – but not the social – network. Increased AG-MFG connectivity suggests that individuals with social cognitive difficulties may recruit prefrontal resources to support semantic processing, a hypothesis we will examine in future task-based studies.

Supported by the Busch Biomedical Grant 2017.

Poster #19 Persistent avoidance in anxiety-vulnerable Wistar-Kyoto rats: The role of danger and safety signals.

Authors

Kevin M. Spiegler, Ian M. Smith, Ashley M. Fortress & Kevin C. H. Pang.

PI Name: Kevin C. H. Pang

Avoidance is a core symptom of anxiety disorders and post-traumatic stress disorder. In order to avoid, an individual must use environmental cues to predict an aversive event. Cues that occur at the onset of the aversive event become danger signals, while cues that occur at the offset of the aversive event signal safety. The Wistar-Kyoto rat (WKY) is used as a model for pathological avoidance. Recently, our lab has shown that WKY and SD are differentially reinforced by danger and safety signals. Given this finding, the question remained as to whether these strains were differentially reinforced by danger and safety signals during extinction. WKY and SD rats were trained to avoid foot shock by lever pressing in response to a danger tone. Upon lever pressing, the tone turned off and a flashing light turned on signaling safety. After training, animals extinguished avoidance in one of four conditions: 1) with both signals present, 2) with danger only, 3) with safety only, and 4) with no signals. The results revealed WKY rats display persistent avoidance when both signals were present and showed persistent avoidance, although to a lesser extent, when only danger or only safety was present. SD rats also showed persistent avoidance when both signals were present, but extinguished avoidance when individual signals were presented. Both strains quickly extinguished avoidance when no signals were present. These data suggest danger and safety signals can individually cause persistent avoidance in anxiety-vulnerable individuals. Such findings have important implications for behavioral treatments of anxiety disorders.

Poster #20

The effects of organophosphate flame retardants on the expression and activity of the M-current in NPY

neurons in adult mice

Authors Gwyndolin Vail and Troy Roepke

PI Name: Troy Roepke

The hypothalamus regulates many important biological functions such as reproduction, thermoregulation, and

energy balance. Orexigenic NPY neurons located in the arcuate nucleus (ARC) of the hypothalamus play an

essential role in energy homeostasis. Disruption of this balance can cause metabolic disease states such as

obesity and anorexia. EDCs such as organophosphate flame retardants (OPFR) are a potential cause of

hypothalamic disruption as they accumulate in human tissues and impinge on endogenous nuclear receptors

such as ERα and PPARγ. Previously, we demonstrated that OPFR oral treatment in adult mice decreased

ARC expression of neuropeptide Y and increased ghrelin receptor and KCNQ channel subunit expression in

a sex-dependent manner. We hypothesized these effects would augment the activity of the M-current in NPY

neurons leading to suppressed NPY excitability and reduced food intake. We used voltage clamp, whole-cell

patch-clamp to record the M-current in NPY neurons utilizing selective KCNQ channel blocker XE991 with

standard activation and deactivation protocols in mice after OPFR treatment. In males, OPFR increased the

peak current (84±15) in NPY neurons at -35 mV compared to control (59±10). These data correlated with an

increased expression of KCNQ-3 in male NPY neurons (1.63±0.16 over 0.97±0.14, p < 0.05) and a significant

decrease in neuropeptide Y expression. Female NPY neurons showed no OPFR effect on KCNQ channel

expression, but did reveal an increase in ghrelin receptor. Our data suggests that adult exposures to EDCs

like OPFR may impact the hypothalamic melanocortin neurocircuitry leading to dysregulation of energy

homeostasis in a sex-dependent manner.

Supported by R21ES027199

Poster #21

Structural Characterization of Reelin Using Cryo-Electron Tomography

Authors Liam S. Turk, Xuyuan Kuang, Khush Patel, Wei Dai, Davide Comoletti

PI Name: Davide Comoletti

Reelin is a glycoprotein, secreted by certain neurons including Cajal-Retzius and Cajal-Retzius-like cells, that

serves important functions in neuronal migration and brain development. Its altered expression has been

linked to various mental health disorders, such as ASD and schizophrenia. This roughly 400 kDa protein

contains a signal peptide, an F-spondin-like domain, eight Reelin repeats (RR1-8), and a stretch of positively

charged amino acids at the C-terminus. Reelin has a complex degradation pattern; after secretion, it is cut

into 3 discrete fragments: the N terminal fragment containing RR1-2, the central fragment of RR3-6, and the

C terminal fragment containing RR7-8. Previous inquiries have identified the apolipoprotein E receptor 2 and

the very-low-density lipoprotein receptor as binding partners for the central fragment of the Reelin protein.

While the structures of distinct RRs have been studied, the structure of the full length Reelin protein has not

been solved, most likely as a consequence of its large size and apparent flexibility. However, the solution-

based technique of cryo-electron microscopy has made possible the determination of protein structures that

had not previously been possible using x-ray crystallography. Reelin, owing to its large size, is a good

candidate for studies using cryo-ET, and here we report preliminary structural data using techniques in cryo-

ET of full length Reelin and various deletion constructs of the protein to further our understanding of its

architecture and function.

Supported by NIH grant T32 GM008339

Poster #22

Blast and brain injury research at the Center for Injury Biomechanics materials and medicine at NJIT

Authors Madhuvika Murugan, Daniel Younger, Maciej Skotak, Rama Rao, Bryan Pfister, Namas Chandra

PI Name: Namas Chandra

Brain injuries can be caused from impacts in automotive or sports accidents in the civilian world or blast

related neurotrauma in the defense world. The injury produces short and long term neurological and

behavioral dysfunctions and has serious economic and emotional consequences to the victim and their

families. In our Center, we have developed unique facilities that accurately recreate impact and blast events

using drop towers and field validated shock tubes. We have also developed animal injury models with

capabilities to examine pathophysiological and behavioral effects of these injuries. Using these models, we

have identified biomechanical and biochemical mechanisms. These findings have been used in the

enhancement of better protection systems and in the development of new biomarkers, and therapeutics.

Poster #23 Neural precursor cells from 16p11.2 deletion patients exhibit enhanced proliferation and altered FGF mitogenic activity.

Authors R. J. Connacher, M. Williams, S. Prem, J. H. Millonig, E. M. Diccio-Bloom

PI Name: E. M. Diccio-Bloom

Autism spectrum disorder (ASD) genetic etiology is complex and heterogeneous. Within ASD, ~1% contain a copy number variation (CNV) within the 16p11.2 chromosomal region. This CNV affects one copy of 27 genes. Within this region is MAPK3 encoding for ERK-1, which responds to extracellular factors to stimulate proliferation and growth. Humans with 16p often have macrocephaly, suggesting developmental growth phenotypes due to this deletion. We investigated induced pluripotent stem cell (iPSC) derived neural precursor cells (NPCs) from 3 16p individuals (2:1; M:F) diagnosed with ASD to various degree, compared to 3 age matched controls. We hypothesized there is a proliferation phenotype in 16p NPC and altered ERK signaling. CNV 16p patients NPCs exhibited 2-fold greater DNA synthesis than controls at 2 days. Exposure to FGF, a well-known neurogenic regulator and stimulator of ERK, increased DNA synthesis in 16p and unaffected NPCs. Interestingly, the magnitude of the FGF-induced stimulation of DNA synthesis was blunted in 16p NPCs. Cell counts for 16p were increased after 6 days of culture, reflective of earlier increases in DNA synthesis. Preliminary analysis of total ERK-1 protein in 16p NPCs revealed a 30% reduction, while P-ERK normalized to total ERK revealed a non-significant increase compared to control. Interestingly, mitogenic signals downstream of ERK, were also increased in 16p NPCs. We observe that 16p NPCs exhibit greater DNA synthesis, proliferation, and alterations in signaling compared to unaffected controls. Analyses of ASD NPCs may provide insights into developmental dysregulation that contribute to these disorders, and define underlying mechanisms.

