Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
Research trends in understanding how maternal
stress and health interacts with prenatal brain development
Hanna Stevens, M.D., Ph.D. Department of Psychiatry
Iowa Neuroscience Institute Carver College of Medicine
University of Iowa
Disclosures
• Advisory board – Klingenstein Third Generation Foundation
• Research funding (past year): – Roy J Carver Trust – Nellie Ball Trust – Chromadex – Environmental Health Sciences Research Center
(NIEHS) – Hypertension Research Center
Important Questions
• What happens during prenatal brain development?
• Does maternal prenatal stress and health matter for brain development that occurs in utero?
• How can we think about buffering brain development in utero? – What molecular mechanisms are involved?
Prenatal Brain Development
Andersen (Neurosci and Biobehav Rev; 2003)
General Principles of Development
Patterning the Nervous System: regions defined by unique combinations of factors
Patterning and Regional Differences • Different regions
become defined by these early patterning signals to be the place where complex sensory, motor, emotional, executive and integrated processing occurs.
Development of the Nervous System Sanes, Reh and Harris, Copyright 2006.
Expanding Cell number
Vaccarino et al. J. Autism Dev. Dis., Vol 39, 2009
Human Brain Expansion
Dorus et al. Cell, Vol 119, 2004
Processes for Cortex Formation • Neuronal Migration:
– newer cells migrate along processes of older, parent cell
Development of the Nervous System Sanes, Reh and Harris, Copyright 2006.
Marin et al (CSH Perspectives; 2010)
Processes for Cortex Formation
• The caudate is >95% inhibitory GABAergic neurons of multiple types
– Decreased caudate GABAergic interneurons in Tourette Syndrome patients
– Overgrowth of GABAergic progenitors in macrocephalic Autism
Childhood psychiatric disorders and GABAergic neurons of the Caudate nucleus
García-Montes et al 2012; Health
García-Montes et al 2012; Health
Andersen (Neurosci and Biobehav Rev; 2003)
Maternal Health and Stress Factors • Anxiety and mood disorders are
common and can disrupt adaptive physiology & health behaviors
• The demands of pregnancy are high and can be difficult to meet
• Psychological and biological problems that arise or continue in pregnancy are highly interactive
• Medication treatment during pregnancy should be personalized, but access to care impedes this process
Christian 2012
Modeling Maternal Health and Stress Factors
Bale 2015
Bergman et al., 2007
Prenatal Stress and Later Brain Function
Prenatal stress and stress-related states are associated with:
•Neonatal outcomes: –Preterm birth and low birth weight
•Childhood outcomes: –Cognitive developmental delay –Increased behavioral & stress reactivity –Altered cortical development
•Childhood diagnosis: –Autism Spectrum Disorder risk –Tourette Syndrome symptomatology –Mood, anxiety, and ADHD symptoms
Buss et al., 2009
Model System of Prenatal Stress
Repetitive Restraint Stress 45 min of physical restraint Three times daily Days E12-E19
Embyonic Day 0 (E0)
E12
Postnatal Day 0
Elevated Plus: increased anxiety
Forced Swim: increased immobility
HPA axis dysregulation
Electrophysiological Studies showing reduced hippocampal LTP
