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 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: 1 st trial Interaction Zone No aggressor mouse

Materials & Methods  Social interaction: 2 nd 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 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

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