This work was supported by Governor’s Council for Medical Research and Treatment of Autism Pilot Grant CAUT15APL041 and the Nancy Lurie Marks Family Foundation

Poster #24 Acute and long-term effects of traumatic brain injury on neuronal activity in somatosensory cortex

Authors Y. Bibineyshvili, N. Fliss, M. DelRocini, D. Margolis

PI Name: David Margolis

The present study examines the effect of traumatic brain injury (TBI) on neuronal activity in mouse sensory cortex. Using two-photon and wide-field microscopy, we measured changes in the fluorescent calcium sensor GCaMP6s in barrel cortex neurons of Thy1-GCaMP6s transgenic mice during whisker deflections or spontaneous activity. Mice were prepared with glass windows (for two-photon imaging) or transparent transcranial windows (for wide-field imaging) and trained to sit in a tube under the microscope. Each session contained 30—50 trails of 5 s duration for sensory-evoked activity, or 20 s for spontaneous activity. After several baseline sessions, mice were randomly divided into the injury or control groups. Both groups on the day of injury had small unilateral craniotomy in the motor cortex region. One hour after isoflurane anesthesia, mice in the injury group were subjected to a mild controlled cortical impact injury (CCI) during imaging. After the initial response was captured, neuronal activity was followed in imaging sessions at 0.3 and 1 h, and 1, 3, 7 and 14 d after CCI. During the injury, we observed a wave of hyperactivity followed by significant activity decrease. Ongoing experiments aim is to show the difference in post-CCI neuronal activity, and to estimate the correlation between the initial wave response to the subsequent recovery processes. Our future goals are to specify the effect of sensory cortex neurons directly connected to motor cortex (using retrograde tracers), and to relate neuronal dynamics during and after CCI to behavior and recovery.

Poster #25 Blood pressure and cerebral blood flow following concussion

Authors Allan Knox, Michelle Favre, Michael Falvo, Jorge Serrador.

PI Name: Jorge Serrador

The increasing prevalence of Mild Traumatic Brian Injury (mTBI) has reached epidemic levels, accounting for

75% of all reported head injuries. No anatomical changes have been observed following mTBI, although data

regarding more sensitive measures following mTBI are deficient. The objective of this work was to determine

if any changes in blood pressure (BP), cerebral blood flow (CBF) or cerebral autoregulation exist following

mTBI and to establish if previous mTBI history has any influence. We assessed BP, CBF, and cerebral

autoregulation in rugby players immediately following mTBI (n=41) and compared with a control group (n=75)

of players who completed a rugby match with no reports of mTBI. History of mTBI was self-reported. Mean

arterial pressure was higher following mTBI compared to controls. (Ctrl 74±11vs 83±12 mmHg, p<0.001).

Internal carotid artery (ICA) blood flow was reduced in the mTBI group (Ctrl 477±175 vs mTBI 317±140

mL/min, p=0.002). End tidal CO2 was lower following mTBI than controls (Ctrl 38.9±6.0 vs mTBI 36.5±3.9

mmHg, p=0.013). History of mTBI had no influence on any of these measure (p>0.05 for all). Internal carotid

CVR was also greater in those with concussion (Ctrl 0.20±0.15 vs mTBI 0.36±0.27, p=0.007) that was

affected by concussion history (p=0.022). Players experiencing a first-time concussion had higher CVR

values than those with a history of concussion (0.45±0.31 vs 0.26±0.12, p=0.028). Changes in BP and CBF

are evident following mTBI which may help in diagnosis. Further research is necessary to determine the role

of cerebral hypoperfusion in concussions.

Poster #26 Using galvanic vestibular stimulation to improve balance and gait in veterans

Authors Yaa Haber, Kelly Brewer, Bishoy Samy, Leslie De La Cruz, Faria Sanjana, Maran Shaker, Jorge Serrador

PI Name: Jorge Serrador

Vestibular disorders are often underdiagnosed in a primary care setting and vestibular dysfunction can lead to greater difficulty in daily tasks and increased fall risk. Common symptoms of vestibular hypofunction include dizziness, nausea, vertigo and imbalance. Our preliminary findings show high levels of reduced vestibular function amongst veterans. Application of stochastic noise galvanic vestibular stimulation has been shown to improve response to walking stability as well as improving postural balance. Our aim was to determine if stochastic noise galvanic vestibular stimulation can improve balance and gait in a population of veterans with vestibular dysfunction. Thirty-one veterans with vestibular hypofunction participated in study procedures with and without stochastic noise galvanic vestibular stimulation. To measure balance, veterans stood on a force plate under conditions of eyes open, eyes closed, eyes open while standing on a foam block, and eyes closed while standing on a foam block. To measure gait, veterans were instructed to walk at their normal pace on an electronic walkway. All subjects showed an improvement in balance stability in the mediolateral direction with application of stimulation (a significant overall average of 30% improvement). A moderate improvement in gait velocity was seen for most veterans, however, results did not reach statistical significance. These data demonstrate that imperceptible levels of galvanic vestibular stimulation can be used to improve balance and moderately improve gait in some veterans who have vestibular hypofunction. Further work is needed to determine the long term effects of continuous stochastic noise galvanic vestibular stimulation.

Supported by: CDMRP grant W81XWH-14-1-0598, Use of a Portable Stimulator to treat Gulf War Illness and

grant W81XWH-14-2-0012, Treatment of Vestibular Dysfunction Using a Portable Stimulator. Supported by

War Related Illness & Injury Study Center, Dept of Veteran Affairs.

Poster #27 HDAC3-inhibition enhances time-dependent consolidation of long-term memory for specific auditory associations

Authors Andrea Shang, Sooraz Bylipudi, Kasia M. Bieszczad

PI Name: Kasia M. Bieszczad

Epigenetic mechanisms like histone acetylation modulate gene expression to alter long-term memory (LTM) in the adult brain (Sweatt 2013). Recent work in auditory models of memory has shown that pharmacological inhibition of histone deacetylase 3 (HDAC3i) during consolidation of auditory associative learning enhances both the strength and precision of memory for behaviorally-salient sounds. Furthermore, these sounds have enhanced cortical representation in primary auditory cortex (A1) (Bieszczad et al. 2015). We examined the role of HDAC3 on both the acquisition and consolidation of an auditory associative discrimination between sound frequencies. Adult male Sprague-Dawley rats (n=24) learning a two-tone frequency discrimination (2TD) task with systemic injections of HDAC3i (RGFP966; 10mg/kg s.c.) in the early days of 2TD training showed facilitated acquisition for both excitatory (for the rewarded CS+ sound) and inhibitory associative memories (for the unrewarded CS- sound). A stimulus generalization test (“SGTimm”) was conducted immediately after the 2TD task was well-learned in both groups. HDAC3i (n=9) and vehicle groups (n=9) differed in SGTimm, which indicated that HDAC3i-treated animals had formed a more frequency-specific memory for both the CS+ (r=0.99, p<0.001) and CS- (r=0.93, p=0.073) sounds. SGTs after a 2 or 4 week delay (“SGTdelay”; HDAC3i, n=5; Veh, n=5) indicated that limited HDAC3i had long-lasting effects on frequency-specific memory up to 4 weeks later. Furthermore, the HDAC3i-treated group behavior in SGTimm was similar to vehicle-treated at SGTdelay, which suggests that HDAC3i mimics naturally delayed time-dependent consolidation effects. Thus, HDAC3i may alter memory formation by accelerating the consolidation of highly-specific memory for sound, which would naturally occur over weeks. Supported by NIH/NIDCD R03 DC014753-01 and start-up funding from the School of Arts and Science, and Psychology Department at Rutgers University – New Brunswick (KMB). Aresty Research Funding Poster #28 Attenuating hippocampus serotonin or norepinephrine signaling on extinction day 1 prevents cocaine relapse in a sex-dependent manner.

