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