Chronic non-discriminatory social defeat is an effective chronic stress paradigm for both male and female mice

Yohn, Christine N.; Dieterich, Andrew; Bazer, Allyson; Maita, Isabella; Giedraitis, Megan E.; Samuels, Benjamin Adam

doi:10.1038/s41386-019-0520-7

Cited by 56 publications

(52 citation statements)

References 48 publications

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“…Moreover, while males engage in more overt acts of aggression than females, the overall number of agonistic acts is similar between sexes ( van den Berg et al, 2015 ; Choleris et al, 2018 ). This claim is consistent with our agonistic behavior findings overall, but future studies should investigate whether TK mice with inhibited adult neurogenesis display alterations in agonistic behavior in response to resident-intruder challenges, which can be designed to stimulate increased aggression in both males ( Olivier et al, 1995 ; Yohn et al, 2019 ) and females ( Haug et al, 1986 ; Newman et al, 2019 ).…”

Section: Discussionsupporting

confidence: 89%

Adult-Born Neurons in the Hippocampus Are Essential for Social Memory Maintenance

Cope

Waters

Diethorn

et al. 2020

eNeuro

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Throughout adulthood, the dentate gyrus continues to produce new granule cells, which integrate into the hippocampal circuitry. New neurons have been linked to several known functions of the hippocampus, including learning and memory, anxiety and stress regulation, and social behavior. We explored whether transgenic reduction of adult-born neurons in mice would impair social memory and the formation of social dominance hierarchies. We utilized a conditional transgenic mouse strain (TK mice) that selectively reduces adult neurogenesis by treatment with the antiviral drug valganciclovir (VGCV). TK mice treated with VGCV were unable to recognize conspecifics as familiar 24 hr after initial exposure. We then explored whether reducing new neurons completely impaired their ability to acquire or retrieve a social memory and found that TK mice treated with VGCV were able to perform at control levels when the time between exposure (acquisition) and re-exposure (retrieval) was brief. We then explored whether adult-born neurons are involved in dominance hierarchy formation by analyzing their home cage behavior as well as their performance in the tube test, a social hierarchy test, and did not find any consistent alterations in behavior between control and TK mice treated with VGCV. These data suggest that adult neurogenesis is essential for social memory maintenance, but not for acquisition nor retrieval over a short time frame, with no effect on social dominance hierarchy. Future work is needed to explore whether the influence of new neurons on social memory is mediated through connections with the CA2, an area involved in social recognition. 3 Significance Statement Adult hippocampal neurogenesis has been implicated in behaviors linked to the hippocampus, including social behavior. We utilized a conditional transgenic mouse line to reduce adult-born neurons and explored social memory and social dominance hierarchy formation. We found that mice with reduced numbers of new neurons were unable to recognize conspecifics as familiar with a long delay after initial exposure but were able to recognize them as familiar with a short delay. We did not observe changes in social dominance as measured by home cage behavior or tube test performance in mice with reduced numbers of new neurons. These data confirm and extend previous reports to show that adult-born neurons are essential for maintenance but not for acquisition or short-term retrieval of social memories, nor for social dominance.

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Section: Discussionsupporting

confidence: 89%

Adult-Born Neurons in the Hippocampus Are Essential for Social Memory Maintenance

Cope

Waters

Diethorn

et al. 2020

eNeuro

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“…Adult male and female C57BL/6 J mice (Jackson Laboratories, Bar Harbor, ME) were randomly assigned to control or CNSDS conditions, and then completed Control or CNSDS protocols as previously described 27 , 28 . In the control condition, a male and female C57BL/6 J mouse interacted for 5 min daily, followed by co-housing with a perforated Plexiglas cage divider.…”