Authors Amy Kohtz, Gary Aston-Jones

PI Name: Gary Aston-Jones

There is growing evidence for sex differences in cocaine abuse with clear treatment implications. Abundant reports indicate that women progress more quickly from casual drug use to dependence, have greater difficulty quitting, and have shorter periods of abstinence that are exacerbated by stress. Rodent models of addiction/relapse recapitulate these sex differences. Cravings during initial abstinence (e.g. extinction day 1, ED1) in humans and rodents can predict later relapse in both species, indicating that ED1 may be a critical time point for treatment that promotes long-term abstinence in addiction. We previously identified sex-specific recruitment of stress sensitive brain regions on ED1, including locus coeruleus norepinephrine (LC-NE) neurons, dorsal raphe serotonin (DR-5HT) neurons, and dorsal hippocampus pyramidal neurons (dHPC), and thus investigated the role of adrenergic and serotonergic signaling on ED1 in later cocaine-seeking persistence. We microinfused a cocktail of beta-adrenergic antagonists (betaxolol plus ICI-118,551), 5HT1 antagonists (WAY100365 plus GR127935) or saline into dHPC on ED1, and observed drug-seeking behavior on ED1 as well as following 2 weeks of home-cage abstinence. Compared to saline, 5HT antagonists administered to dHPC on ED1 persistently reduced cocaine-seeking behavior in both males and females. Interestingly, beta-adrenergic antagonists were only effective in females. We then recapitulated these results using chemogenetic techniques. Thus, we propose treatments that modulate noradrenergic or serotonergic signaling during initial abstinence may facilitate later maintenance of abstinence in a sex-dependent manner.

Supported by PHS DA016511 and DA006214 to GAJ and NIEHS 4T32ES007148 to ASK.

Poster #29 The effects of synaptic conductance regulation on conductance correlations in an activity based sensor model

Authors Omar Itani, Jorge Golowasch, Horacio G. Rotstein

PI Name: Horacio G. Rotstein

Circuit output of central pattern generators is stereotyped and consistent across individuals. The neurons that

constitute these networks can express conductances with widely varying magnitudes within the same cell

type. Experimental work of how networks can achieve similar activity patterns despite the variability of

conductances revealed correlations of different ion channel expressions within a population of the same cell

type. Theoretical work shows that this phenomenon can be captured by a model where conductances are

regulated in an activity-based fashion. In this work, we explore how the presence of synaptic currents

between neurons affects the conductance correlation properties and the maintenance of robust activity in

minimal network models and the extent to which correlations exists between synaptic and ionic

conductances. This additional layer of biological plausibility provides insight into how robust network activity

can be achieved despite cell-to-cell variability across individuals.

Supported by NSF-DMS 1715808 (HGR & JG)

Poster #30 The Metabotropic Glutamate Receptor Agonist 2-chloro-5-hydroxyphenylglycine (CHPG) Increases BDNF

and Myelin Proteins after Cuprizone-Induced Demyelination

Authors Kyle Saitta, Lauren Lercher, Yangyang Huang, and Cheryl F. Dreyfus

PI Name: Cheryl F. Dreyfus

Cuprizone causes decreases in brain-derived neurotrophic factor (BDNF) and myelin proteins in mice after 4

weeks. It also upregulates metabotropic glutamate receptors (mGluRs) within the lesion site. Therefore, we

aim to enhance myelin proteins by increasing endogenous levels of BDNF through the use of the selective

mGluR Group I agonist, 2-chloro-5-hydroxyphenylglycine (CHPG). Mice received cuprizone or identically

processed control feed for 4 or 6 weeks starting at 8 weeks of age prior to intraperitoneal injections of saline

or CHPG. CHPG increased levels of BDNF and myelin proteins 24 hours later. Myelin proteins increased

without increases in CC1+ mature oligodendrocytes, suggesting that CHPG increases myelin proteins per

cell. To determine if multiple injections of CHPG can elicit prolonged effects, CHPG was injected over a 2-

week period. Preliminary data suggests that BDNF and myelin proteins remain elevated over this time. This

same dosing regimen increases the number of myelinated fibers as analyzed by electron microscopy. To

begin to elucidate the receptor responsible for CHPG’s actions and the site of action, the selective mGluR-5

antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) was injected directly into the lesion site prior to

intraperitoneal injection of CHPG. In initial studies, CHPG’s effects were reduced when MPEP was

administered before CHPG, suggesting both a role of mGluR-5 in mediating the actions of CHPG and that

CHPG injected peripherally acts within the lesion site. Overall, these data suggest that selective mGluR

Group I agonists such as CHPG may be a therapeutic approach for treating demyelinating diseases.

Supported by NIH NS036647; T32ES007148; F31NS098642 and NMSS RG 4257B4/1

Poster #31 Chemogenetic activation of a retinal circuit that activates locus coeruleus neurons prevents the development of light-deprivation induced depression-like behavior

Authors H.E. Bowrey, M.H. James, A. Mohammadkhani, M. Omrani, G. Kane, Gary Aston-Jones

PI Name: Gary Aston-Jones

Chronic light-deprivation induces a depressive-like phenotype via a locus coeruleus norepinephrine (LC-NE)-dependent mechanism. Suprachiasmatic nucleus (SCN) provides indirect circadian input onto LC via dorsomedial hypothalamus (DMH). SCN is therefore in a key position to integrate light information with LC via the pathway: retina→SCN→DMH→LC. We refer to this pathway as the Photic Regulation of Arousal and Mood (PRAM) pathway. We tested the hypothesis that increasing PRAM pathway activity prevents darkness-induced depression-like behavior. Sprague Dawley rats received intraocular injections of excitatory hM3Dq DREADD, control virus, or no virus. Rats were placed in continuous darkness for 8 weeks, and those that received virus were concurrently subjected to daily intraperitoneal injections of clozapine-N-oxide (CNO; 2 mg/kg), the DREADD-activating ligand, before being subjected to assays of mood. LC tissue was stained for Poly ADP ribose polymerase (PARP, a marker of apoptosis) and tyrosine hydroxilase (TH). Expt 2. To determine the retinal cell-type responsible for depression-like behavior, intrinsically photosensitive retinal ganglion cells (ipRGCs) of animals raised in 12:12 light:dark conditions were ablated using a saporin (SAP) toxin that selectively eliminates melanopsin-expressing cells (Mel-SAP). Two control groups received intraocular injections of vehicle and were kept in either continuous darkness or in 12:12 light:dark conditions. Ten weeks later, rats were subjected mood assays. Daily activation of retinal DREADDs prevented depressive-like behavior. Mel-SAP induced a depression-like phenotype. This was also associated with increased apoptosis in LC-NE cells as seen with PARP staining. Dysregulation of the PRAM pathway may induce neural damage in LC-NE neurons that is associated with a depressive behavioral phenotype.

Poster #32 Role of Neuropilin 2 in the development and maintenance of functional neuronal connectivity in the mouse primary visual cortex

Authors Hussein Khdour, Tracy S. Tran, Pierre-Olivier Polack

PI Name: Pierre-Olivier Polack

The function of cortical neurons is determined by their connectivity. In sensory cortices, the neuronal tuning properties and receptive fields result from the convergence of complementary or redundant inputs from the thalamus and/or from other cortical regions. The mechanisms responsible for establishing this connectivity during development and for maintaining it during adulthood remain poorly understood. The Class 3 Semaphorin Sema3F, which binds to its obligate receptor Neuropilin-2 (Nrp2), was found to guide thalamocortical axons to their targets during embryonic development, and is necessary for restraining excess number of dendritic spines in layer 5 cortical neurons in postnatal ages. Here, we show that mice deficient for Nrp2 exhibit supernumerary excitatory synapses in the infragranular layers of the primary visual cortex (V1). The number of responsive neurons as well as the magnitude of the evoked response in responsive neurons was smaller in the V1 of Nrp2-/- mice compared to WT. The absence of Nrp2 was also associated with a degradation of the receptive field structure but had little impact on the orientation and direction selectivity of responsive V1 neurons. We also demonstrated that Nrp2 is still expressed in adult cortical neurons, suggesting a role of Sema3F during adulthood. Acute deletion of Nrp2 in the V1 of adult mice leads to decrease in the number and the amplitude of the response of V1 L5 neurons to visual stimuli. However, the orientation and direction selectivity of responsive V1 neurons was only slightly degraded. Altogether our results showed that Np2 plays an important role for the establishment and the maintenance of the functional connectivity in the cerebral cortex that is important for the computing properties and the function of the neocortex.

