Transcript Adult hippocampal neurogenesis is functionally important for stress

Adult hippocampal neurogenesis
is functionally important for
stress-induced social avoidance
Lagace 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 stressinduced 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 x 100%
Time spent in interaction zone with no aggressor mouse
Interaction
Zone
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