Uconn Abroad ProgramJune 2014

Long term auditory lesion plasticity :On how the nervous system responds to

the auditory cortex ablation.

1899 –Term plasticity

INDEX

1. KEY CONCEPTS IN NEUROPLASTICITY.2. ASCENDING-DESCENDING FEEDBACK LOOPS IN THE

AUDITORY PATHWAY.3. AN ANIMAL MODEL OF RESTRICTED CORTICAL ABLATION

FOR EXPLORING THE ROLE OF THE DESCENDING CONNECTIONS AND PLASTIC REPAIR OF THE CENTRAL AUDITORY PATHWAY.

4. PAPERS I – FEEDBACK LOOP N3 – CORTICO-COLLICULAR CONNECTIONS. (C-FOS,CALRETININ AND MASSIVE GENE ANALYSIS OF THE MIDBRAIN)

5. PAPERS II – FEEDBACK LOOP N4 – CORTICO PONTINE CONNECTIONS. (ABRS AND Q-PCR ANALYSIS OF THE INNER EAR.

“nerve cell processes have amoeboid movement and contacts

between terminal axonal branches and the soma and dendrites could

loosen by protoplasmic retraction. In this way, dissociation would

take place with the consequent functional rest of the cells. Thus

during sleep, dendrites of pyramidal cells would shrink and cease

excitation arriving from the sense organs” (p. 189, Cajal, 1899)

Santiago Ramón y Cajal

A review that I recommend to read…Cajal and brain plasticity: Insights relevant to emerging concepts of mind.Efrain C. Azmitia�Center for Neural Science, NewYork University,, USABrain Res. Rew. 55 (2007) 395-405

Learning and memorySynaptic plasticity: Homesotatic / HebbianLesionalDevelopmental / AdultOthers – Functional, cross-modal, ultrastructural, topographic and dynamic representational, residual, anatomical, etc.

CURRENTLY NEURAL PLASTICITY IS A WIDE CONCEPT WITH MANY DIFFERENT MEANINGS

HOWEVER FOR SOME GROUPS OF NEUROSCIENTIST, PLASTICITY IS SIMPLY HOW THE BRAIN WORKS !!!

Neuroplasticity = Brain function

•What kind of changes can trigger neuronal plasticity programs?❧External induction. Environmental interaction❧Internal activation. Immunological or Genomic changes

•What are the basic tools ?•Anatomical -❦Changes in number of functional units (Neurons) of the networks. (Apoptosis and cell proliferation).❦Rewiring – Collateral sprouting and pruning.•Functional -❦Adjustment of synaptic strength ❦Changes in genomic and protein synthesis

What are the fundamentals of neuroplasticity?Plasticity is basically networks reorganization

1899 –Term plasticity

INDEX

1. KEY CONCEPTS IN EUROPLASTICITY.2. ASCENDING-DESCENDING FEEDBACK LOOPS IN THE

AUDITORY PATHWAY.3. AN ANIMAL MODEL OF RESTRICTED CORTICAL ABLATION

FOR EXPLORING THE ROLE OF THE DESCENDING CONNECTIONS AND PLASTIC REPAIR OF THE CENTRAL AUDITORY PATHWAY.

4. PAPERS I – FEEDBACK LOOP N3 – CORTICO-COLLICULAR CONNECTIONS. (C-FOS,CALRETININ AND MASSIVE GENE ANALYSIS OF THE MIDBRAIN)

5. PAPERS II – FEEDBACK LOOP N4 – CORTICO PONTINE CONNECTIONS. (ABRS AND Q-PCR ANALYSIS OF THE INNER EAR.

The Auditory PathwayAscending inputs to the auditory cortex originate a descending top down control that is able to change the

way of processing of all relay stations of the pathway, from the inner ear to the thalamus

The AP is functionally organized in feedback loops

MAIN FEEDBACK LOOPS IN THE CENTRAL AP.