Supported by Rutgers University–Newark Chancellor’s Seed Grant Initiative to TST and POP.

Poster #33 Evidence for presynaptic protein synthesis and its effects on neurotransmitter release at a CNS synapse

Authors Matthew S. Scarnati and Ken Paradiso

PI Name: Ken Paradiso

Presynaptic activity requires the localization and maintenance of thousands of proteins that are typically thought to be synthesized in the soma and transported to nerve terminals. However, local protein synthesis occurs at dendritic locations and local presynaptic protein synthesis has recently been shown to occur in an inhibitory neuron in the brain, but the small size of most nerve terminals complicates further studies. Here, we study presynaptic protein synthesis at the calyx of Held nerve terminal, located in the auditory brainstem. The size of this terminal, its long axon, and high firing frequency make it an ideal choice to study presynaptic protein synthesis. We show two major ribosomal components, 5.8s and s6 rRNA, are present in presynaptic nerve terminals. To verify the presence of functional presynaptic ribosomes, we used the surface sensing of translation (SUnSET) technique. This produced well defined fluorescent signals in presynaptic terminals and postsynaptic cell bodies, and the fluorescent signal was eliminated by inhibiting protein synthesis. To determine effects on synaptic transmission, we measured electrical activity. After inhibiting translation, the initial frequency of spontaneous events increased by ~2-fold but the amplitude was unaffected, indicating a presynaptic mechanism. In addition, we find that evoked responses show less depression during high frequency firing (≥ 100 Hz), which is not consistent with effects on desensitization and indicates an additional presynaptic effect. These findings further indicate that presynaptic protein synthesis occurs, that it can affect spontaneous and evoked release of neurotransmitter, and it affects neurotransmitter release at high firing frequencies.

Poster #34 Brain Mapping with qEEG and fMRI for Motor Rehabilitation

Authors Rob Beetel, Michael Wininger and William Craelius

PI Name: William Craelius

Introduction: The potential value of quantitative EEG and fMRI as rehabilitation tools for both stroke and loss of limb is demonstrated. Methods for Protocol 1: fMRI responses of 4 persons with right upper-limb amputation, were compared with those of 11 controls during arm movements. Trials with amputees involved moving their sound (left) hand, while watching a mirrored image of it superimposed on their residuum; control subjects experienced analogous illusions by observing their hand and its mirror image simultaneously moving, while keeping their right hand stationary. Control subjects experienced analogous illusions by observing their left hand and its mirror image simultaneously moving, while keeping their right hand stationary. Both amputee and control subjects thereby visualized an illusory hand opposing their left hand during hand motions. Results for Protocol 1: BOLD (Blood Oxygen Level Dependency) signals revealed: (1) during natural motions of their real hands, controls and amputees exhibited similar brain activities primarily within the primary motor cortices, (2) during volitions for moving their missing right hand, amputee subjects exhibited prominent activity bilaterally in the insula regions of the brain , (3) insula activity was not present when the amputee subjects perceived a restored hand moving from their right limb, as represented by their own reflected left hand. Methods for Protocol 2: QEEG signals from a subject with left-side stroke were analyzed at rest and during arm motions. Results for Protocol 2: Beta 2 waves were abnormally high at rest, and large ipsilateral activity was noted during movement of the affected limb.

Supported by the National Institute of Disability Rehabilitation Research

Poster #35 The Orexin/Hypocretin system as a novel target for binge-like eating in female rats

Authors Samuel Liu, Sarah Walsh, Morgan James, Gary Aston-Jones, Nicholas Bello

PI Name: Nicholas Bello

Binge eating disorder (BED) is characterized by uncontrollable food consumption. It is unknown whether this phenomenon reflects pathological motivation for food or a change in the reinforcing (hedonic) properties of food. Behavioral-economic (BE) demand curve analysis allows the motivational vs hedonic properties of food to be measured independently. Here, we used a binge eating rat model to determine the effects of binge-like eating on demand for palatable food (sucrose). Since BED is seen disproportionately in obese individuals, we assessed the effects of bingeing in both normal weight and obese rats. Sixteen female Long-Evans rats were trained to lever press for sucrose pellets at increasing prices. Rats were then given access to sweetened fat (vegetable shortening + 10% sucrose) for 30 min, twice a week for 4 weeks. Because the hypothalamic orexin/hypocretin system is a known modulator of motivation for reinforcing stimuli, we also examined the effects of the orexin-1 receptor antagonist SB-334867 (SB) on demand for sucrose. Animals were then given ad libitum access to a high fat diet (HFD; 45% fat) for a period of 8 weeks, and the experiment was repeated. Binge eating increased animals’ motivation for sucrose only after diet-induced obesity, while SB dose-dependently reduced motivation for sucrose only in obese animals. Our findings indicate an interaction between binge eating and obesity with respect to motivation for food. Our data also suggests that the orexin system may be a novel target for pharmacotherapies designed to reduce food seeking in individuals with a history of BED.

Supported by One Nutrition Initiative and the Rutgers Nutrition, Food, and Dietetics Intramural Grant Program.

Poster #36 Emotional regulation in children with ASD with and without concurrent language impairment.

Authors Yuli Fradkin, Judy Flax, Christine Gwin, Sherri Wilson, Karen Law, Linda Brzustowicz

PI Name: Linda Brzustowicz

A family genetics study of ASD identified 134 children and adolescents ascertained for ASD and determined their language ability based on standardized language assessments of structural and higher order language and on research reliable autism diagnostic tools. From the identified children, 59 subjects had known language status. Included were 21 children with at least average structural language ability (syntax, grammar, phonology, vocabulary) as determined by scoring within one standard deviation of the mean (mean=100, s.d. =15) on the Clinical Evaluation of Language Fundamentals (CELF-4). There were 38 children with impairment in structural language determined by scoring below one standard deviation on the CELF (N=45_) For those children who had enough language to take the structural language measures (N=59), higher order language abilities (sometimes referred to as metalinguistic language) were assessed. All children were assessed with presence of aggressive and self-aggressive tendencies.

This study indicates that greater deficits in social communication/pragmatics but not structural language predict greater associated aggression in ASD. It is the first study which distinguished importance of separation structural and in relationship with aggressive behavior

Poster #37

The small GTPase Rab11 is required for spinal cord afferent projections and cerebellum development.

Authors Edward Martinez, Victor Danelon, Carol Eisenberg, Oday Abushalbaq, Maria B. Harreguy, Kimberly Wang,

Guersom Ralda, Nan Gao, Tracy S. Tran

PI Name: Tracy S. Tran

The development of the nervous system is a complex process that requires the coordinated interpretation of

temporal and spatial cues. Proper protein trafficking to distinct sub-compartments of the developing neuron

is essential for this process. The recycling endosome is responsible for maintaining the abundance of key

proteins, such as cell signaling receptors, to the plasma membrane surface. Members of the small GTPase

family of Rabs, Rab11a and Rab11b that reside within the recycling endosome, are required for this function.

Previous studies have shown that disruption of Rab11 function in vitro has led to defects in developmental

events, such as axon outgrowth and dendritic branching, however, little is known about its role in vivo. To

address this, we use a mouse genetic approach to specifically delete Rab11a, Rab11b, or both isoforms to

investigate the in vivo function for Rab11. Loss of the Rab11b isoform results in a misguidance of central

projections of sensory axons to the dorsal root entry zone during early development, leading to a change in

final target pattern found in early postnatal stages. Also, the analysis of the adult brain has revealed a

striking size decrease and disorganization of the cerebellum in the Rab11a and Rab11b double mutants.

