Adult hippocampal neurogenesis is functionally important for

stress-induced social avoidanceLagace et al.

Sorry James, there is no serotonin in this paper…

Introduction

• An individual’s emotional response to either acute or chronic stress involves both genetic and environmental factors that interact in complex ways

• Literature describes effects of stress on an individual’s physiology and behavior

• Most individuals exposed to stress don’t show signs of psychopathology

• Mechanisms that mediate resistance or promote resilience can be complex

Molecular Adaptations…Reward Regions

24 hours after avoidance testing revealed that only susceptible mice showed increased levels of BDNF in NAc

Infusion of BDNF into NAc enhances susceptibility

Overview

Objective: Determine whether the susceptibility to stress- induced social avoidance was related to changes

in SGZ cell proliferation and neurogenesis.

Results: Although there is a transient decrease in SGZ proliferation in all mice after exposure to

chronic social defeat, susceptible mice have enhanced dentate gyrus neurogenesis after cessation of

defeat.

Materials & Methods

Animals Control mice Subject/test mice Aggressor mice

Social defeat Social interaction

Interaction ratio Passive Avoidance Juvenile interaction

Materials & Methods

Social defeat: normal

Materials & Methods

Social defeat: testing

Materials & Methods

Social interaction: 1st trial

Interaction Zone

No aggressor

mouse

Materials & Methods Social interaction: 2nd trial

Interaction ratio: Time spent in interaction zone with aggressor mouse Time spent in interaction zone with no aggressor mouse

Interaction Zone

x 100%

Materials & Methods

Animals Control mice Subject/test mice Aggressor mice

Social defeat Social interaction

Interaction ratio Passive Avoidance Juvenile interaction

Procedure

Materials & Methods

Animals Control mice Subject/test mice Aggressor mice

Social defeat Social interaction

Interaction ratio Passive Avoidance Juvenile interaction

Procedure

Dentate Gyrus

Results

Chronic Social Defeat Stress Leads to Specific Avoidance of a Potential Aggressor

Results

Chronic Social Defeat Stress Leads to Specific Avoidance of a Potential Aggressor

Results

Stress Transiently Reduces the Number of S-Phase SGZ Cells in Susceptible and Unsusceptible Mice

Results

Stress Transiently Reduces the Number of S-Phase SGZ Cells in Susceptible and Unsusceptible Mice

Results

Stress Transiently Reduces the Number of S-Phase SGZ Cells in Susceptible and Unsusceptible Mice

Results

Stress Transiently Reduces the Number of S-Phase SGZ Cells in Susceptible and Unsusceptible Mice

Results

Mice with Long-Term Susceptibility to Stress Have Enhanced Dentate Gyrus Neurogenesis

Results Mice with Long-Term Susceptibility to Stress Have Enhanced

Dentate Gyrus Neurogenesis

Results Mice with Long-Term Susceptibility to Stress Have Enhanced

Dentate Gyrus Neurogenesis

Results Enhanced Dentate Gyrus Neurogenesis in Susceptible Mice is

Associated with Altered Number of Transient Amplifying Progenitors but Not with Altered BDNF signaling or Cell Death

Results Enhanced Dentate Gyrus Neurogenesis in Susceptible Mice is

Associated with Altered Number of Transient Amplifying Progenitors but Not with Altered BDNF signaling or Cell Death

Neurogenesis in the Dentate Gyrus: Type 1 and Type 2 progenitor cells in the SGZ can be identified by their distinct morphologies and their expression of specific molecular markers. Newborn neurons in the dentate gyrus of the hippocampus go through several stages of morphological and physiological development. Specifically, a transition from GABA (blue) excitatory to GABA inhibitory and glutamate excitatory inputs to newborn neurons occurs during the third week after cell birth, concomitant with the growth of dendritic spines. (Zhao C., et al. 2008. Mechanisms and Functional Implications of Adult Neurogenesis)

Results

X-Ray Irradiation Before Social Defeat Attenuates the Percentage of Mice that Have a Susceptible Phenotype

Results

X-Ray Irradiation Before Social Defeat Attenuates the Percentage of Mice that Have a Susceptible Phenotype

Results X-Ray Irradiation Before Social Defeat Attenuates the

Percentage of Mice that Have a Susceptible Phenotype

Results X-Ray Irradiation Before Social Defeat Attenuates the

Percentage of Mice that Have a Susceptible Phenotype

Results X-Ray Irradiation Before Social Defeat Attenuates the

Percentage of Mice that Have a Susceptible Phenotype

Discussion Lagace et al. agrees with

common data that stress decreases SGZ proliferation, but also shows that proliferation is only transiently reduced immediately after the last stress.

Seems counterintuitive that both antidepressants (which enhance neurogenesis) and ablation of neurogenesis lead to decreased social avoidance. Antidepressants act on different

neural circuits?Warner-Schmidt, J.L. and Duman, R.S. 2006.

Take-home messages…

Stress transiently decreases SGZ proliferation Susceptible mice have significantly enhanced survival of

dentate gyrus neurons, compared to control or unsusceptible mice, that were generated after defeat stress

When x-ray irradiation ablated neurogenesis, significantly fewer mice exhibited social avoidance

Hippocampal neurogenesis appears to be involved in the persistent social avoidance behavior (i.e., direct correlation)

The period after cessation of stress is a critical period for the establishment of persistent cellular and behavioral responses to stress