OC bundle

3

4

2

1

1899 –Term plasticityINDEX

1. KEY CONCEPTS IN EUROPLASTICITY.2. ASCENDING-DESCENDING FEEDBACK LOOPS IN THE

AUDITORY PATHWAY.3. AN ANIMAL MODEL OF RESTRICTED CORTICAL ABLATION

FOR EXPLORING THE ROLE OF THE DESCENDING CONNECTIONS AND PLASTIC REPAIR OF THE CENTRAL AUDITORY PATHWAY.

4. PAPERS I – FEEDBACK LOOP N3 – CORTICO-COLLICULAR CONNECTIONS. (C-FOS,CALRETININ AND MASSIVE GENE ANALYSIS OF THE MIDBRAIN)

5. PAPERS II – FEEDBACK LOOP N4 – CORTICO PONTINE CONNECTIONS. (ABRS AND Q-PCR ANALYSIS OF THE INNER EAR.

Which anatomical, functional and metabolicreorganization take place in the AP after theloss of the corticofugal projection?

Are they these changes reversible?

t

Albino Rats (Wistar), male (230-240 gr)

Lesion by aspiratio stereotaxicallyguided

1899 –Term plasticity

INDEX

1. KEY CONCEPTS IN EUROPLASTICITY.2. ASCENDING-DESCENDING FEEDBACK LOOPS IN THE

AUDITORY PATHWAY.3. AN ANIMAL MODEL OF RESTRICTED CORTICAL ABLATION

FOR EXPLORING THE ROLE OF THE DESCENDING CONNECTIONS AND PLASTIC REPAIR OF THE CENTRAL AUDITORY PATHWAY.

4. FEEDBACK LOOP N3 – CORTICO-COLLICULAR CONNECTIONS. (C-FOS,CALRETININ AND MASSIVE GENE ANALYSIS OF THE MIDBRAIN). COCLEOTOPY (C Fos)

5. FEEDBACK LOOP N4 – CORTICO PONTINE CONNECTIONS. (ABRS AND Q-PCR ANALYSIS OF THE INNER EAR.

3How to respond tosound the IC when partof the descendingprojection is lost?

Nervous system self-repairs ?

Immunoreactivity = synthesis = neuronal activity

Sound stimulation for c- Fos

Fundamental frequency: 5.0 kHzRepetition frequency: 1.25 sOpen field

Three parameters were measured to analyze the fosactivation by sound in groups of normal and lesionedrats :

Total number of neurons

Density of the immunoreaction

Perimeter

c - Fos immunoractivity analysis :1. Sterology2. Topographic densitometry maps. Positional

values of each particle segmented in 2D (0-88) and gray level were fed into MATLAB.

3. Morphometry. The perimeter of all nuclei c-Fos Ir (0-88) in all experimental case wasmeasured with Image J.

Low

High

3 Perimeter2 Gray Values

1 Total number of ir-neurons

Fos activation

Neuronal nucleus

Chromogen

Topographic densitometry maps. Graphic Representation of Gray values

Densitometry

Stereology

An increase in fos activity produces an increase ofneuronal nuclei perimeter

Morphometry

Many IC neurons lose their sensitivity tosound after removing the AC. However are recovered in the long term.

These changes are only functional orstructural?.In other words the decrease and recoveryin fos-ir activation is due to a transientdrop in function by the lost of connection(residual plasticity) or to an active plasticmechanism ?

Activity-dependent changes- Ca++ and Calretinin Homeostasis of Ca2+

Synaptic plasticity depend from changes in intracellular Ca2+ (2ndmessengers).

CR Ca2+ Binding proteide - EF-hand protein familiy

FUNCTION

MODULATOR OFNEURONAL DISCHARGE

Fast and slow Ca2 + Buffer

Fast trasporter of Ca2+Ca2+ modulation of receptor synthesis

24694 Genes

Clustering FC 2135 genes

GEN

E EX

PRES

SIO

N

1899 –Term plasticity

INDEX

1. SOME GENERAL IDEAS ABOUT PLASTICITY.2. ASCENDING-DESCENDING FEEDBACK LOOPS IN THE

AUDITORY PATHWAY.3. AN ANIMAL MODEL OF RESTRICTED CORTICAL ABLATION

FOR EXPLORING THE ROLE OF THE DESCENDING CONNECTIONS AND PLASTIC REPAIR OF THE CENTRAL AUDITORY PATHWAY.