Currently, we are analyzing the cellular and molecular mechanisms underlying the role of Rab11 in

controlling the central projections of sensory axons into the CNS and cerebellar development. Taken

together, our findings suggest key in vivo roles for Rab11 in the proper formation of connections and overall

organization of the central nervous system.

This study is supported by the NJ Commission on Spinal Cord Research to TST.

Poster #38 The role of p75NTR in inducing neuronal death and axonal degeneration after injury

Authors Laura E. Montroull, Deborah Rothbard, Juan P. Zanin, Steven W. Levison, and Wilma J. Friedman.

PI Name: Wilma J. Friedman

Factors that regulate neuronal survival or death, especially after injury, have a critical impact on neural

function. Proneurotrophins are selective, high-affinity ligands for p75NTR with its co-receptor sortilin, and can

activate p75NTR-mediated apoptosis. After damage in the adult brain, expression of p75NTR is induced in

numerous CNS neurons and has been shown to regulate neuronal cell death in several injury models. We

have previously demonstrated that p75NTR is induced after injury induced either by seizures or by contusion

in a model of traumatic brain injury (TBI). Moreover, blocking either p75NTR or the proNGF ligand, can

attenuate neuronal death. To test the hypothesis that p75NTR promotes secondary cell death, we provided a

p75NTR siRNA intranasally immediately following a controlled cortical injury administered to adult C57/Bl6

mice. Data obtained are in agreement with previous findings that p75NTR KO mice demonstrated 2fold fewer

apoptotic neurons 3 DPI. Furthermore, knockdown of p75NTR improved overall neurological function and in

particular, improved sensorimotor performance on beam walking tests. Similar results were obtained when

p75NTR ligands (proNGF and proBDNF) were blocked, suggesting an active role of this receptor and its

ligands in inducing neuronal death after TBI. In addition to promoting neuronal apoptosis, we are also

investigating a role for p75NTR in regulating axonal degeneration in a model of concussive brain injury and

determining whether this is independent of neuronal death, or part of a continuum leading to neuronal death.

Supported by New Jersey Commission for Brain Injury Research.

Poster #39

Alterations in Oligodendrocyte Progenitor Cells with Loss of mTOR

Authors Luipa Khandker, Isis Ornelas, Nathanael Joseph, Alex Lemenze, Robert Donnelly and Teresa L. Wood

Oligodendrocyte progenitor cells (OPCs) undergo distinct stages of differentiation to form mature myelinating oligodendrocytes. One major pathway that regulates oligodendrocyte differentiation and myelination is PI3K/Akt/mTOR. Deletion of mTOR in OPCs results in a delay in oligodendrocyte differentiation and initiation of myelination as well as long-term hypomyelination of the spinal cord. In contrast, these mice have normal myelination of the developing brain, implying variations in cellular response to loss of mTOR. We have identified the stage of differentiation where spinal cord OPCs are delayed and accumulating in the absence of mTOR. By flow cytometry, we detect decreased numbers of O4+ late-stage progenitors in the developing mTOR knockout spinal cord, with a corresponding increase in early-stage progenitors, suggesting an accumulation of many early progenitors that are unable to progress to the O4+ stage when mTOR is deleted. To further define alterations in OPCs and differentiating oligodendrocytes with loss of mTOR, we are employing Drop-seq, an innovative technology for single-cell RNA sequencing. In initial studies, we isolated O4+ OPCs from mTOR knockout and control animals and simultaneously analyzed the mRNA transcripts of thousands of individually identifiable cells. Transcriptional variation across the single cells can be used to define distinct populations. Sequence data from our Drop-seq experiment is currently under analysis. Our long-term goal is to further understanding of heterogeneity of OPCs and how it contributes to differences in oligodendrocyte function. Future directions will include studying changes in specific cellular functions and pathways with loss of mTOR.

Supported by NINDS R01 NS082203 and National Multiple Sclerosis Society RG5371-A-4 to TLW

Poster #40 Dietary hyperhomocysteinemia accelerates neurodegeneration by upregulating mTOR signaling and impairing autophagy in the mouse brain

Authors Joanna Suszyńska-Zajczyk, Hieronim Jakubowski

PI Name: Hieronim Jakubowski

Elevated plasma homocysteine (Hcy) - hyperhomocysteinemia (HHcy) - is associated with neuropathies, including Alzheimer’s disease. However, molecular bases of HHcy-related brain disease are not fully understood. Previous work has shown that HHcy activates mechanistic target of rapamycine complex 1 (mTORC1) signaling and inhibits autophagy, which leads to the accumulation of abnormal protein aggregates in cultured human neurons and in a mouse model of genetic HHcy (Khayati K et al., FASEB J 2017; 31:598-609). However, whether dietary HHcy affects the mTOR signaling and/or autophagy was not known. We induced HHcy in 6-week-old C57BL/6J mice by providing 1% methionine in drinking water for 14 weeks, which increased Hcy levels 12- and 32-fold in females and males, respectively, relative to control mice. Starting by week 6 of the HHcy diet, the HHcy mice developed a neurodegeneration phenotype, revealed by the hind limb clasping and the ledge tests. We found that levels of mTOR mRNA and protein, as well as PRAS 40 protein were significantly increased in HHcy brains, relative to controls. In contrast, AMPK protein and its phosphorylated form pAMPK, which directly inhibits mTOR and promotes autophagy, were significantly decreased. Other autophagy markers, Beclin1, LC3A/B, Atg5, and Atg7 were also significantly decreased in HHcy brains. Treatment of HHcy mice with the mTOR inhibitor Torin 2 normalized pmTOR and pRAPTOR, but not Atg7 and Beclin1 levels. Taken together, these findings suggest that up-regulation of mTOR signaling and down-regulation of autophagy contributes to the impairment of brain function induced by dietary HHcy.

Supported by NCN grants 2016/21/D/NZ4/00478, 2013/09/B/NZ5/02794 and the Rutgers BHI-RUN-NJIT Pilot Grants in Neuroscience 2016

Poster #41 Capturing the glial cell interactions with artificial axons at high definition

Authors

Stephanie Fung, Viaceslav Manichev, Yong Mao, Daniel Martin, Prahabas Moghe, Leonard Feldman, Torgny Gustaffson, Joachim Kohn, Cheryl Dreyfus, Antonio Merolli

PI Name: Antonio Merolli

Understanding the process of myelination/remyelination is essential for the development of strategies for

nerve repair in the CNS and PNS. Yet, this process has been difficult to approach because of the complexity

of the models available. Co-existence of neuronal cells in most of the models makes the selective response

from glial cells difficult to isolate. Observations are made on a large number of cells (millions) seeded on a

large number of fibers (thousands) so the behavior of single cells is difficult to monitor. We developed a

novel in-vitro model where a limited number of cells (in the range of 50) interact with artificial fibers, acting as

surrogate axons, far from the floor of the well (Merolli A, et Al. J Mater Sci Mater Med 2017 28(4):57).

Oligodendrocytes and Schwann cells are seeded on Carbon and PCL fibers respectively and this

“suspended-wire model” enables them to wrap around the “artificial axons” without interference from the well

floor. We captured the interaction of glial cells with the fibers at single-cell level, at high spatial and temporal

definition, applying comparative multimodal imaging (live fluorescent tracking, immunostaining, Helium-Ion

Microscopy). The use of HIM is unique in allowing un-coated samples to be imaged at nanometer scale but

without the artifacts of SEM coating. Our reductionist approach will enable us to identify the roles played by

different factors: BDNF and patterned electrical impulses are our present topics of interest. This novel

approach may lead to the identification of molecules and processes that may be therapeutically useful.