Serotonin receptor and ligand changes in prefrontal cortex
REM sleep alterations
Increased sensitivity to drugs of abuse
Decreased dopamine transporter in ventral telencephalon
Pregnant Dam
Changes in Caudate GABAergic Neuron populations
Neurobiological differences • Increased production and populations of GABAergic neurons in
caudate: Only in Males
Lussier et al in preparation
Parker Abbott
Stephanie Lussier
Caudate GABAergic neurons
Childhood Psychiatric Disorders and the Caudate Nucleus
• Autism, ADHD, and Tourette syndrome affect the same brain functions: – Repetitive behavior and procedural learning
– Disruptions of motor regulation (hyperactivity, impulsivity)
• These brain functions depend on the caudate nucleus, a subcortical region in the forebrain that contributes to cognitive and motor behaviors
• MRI changes in caudate – Activation during motor tasks, habits, and procedural learning
– Volume changes in patients with schizophrenia, autism, Tourette syndrome, and ADHD
Anatomography
Persistence in Caudate GABAergic Neuron populations Adult GABAergic differences • Increased Caudate
GABAergic numbers: Only in Males
Behavioral differences • Learning impairments and
motor hypoactivity: Only in Males
Lussier et al in preparation
Stephanie Lussier
Rotarod: Motor learning
* *
P24 P150 P24 P150
NS PS NS PS NS PS NS PS
Fcon|Fps|Mcon|Mps
Moderators of Prenatal Stress: Sex Differences Interaction of Sex with Prenatal Stress in effects on Gene Expression in GABAergic Progenitors at Embryonic Day 13
Upregulated in Males • Cellular Proliferation/Stem Cell Genes
Sox2; Ankrd17; PCNA; Smc3; Cdc6; Cdk2; Cenph; Kif18a; Kif4; Mtbp; Nusap1; Rad21
• Mitochondrial Genes Aifm1; Atp5a1; Cox7b; Hadhb; Idh2; Ndufa5; Ndufb4; Ndufb5; Ndufs4; Pmpcb; Sdh
Upregulated in Females • Neural Differentiation Genes
Adora1; Alk; Diap1; Epb4.1l1; Hcn3; Hnmt; Kcnc4; Klhl14; Map3k12; Mapt; Nrxn1; Rac3; Rgs7; Sort1; Stx1a; Stxbp1
Jake Michaelson Lab Collaboration
00.10.20.30.40.50.6
NSF
NSM
PSF
PSM
*
*
Sox2
Ankrd17
00.00020.00040.00060.0008
0.0010.00120.0014
05
10152025 Pcna
p=0.1
Male susceptibility to Stress Factors in vitro Neurosphere preparation from embryonic mouse brain • Neuronal proliferation of male and female neural stem cells • The inflammatory stress mediator, interleukin-6 (IL6), increases
neurosphere growth only in males, not females Interleukin-6 blockade during stress blocks proliferation increase
012345
Control IL6
Rel
ativ
e 48
Hr
Neu
rosp
here
gro
wth
Control IL6
Edenia Menezes; Jessica Armer, Stevens Lab 2018
00.5
11.5
22.5
33.5
NS PS NS PS
Males Females
E13 Placenta IGF-1 Expression
Dimasuay et al 2016
Moderators of Prenatal Stress: Sex Differences
*
00.050.1
0.150.2
0.25
NS PS NS PS
Females Males
E13 Placenta Endogenous Antioxidant Glutathione
Peroxidase
• Stress differential impacts on males and females may diverge in the placenta and its support for growth
*
Prenatal Stress and Mechanisms
Mechanisms & Developmental Stage =
potential targets for treatment and prevention
What mechanisms at the molecular
and cellular level may be responsible for:
Changes in the brain during Prenatal
Stress?
What could define maternal stress that is important for these effects?
Consequences for mature brain?