4. PAPERS I – FEEDBACK LOOP N3 – CORTICO-COLLICULAR CONNECTIONS. (C-FOS,CALRETININ AND MASSIVE GENE ANALYSIS OF THE MIDBRAIN)

5. PAPERS II – FEEDBACK LOOP N4 – CORTICO PONTINE CONNECTIONS. (ABRS AND Q-PCR ANALYSIS OF THE INNER EAR.

III

IIIIV

the short-latency evoked potentials

Septiembre 2013. Vol 8-Issue 9 e73585

DIRECT EFFECT BY THE LOSS OF CONNECTIONS TO THE IC

INDIRECT EFFECT BY CHANGES IN INCOMING SIGNALS. FEED BACK LOOP 4

Modified from John J. Guinan, Jr.

AuditoryCortex

MOC = OHCB (Outher hair cell bundle)LOC = IHCB (Inner hair cell bundle)

Efferent pathway

Mainly ContralateralMainly Ipsilateral

Which is the effect?

Modified from John J. Guinan, Jr.

Auditory Cortex

MOC = OHCB (Outher hair cell bundle)LOC = IHCB (Inner hair cell bundle)

Modified from John J. Guinan, Jr.

Auditory Cortex

MOC = OHCB (Outher hair cell bundle)LOC = IHCB (Inner hair cell bundle)

Lost of excitation on LOC and MOCDecrease in SOC activityIncrease in CAP and ABRS ?????Decrease in CM ?????

Tucker-Davis Technologies [TDT], System 3.

FUNCTIONAL ANALYSIS BY ABRs

A tube length of 24 cm resulted in an air conduction time of 0.75 ms forthe stimulus to arrive at the tympanic membrane.Stimuli -> 0.1 ms alternating polarity click with a repetition rate of 11bursts/s. delivered in 10 dB ascending steps from 30 to 90 dB (SP). Thisdelay was added to the 1 ms prestimuli period to calculate the onset ofthe ABR (1.7 ms). Responses were averaged 1000 times

SUMMARY OF THE MAIN FINDINGS

1 DAY PL 7 DAYs PL 15 DAYs PL 30 DAYs PLControlTreshold and amplitudes

So it's no problem. The effect of AC lesions on the IC was primarily direct.

However … What happens when we analyzed the latencies of ABRS waves?

MOC IHC ContraLOC OHC Ipsi

We hypothesize that shorter waves latencies at long term can be due to alterations in gaincontrol and cochlear amplification. Broad frequencies responses need less time to be elaboratedand consequently produces faster responses from the cochlea.

NEXT STATION - TERMINAL :

EFFERENT SYSTEM AND PRESTIN

glud1

GluA2

GluA3

GluA4

Pvα

α7 Ach

α10 Ach

D1

D2

α1 GABA

γ2 GABA

Prestin

LOC

MOC

Glutamate

Neu

riotrasmisssio

nGAB

Areceptors

IHC OHC

LOCCholinergic

LOCDopaminergic

Unmyelinated

Myelinated

MOC

Type I

Type II

α9/α10 nAch

AMPA GluRs

D1 Rs

D2 Rs

Maison et al., J Neurosci. 2012.

EXPERIMENTAL GROUPS – SINGLE RESTRICTED AUDITORY CORTEX ABLATION1, 7 AND 15 DAYS AFTER SURGERY.

IHC Ca reg.

IPISLATERAL

Early Effect 1 day ps

HOMEOSTATIC COMPENSATION

Activation of nicotinic α9α10 acetylcholine receptors results in the inward Ca2+ current that activates nearby Ca2+-dependent K+ channels. This effect is amplified by Ca2+-induced

Ca2+-release from synaptoplasmic cistern.

Frolenkov G I J Physiol 2006;576:43-48

©2006 by The Physiological Society

MOC OHC ContraLOC IHC Ipsi

Nacho Plaza

C. ClarksonVero Lamas

J. Herrero

Lab. 4 Auditory Plasticity