This research has been funded in part by a grant from New Jersey Health Foundation

Poster #42 Autophagy induction drives neuroprotection by inhibiting the TFEB/ATF4-mediated integrated stress

response after traumatic brain injury

Authors Chaitali Saqcena, Israel Nnah, Biao Wang, Henri Antikainen, Pelin Avcu, Ashley M. Fortress, Alexandra Adams, Haesun Kim, Edward M. Bonder, Thomas Biederer, Kevin C.H. Pang, and Radek Dobrowolski

PI Name: Radek Dobrowolski

Traumatic brain injury (TBI) is associated with accumulation of aggregated proteins and neuronal cell death,

underscoring the importance of degradation pathways such as autophagy. In this study, the role of

autophagy in TBI-related neuronal cell death was investigated. We find that Beclin1-mediated autophagy

counteracts lysosomal inhibition and increases autophagic flux by temporarily sequestering lysosomal

substrates and reducing lysosomal load after TBI. Restoration of autophagic function following TBI prevents

neuronal death driven by the integrated stress response. That pathway includes the transcription factor EB

(TFEB) which potentiates expression of the activating transcription factor (ATF4) and the pro-apoptotic

C/EBP homologous protein (CHOP). These findings present a novel way to restore lysosomal function and

show that restoration of autophagic function is neuroprotective by inhibiting pro-apoptotic stress pathways

after TBI.

The work was supported by grants from the Rutgers University-Newark Research Office through the initiative for multidisciplinary research teams (IMRT) and the NJ state commission for traumatic brain injury CBIR14PIL001 (to RD).

Poster #43 Identifying inter-relations between genetic polymorphisms and reinforcement learning: multivariate insights

from behavior and computational modeling

Authors Carrisa Cocuzza, Jim Cavanagh, Michael Cole, Travis Baker

PI Name: Travis Baker

Background: Successful application of reinforcement learning (RL) is critical for daily decision-making. A neurocomputational theory posits that an individual’s ability to learn from positive and negative reinforcement can be predicted by genetic factors related to the midbrain dopamine system. However, support for this claim remains highly controversial. The purpose of this study is to expand upon those findings and apply structural equational modeling to identify the inter-relationships between genetic factors related to striatal and prefrontal dopaminergic functioning and optimal RL in humans. Methods: Data were collected from undergraduate students in two studies and concatenated here to yield a total sample size of N=280, dramatically increasing statistical power. Single-nucleotide polymorphisms (SNPs) of interest include DRD2-957, DRD4-521, DARPP-32-rs907, and COMT, and participants’ trial-to-trial training choices during a probabilistic reinforcement learning task were modeled using an algorithm (Q-learning) adapted from machine learning, which calculates separate learning rates associated with positive and negative prediction errors. Results: We identified significant bivariate differences between DRD4-allele groups on positive learning rate, and the interaction between COMT and DRD4 allele pairs significantly discriminated between positive and negative learning-rate parameters. No differences were observed for striatal dopamine SNPs. Conclusion: These findings point to a critical role for prefrontal dopamine expression in RL, which has been typically described in terms of subcortical mechanisms. Moreover, our structural equation model provided a theoretical framework for bridging the gap between genes, reinforcement learning, and psychiatric conditions, highlighting new directions into individuated and nuanced clinical assessment.

This work was supported by Rutgers University Behavioral Neuroscience Graduate Assistantship

Poster #44 Brain-region specificity of microtubule destabilizer stathmin in postpartum depression

Authors Jan Tuma, Shusaku Uchida, Itzamarie Chevere-Torres, Ileana Fuentes, Yoshikazu Morishita, Dominick Dolorenzo and Gleb Shumyatsky

PI Name: Gleb Shumyatsky

Stathmin—a protein that blocks microtubule (MT) formation by binding to tubulin while in its un-phosphorylated form—has a role in fear, post-traumatic stress disorder (PTSD), and maternal and social behaviors. We have found that stathmin phosphorylation is increased in the dentate gyrus (DG) of wild type mice during pregnancy and postpartum, suggesting increased MT stability. We use mice expressing a mutated form of stathmin (Stat4A) that binds irreversibly to tubulin, causing MTs to be unstable. Stat4A is predominantly expressed in DG, basolateral amygdala (BLA), medial prefrontal cortex (mPFC) and hypothalamic paraventricular nuclei (PVN). Ongoing work in our lab suggests that eliminating Stat4A mice may have depressive-like symptoms in the postpartum state—such as deficiency in forced swim test, sucrose preference test, increased anxiety and decreased pup retrieval. Stat4A females showed changes in spine density compared to wild type females in DG, BLA, central amygdala as well as mPFC in postpartum and virgin condition. Stat4A females also did not show significant reduction of hippocampal neurogenesis during gestation, which was observed in their wild type littermates. The results show a link between stathmin-dependent microtubules, and depressive-like behaviors after delivery. Therefore these mice might be considered an animal model of postpartum depression. Future studies to identify brain structures responsible for PPD will use viral vectors to induce Stat4A expression in selected brain regions, e.g. DG, BLA, mPFC, and PVN.

This work was supported by NIH R01MH107555

Poster #45 Absence of p75NTR in granule cell precursors of the cerebellum increase cell proliferation and anxiety levels

Authors J.P. Zanin, M. Shiflett, Y. Li, V. Santhakumar and W.J. Friedman

PI Name: Wilma J. Friedman

The cerebellum is involved in motor coordination, balance and posture. However, recent functional and anatomical evidence has demonstrated that the cerebellum is also required for cognitive non-motor tasks such as reward anticipation, anxiety and social interaction, among other functions. The p75 neurotrophin receptor (p75NTR) is highly expressed in the External Granule Layer (EGL). In previous work, we observed a delay in cell cycle exit in p75NTR full KO mice, as well as in EGL-specific KO mice (p75fl/fl; Atoh1Cre) compared with WT animals. This delay was sufficient to produce an abnormally large cerebellum that persisted into adulthood, with behavioral consequences. In the present work, we have observed increased anxiety levels demonstrated in paradigms such as open field and elevated zero maze. The basic motor parameters such as speed and total distance travelled showed no difference among any of the three genotypes. However, both global and EGL-specific KO mice showed an increased anxiety level compared with the WT mice, suggesting that the absence of p75NTR during cerebellar development might also affect non-motor behavior. We have determined that signals that promote cell cycle exit lead to downregulated levels of p75NTR indicating a strong connection between p75NTR expression and cell cycle regulation. Our results suggest that p75NTR must be spatio-temporally regulated during cerebellar development. The absence of p75NTR promotes a deregulation in cell cycle, with motor and non-motor consequences that persist through the adulthood.

Poster #46 The effect of social stimulation in alcohol drinking in mice

Authors Shivani Mehra and Shruti Nair

PI Name: Arthur Tomie

Alcohol drinking is multi-determined and clearly influenced by environmental factors and genetic factors. An important environmental factor is social interaction which reliably stimulates alcohol drinking. However, the gene expression profile of socially stimulated alcohol drinking is unclear. Statistical analysis which includes ANOVA and regression are being used to determine how gene expression and different gender pairings can affect the amount of ethanol consumption. The gene expression of ten genes are being assessed by RT-PCR. Previous semesters, male drinkers along with different gender pairings were analyzed to determine if any genes in the nucleus accumbens were significant and if there was a higher consumption of alcohol as a result of the genes well as the gender difference. This semester the analysis of the genes are continued to be analyzed in the nucleus accumbens by comparing the results from the ANOVA of female drinkers paired with female cage mate, female drinker paired with male cage mate, and same gender pairings. The significance of the gene expression are being assessed by p values that are below .05. ANOVAS revealed that DRD4, DRD3, and GABA2 were significantly elevated within female drinkers paired with male cage mates compared to female drinkers paired with female cage mates among high drinkers versus low drinkers. However, the ANOVAS revealed that CLIC4, PAX6, PTEN, SCL6A1, NR4, and SL35 were insignificant for both female drinkers paired with female cage mates and female drinker paired with male cage mate. Further analysis which includes regression analysis is needed to determine the relationship between gene expression and ethanol intake in both gender pairing.