GeneDisRegulationGene DisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulatio
nGeneDisRegulationGene
Abnormal Childhood, Adolescent and Adult
Brain Structure and Function
GeneDisRegulationGene DisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulatio
nGeneDisRegulationGene
Embryonic Brain Development
Cortical Inhibitory Neuron Development
• GABAergic interneurons are born in the ganglionic eminence (at embryonic day 10 to 11 in mice- at about 4 weeks gestation in humans)
• Cortical interneurons migrate tangentially into the cortical plate, then migrate/integrate radially into the cortical layers
Stevens et al 2013; PNEC
Altered distribution of inhibitory cells at Embryonic Day 14
Non-stressed
Prenatally Stressed
GAD67GFP
Embryonic Day 14: GABA Cell Tangential Migration
Rostral Caudal
Stevens et al 2013; PNEC
Non stressed Prenatally Stressed
Postnatal Trajectories of GABA Populations and Inhibited Behavior
Lussier and Stevens 2016
Maternal Stress Factors and the Embryonic Brain
Repetitive • Corticosterone • IL1beta • IL6 injection compared to oil or PBS injection Three times daily Days E12-E13
Embyonic Day 0 (E0)
E12
E14 Collection for Migration Assay
Pregnant Dam
????? No delay
Results: Migration Delay with cytokines but not glucocoticoids
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
NS PS NS/Saline NS/IL-6 NS/anti IL-6 PS/anti IL-6
GPM
as a
% o
f tot
al c
ortic
al p
late
di
stan
ce
* p=.030 * p<.001
* p=.004
IL-6 but no other mediator alone can reproduce the effect of prenatal stress on inhibitory neuron migration
Blocking IL-6 during prenatal stress does not rescue migration delay in embryonic brain
NS/IL-1beta NS/Cort
Jada Bittle and Banu Gumusoglu
Mechanisms of Prenatal Stress
Barry et al 2006
Oxidative stress and the mitochondrial function that regulates it may be critical for effects on migrating cells Ant1 mutants have disrupted mitochondrial ADP/ATP flux and abnormal build up of pro-oxidants. Inhibitory neuron migration is also disrupted
Lin-Hendel et al 2016
• Collaboration with Mike Dailey’s lab to do live imaging of neuronal migration in mouse embryonic cortical slices to directly test mediators
Jada Bittle
Oxidative Stress and Neuronal migration
Oxidative state: Disrupted migration
n = 4 n = 4
01020304050607080
Control H2O2
μm p
er h
our
Velocity
n = 4
n = 4
0
20
40
60
80
100
Control H2O2
Aver
age
devi
atio
n in
deg
rees
Angle Deviation
Oxidative Stress and Neuronal Migration
• There was a significant effect of the antioxidant, N-acetyl cysteine (NAC), on Inhibitory Neuron migration
Jada Bittle
0
20
40
60
80
100
NS PS NS NAC PS NAC
Perc
ent M
igra
tion
into
Co
rtex
Inhibitory Neuron Migration at E13 *
• Insecticides are commonly used to reduce the risk of mosquito born diseases and agricultural pests – This is becoming more
common during pregnancy to protect against the neurodevelopmental risks of mosquito born diseases
– The CDC specifically recommends two insecticides for pregnant women: DEET and permethrin
– Evidence is lacking on neurodevelopmental impacts of permethrin/cypermethrin
Prenatal toxic exposure and GABAergic migration
Prenatal toxic exposure and GABAergic migration %
Mig
ratio
n
Prenatal Stress and Mechanisms
Mechanisms & Developmental Stage =
potential targets for treatment and prevention
What mechanisms at the molecular
and cellular level may be responsible for:
Changes in the brain during Prenatal
Stress?
What could define maternal stress that is important for these effects?
Consequences for mature brain?
GeneDisRegulationGene DisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulatio
nGeneDisRegulationGene
Abnormal Childhood, Adolescent and Adult
Brain Structure and Function
GeneDisRegulationGene DisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulationGeneDisRegulatio
nGeneDisRegulationGene
Embryonic Brain Development
Preventive Measures
Brumbach et al 2017
1980’s Dietary Folate
Supplements and Neural
Tube Defects
1940’s-1960’s Folic Acid and nucleic acid
synthesis
Late 1980’s and 1990’s Folic Acid
RCTs ↓ NTDs by 70-100%
Early 1990’s: CDC recommends
Supplementation for women Mandatory
Fortification by 2000
Crider et al 2011
Acknowledgments Pattern Trust
• Nellie Ball Trust • Nat’l Center for Advancing Translational
Science (Yale Center for Clinical Investigation) • APIRE/Wyeth Pharmaceuticals • NARSAD YI Award: Dr. Mortimer D. Sackler
Developmental Psychobiology Research Program
Glial Development • Begins embryonically
following the production of neurons
• Different types (astrocytes or oligodendrocytes) develop from different regions
• Continues throughout life, particularly in response to damage and injury Development of the Nervous System
Sanes, Reh and Harris, Copyright 2006.
Programmed Cell Death In worms, all neurons have a name and their eventual function/fate is known Death of some cells appears necessary for appropriate fate specification of other cells
www.wormatlas.org
Neuronal Signaling Even as neurons and their branches are being produced, they begin sending nonspecific signals These internally-generated, initial signals play a role in neuronal development