Supported by Rutgers-Department of Psychology

Poster #47 Circadian rhythm and exercise control inflammation

Authors R. Shah, B. Joseph, G. Shimojo, T. Ganapolsky, Luis Ulloa

PI Name: Luis Ulloa

Sepsis is a systemic inflammatory response to infection, with no preventative strategies. The beneficial effects of exercise on brain function were demonstrated in animal models and in a growing number of clinical studies on humans. Dopamine (DA), noradrenaline (NE), and adrenaline (E) are the three major catecholamine neurotransmitters that are known to be modulated by exercise. This study focuses on how exercise affecting these three neurotransmitters and how it can work against sepsis. The suprachiasmatic nucleus of the brain regulates the circadian through several mechanisms including autonomic innervations. As sympathetic and parasympathetic activity fluctuates throughout the day, we hypothesized that the inflammatory reflex arc may behave differently at different times. In this in vitro study blood is collected by cardiac puncture from control and experimental mice. We use an LPS (endotoxin) as a sepsis model. TNF and catecholamine are measured by ELISA. Blood TNF in morning is higher than evening (AM: 0.865 vs. PM: 0.667 ng/ml). Blood TNF in exercised mice is lower than control (Ex: 0.646 vs. C: 0.940 ng/ml). We conclude that inflammatory responses in sepsis are more severe in the morning as compared to evening and exercise decrease inflammation.

Supported by NIH R01RGM114180 and NJ Health Foundation.

Poster #48 Pannexin channel blockers attenuate neuroinflammation and improve outcome after traumatic brain injury (TBI)

Authors Joon Ho Seo, Charu Garg, Kelsey Miller, Jayalakshmi Ramachandran, Miloni Dalal, Frances Calderon, Jorge Contreras

PI Name: Jorge Contreras

Neuroinflammation is a major component of secondary damage after brain injury, and if uncontrolled, it prevents the resolution of the inflammation and enhances secondary injury damage. Elevated extracellular levels of ATP released upon injury has been shown to be pro-inflammatory. Recently, pannexin channel proteins have been identified as an important conduit for ATP release from dying cells enhancing the inflammatory response in peripheral immune cells. Here, we examined the potential beneficial actions of pannexin blockers, trovafloxacin (TVX) and brilliant blue FCF (BBFCF), after TBI using the Controlled Cortical Impact (CCI) model in rodents. We first found that pannexin blockers reduced tissue damage and blood brain barrier leakage at the injury site in CCI-injured animals. Both TVX and BBFCF significantly improved locomotor behavioral outcomes after CCI. In addition, we found that TVX and BBFCF reduced the expression of pro-inflammatory cytokines in CCI-injured animals. An overall reduction in the accumulation of inflammatory cells at the injury site was also observed in TVX-treated mice. Because ATP release and cell migration are critical for the accumulation of inflammatory cells at sites of injury, we evaluated whether these features were affected by TVX and BBFCF in vitro. Both blockers significantly reduced acute ATP release and migration in stimulated microglial cell lines. Moreover, a macrophage/microglia specific pannexin-1 knockout mice displays improved behavioral outcome after TBI when compare to wild type mice. Thus, we propose that blockade of pannexin-1 channels might serve as an effective therapeutic approach to reduce brain damage and improve outcome after TBI

Supported by the NJCBIR (Pre-doctoral CBIR14FEL006 to C. Garg, CBIR13IRG015 to F. Calderon, CBIR15IRG018 to J.E. Contreras)

Alphabetical List of Symposium Attendees

Name Affiliation E- mail Poster #

Aida Mohammadkhani Brain Health Institute aida366@gmail.com 6

Alejandra Laureano RU-SAS-Cell Biology and Neuroscience

laureano@dls.rutgers.edu

Ali Haddad RU-SOE-Electrical and Computer Engineering

ali.haddad@rutgers.edu 16

Allan Knox RBHS-NJMS-Pharmacology, Physiology & Neuroscience

ak1451@njms.rutgers.edu 25

Amy Kohtz Brain Health Institute ask169@ca.rutgers.edu 28

Andrea Shang RU-NB-SAS-Psychology andrea.shang@rutgers.edu 27

Antonio Merolli New Jersey Center for Biomaterials

antonio.merolli@rutgers.edu

Apoorva Halikere RBHS-RWJMS-Neuroscience and Cell Biology

apoorva4@scarletmail.rutgers.edu

Azadeh Kamali Tafreshi RBHS-NJMS-Psychiatry ak1541@njms.rutgers.edu 15

Bogumila Swietek RBHS-NJMS-Pharmacology, Physiology & Neuroscience

swietebo@rutgers.edu 5

Bruce Citron VA - NJHCS, East Orange bcitron@health.usf.edu

Carrisa Cocuzza RU-Newark-CMBN cvc41@scarletmail.rutgers.edu 43

Chaitali Saqcena RU-Newark-Biology cmsaqcena@gmail.com 42

Cheryl Dreyfus RBHS-RWJMS-Neuroscience and Cell Biology

dreyfus@rwjms.rutgers.edu

Courtney Cameron Princeton Neuroscience Institute, Princeton

cmc10@princeton.edu 10

David Briley RBHS-NJMS-Pharmacology, Physiology & Neuroscience

david.briley@rutgers.edu

David Sosidko Brain Health Institute david.sosidko@rutgers.edu

Davide Comoletti RBHS-RWJMS-Neuroscience and Cell Biology

comoleda@rwjms.rutgers.edu

Dina Popova RBHS-RWJMS-Neuroscience and Cell Biology

dina.popova@rutgers.edu 9

Edward Martinez RU-Newark-Biology emart@scarletmail.rutgers.edu 37

Emily C. Kelly-Castro RBHS-RWJMS-Neuroscience and Cell Biology

eck70@gsbs.rutgers.edu

Gerard G Fluet RBHS-SHP-Rehabilitation & Movement Sciences

fluetge@shp.rutgers.edu

Gwyndolin Vail RU-SEBS-Animal Science gwyndolinvail@gmail.com 20

Hannah Bowery Brain Health Institute hannah.bowrey@gmail.com 31

Henri Antikainen RU-Newark-Biology hpa8@scarletmail.rutgers.edu

Hieronim Jakubowski RBHS-NJMS-Microbiology, Biochemistry and Molecular Genetics

jakubows@rutgers.edu 40

Hillary Levinson RU-Newark-Psychology hillarylevinson@gmail.com 18

Huaye Zhang RBHS-RWJMS-Neuroscience and Cell Biology

huaye.zhang@rutgers.edu

Name Affiliation E- mail Poster #

Hussein Y. Khdour RU-Newark-Biolog-CMBN hussain.yk@gmail.com 32

Hye-Jin Park RBHS-RWJMS-Neurology hp331@rwjms.rutgers.edu 7

Ikrak Jung RBHS-RWJMS-Neurology ij68@ewjms.rutgers.edu

Isabella Maita RU-NB-SAS-Psychology im214@rutgers.edu

Israel C. Nnah RU-Newark-Biology israel3748@gmail.com

Jan Tuma RU-NB-SAS-Genetics jt819@dls.rutgers.edu 44

Janet Alder RBHS-RWJMS-Neuroscience and Cell Biology

janet.alder@rutgers.edu

Jay A. Tischfield RU-SAS-Genetics jay.tischfield@rutgers.edu

Ji Liu RBHS-RWJMS-Neuroscience and Cell Biology

jl1852@rwjms.rutgers.edu

Jiang-Hong Ye RBHS-NJMS-Anesthesia and Perioperative Care

ye@njms.rutgers.edu

Jigna Patel RBHS-SHP-Rehabilitation & Movement Sciences

patel421@shp.rutgers.edu

Jihyun Kim RU-Newark-Biology jbmfeel@gmail.com 4

Jing Li RBHS-NJMS-Anesthesia and Perioperative Care

jl1526@njms.rutgers.edu 1

Jiyeon Baek RU-Newark-Biology jb1471@scarletmail.rutgers.edu

Joon Ho Seo RBHS-NJMS-Pharmacology, Physiology & Neuroscience

seojoonho001@gmail.com 48

Jorge Serrador RBHS-NJMS-Pharmacology, Physiology & Neuroscience

serradjo@njms.rutgers.edu

Juan Pablo Zanin RU-Newark-Biolog jz332@newark.rutgers.edu 45

Kasia Bieszczad RU-NB-SAS-Psychology kasia.bie@rutgers.edu

Kelvin Kwan RU-SAS-Cell Biology and Neuroscience

Kwan@dls.rutgers.edu

Kenneth Paradiso RU-SAS-Cell Biology and Neuroscience

paradiso@dls.rutgers.edu

Kevin D. Beck RBHS-NJMS-Pharmacology, Physiology & Neuroscience and VA-East Orange

kevin.d.beck@njms.rutgers.edu

Kevin Pang RBHS-NJMS-Pharmacology, Physiology & Neuroscience and VA-East Orange

kevin.pang@va.gov

Kevin Spiegler RBHS-NJMS-Pharmacology, Physiology & Neuroscience and VA-East Orange

spiegler@njms.rutgers.edu 19

Kristine Conde RU-SEBS-Animal Science Kmc450@gsbs.rutgers.edu

Kyle Saitta RBHS-RWJMS-Neuroscience and Cell Biology

kyle.saitta@rutgers.edu 30

Laura Montroull RU-Newark-Biology lem157@newark.rutgers.edu 38

Liam Turk RBHS-RWJMS-Neuroscience and Cell Biology

lst51@gsbs.rutgers.edu 21

Luciano D'Adamio RBHS-NJMS-Pharmacology, Physiology & Neuroscience

luciano.dadamio@rutgers.edu

Name Affiliation E- mail Poster #

Luipa Khandker RBHS-NJMS-Pharmacology, Physiology & Neuroscience

luipa.khandker@gmail.com 39

Luka Turkalj RBHS-RWJMS-CABM lukaturkalj2@gmail.com

Madhuvika Murugan NJIT-BME madhuvika.murugan@gmail.com 22

Magda Grudniewska RBHS-RWJMS-Neurology mkg97@rwjms.rutgers.edu

Marc Tambini RBHS-NJMS-Pharmacology, Physiology & Neuroscience

marc.tambini@rutgers.edu 13

Marisa Jeffries RBHS-NJMS-Pharmacology, Physiology & Neuroscience

mfa61@gsbs.rutgers.edu

Mark Gergues RU-NB-SAS-Psychology mmg197@psych.rutgers.edu 14

Mark Plummer RU-SAS-Cell Biology and Neuroscience

mplummer@dls.rutgers.edu

Mark West RU-NB-SAS-Psychology markwest@psych.rutgers.edu

Matthew S. Scarnati RU-SAS-Cell Biology and Neuroscience

mss344@rutgers.edu 33

Michael Sheldon RUCDR and HGINJ sheldon@dls.rutgers.edu

Michelle Favre RBHS-NJMS-Pharmacology, Physiology & Neuroscience

mef160@gsbs.rutgers.edu

Mike Kiledjian RU-SAS-Cell Biology and Neuroscience

kiledjian@biology.rutgers.edu

Mimi Phan RU-NB-SAS-Psychology mimi.phan@rutgers.edu

Miriam Rosenberg-Lee RU-Newark-Psychology miriam.rosenberglee@rutgers.edu

Morgan James Brain Health Institute mhj32@rutgers.edu

Nicholas Minar RBHS-RWJMS-Pediatrics nm745@rwjms.rutgers.edu

Nidhi Desai RBHS-RWJMS-Neuroscience and Cell Biology

nd405@scarletmail.rutgers.edu

Nuri Erkut Kucukboyaci Kessler Foundation ekucukboyaci@kesslerfoundation.org

Omar Itani NJIT-Biological Sciences oi7@njit.edu 29

Ozlem Gunal RBHS-NJMS-Psychiatry ozlem.gunal@rutgers.edu

Priscilla White RBHS-NJMS whitep4@njms.rutgers.edu

Pu Hu RU-NB-SAS-Psychology phulj8@gmail.com

Radek Dobrowolski RU-Newark-Biology r.dobrowolski@rutgers.edu

Rao Fu RBHS-NJMS-Anesthesia and Perioperative Care

rf386@njms.rutgers.edu

Robert Connacher RBHS-RWJMS-Neuroscience and Cell Biology

connro01@gmail.com 23

Robin L. Davis RU-SAS-Cell Biology and Neuroscience

rldavis@dls.rutgers.edu

Ron Hart RU-SAS-Cell Biology and Neuroscience

rhart@rutgers.edu

Roshan Shah RBHS-NJMS-Surgery roshu.doc@gmail.com 47

Run Yan RBHS-RWJMS-Neurology ry120@rwjms.rutgers.edu 8

Name Affiliation E- mail Poster #

Samantha Mattheiss RU-Newark-Psychology samantha.smolin@rutgers.edu 17

Samuel Liu Brain Health Institute snl46@scarletmail.rutgers.edu 35

Sara McEwan RU-SAS-Cell Biology and Neuroscience

sm1818@gsbs.rutgers.edu 2

Sean Tsaur RU-NB-SAS-Psychology sean.tsaur@gmail.com

Shavonen Teng RBHS-RWJMS-Neuroscience and Cell Biology

slt119@rwjms.rutgers.edu 12

Shayna O'Connor Brain Health Institute slo50@rutgers.edu

Shivani Mehra RU-NB-SAS-Psychology sm1599@scarletmail.rutgers.edu 46

Smita Thakker-Varia RBHS-RWJMS-Neuroscience and Cell Biology

varia@rwjms.rutgers.edu

Srestha Dasgupta RU-Newark-Biology sd985@scarletmail.rutgers.edu

Stephanie Fung RU-SOE-BME stephanie.fung@rutgers.edu 41

Suchismita Ray RU-NB-Center for Alcohol Studies

shmita@rutgers.edu 11

Suraj B Teegala RBHS-NJMS-Pharmacology, Physiology & Neuroscience

suraj.teegala@rutgers.edu 3

Suril Gohel RBHS-SHP-Biomedical Informatics

gohelsu@shp.rutgers.edu

Terri Wood RBHS-NJMS-Pharmacology, Physiology & Neuroscience

terri.wood@rutgers.edu

Tracey J. Shors RU-NB-SAS-Psychology shors@rutgers.edu

Troy A. Roepke RU-SEBS-Animal Science ta.roepke@rutgers.edu

Vanessa Routh RBHS-NJMS-Pharmacology, Physiology & Neuroscience

routhvh@njms.rutgers.edu

Victor Danelon RU-Newark-Biology victordanelon@gmail.com

Viji Santhakumar RBHS-NJMS-Pharmacology, Physiology & Neuroscience

santhavi@njms.rutgers.edu

Wanhong Zuo RBHS-NJMS-Anesthesia and Perioperative Care

zuowa@njms.rutgers.edu

William Craelius RU-SOE-BME billcraelius@gmail.com 34

William Graves RU-Newark-Psychology william.graves@rutgers.edu

Wilma Friedman RU-Newark-Biology wilma.friedman@rutgers.edu

Yaa Haber RBHS-NJMS-Pharmacology, Physiology & Neuroscience

yaa.haber@va.gov 26

Yangyang Huang RBHS-RWJMS-Neuroscience and Cell Biology

huangy4@rwjms.rutgers.edu

Yelena Bibineyshvili RU-SAS-Cell Biology and Neuroscience

ezbi1984@gmail.com 24

Yoshikazu Morishita RU-SAS-Genetics ym333@dls.rutgers.edu

Yuli Fradkin RU-UBHC and RU-SAS-Genetics

julikfradkin@gmail.com 36

Notes

Notes

Notes

Notes

Rutgers Brain Health Institute SPH/RWJMS Research Bldg.

Room 259 683 Hoes Lane West

Piscataway, NJ 08854 bhi@ca.rutgers.edu