Section: Methodsmentioning

confidence: 99%

“…Female to female aggression is also present in the California mouse, but not in more widely used laboratory strains like C57BL/6 J 26 . However, one recent variant of social defeat, chronic non-discriminatory social defeat stress (CNSDS), which simultaneously exposes a male and a female C57BL/6 J to an aggressive conspecific, produces robust effects in avoidance and other affective behavioral tasks, including a relatively minor effect in sucrose preference, a common behavioral measure of anhedonia 27 . Therefore, CNSDS may provide a way to determine if there are sex differences in how chronic stress affects reward and motivation.…”

Section: Introductionmentioning

confidence: 99%

Chronic non-discriminatory social defeat stress reduces effort-related motivated behaviors in male and female mice

2021

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Reward and motivation deficits are prominent symptoms in many mood disorders, including depression. Similar reward and effort-related choice behavioral tasks can be used to study aspects of motivation in both rodents and humans. Chronic stress can precipitate mood disorders in humans and maladaptive reward and motivation behaviors in male rodents. However, while depression is more prevalent in women, there is relatively little known about whether chronic stress elicits maladaptive behaviors in female rodents in effort-related motivated tasks and whether there are any behavioral sex differences. Chronic nondiscriminatory social defeat stress (CNSDS) is a variation of chronic social defeat stress that is effective in both male and female mice. We hypothesized that CNSDS would reduce effort-related motivated and reward behaviors, including reducing sensitivity to a devalued outcome, reducing breakpoint in progressive ratio, and shifting effort-related choice behavior. Separate cohorts of adult male and female C57BL/6 J mice were divided into Control or CNSDS groups, exposed to the 10-day CNSDS paradigm, and then trained and tested in instrumental reward or effort-related behaviors. CNSDS reduced motivation to lever press in progressive ratio and shifted effort-related choice behavior from a high reward to a more easily attainable low reward in both sexes. CNSDS caused more nuanced impairments in outcome devaluation. Taken together, CNSDS induces maladaptive shifts in effort-related choice and reduces motivated lever pressing in both sexes.

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“…One important limitation of this study is that we only used male mice. Unfortunately, both chronic CORT administration and standard forms of chronic social defeat stress are not effective in female mice 46,68,69 . However, recent variations of social defeat may be useful for assessing the role of Activin signaling in the antidepressant response in female mice 69,70 .…”

Section: The Role Of Activin Signaling In the Antidepressant Responsementioning

confidence: 99%

“…Unfortunately, both chronic CORT administration and standard forms of chronic social defeat stress are not effective in female mice 46,68,69 . However, recent variations of social defeat may be useful for assessing the role of Activin signaling in the antidepressant response in female mice 69,70 . It is especially important for future studies to use females given that disruptions in peripheral Activin signaling can impact both male and female sex organs causing changes in secretion of sex hormones in both sexes 71 .…”

Section: The Role Of Activin Signaling In the Antidepressant Responsementioning

confidence: 99%

Dentate gyrus activin signaling mediates the antidepressant response

et al. 2021

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Antidepressants that target monoaminergic systems, such as selective serotonin reuptake inhibitors (SSRIs), are widely used to treat neuropsychiatric disorders including major depressive disorder, several anxiety disorders, and obsessive-compulsive disorder. However, these treatments are not ideal because only a subset of patients achieve remission. The reasons why some individuals remit to antidepressant treatments while others do not are unknown. Here, we developed a paradigm to assess antidepressant treatment resistance in mice. Exposure of male C57BL/6J mice to either chronic corticosterone administration or chronic social defeat stress induces maladaptive affective behaviors. Subsequent chronic treatment with the SSRI fluoxetine reverses these maladaptive affective behavioral changes in some, but not all, of the mice, permitting stratification into persistent responders and non-responders to fluoxetine. We found several differences in expression of Activin signaling-related genes between responders and non-responders in the dentate gyrus (DG), a region that is critical for the beneficial behavioral effects of fluoxetine. Enhancement of Activin signaling in the DG converted behavioral non-responders into responders to fluoxetine treatment more effectively than commonly used second-line antidepressant treatments, while inhibition of Activin signaling in the DG converted responders into non-responders. Taken together, these results demonstrate that the behavioral response to fluoxetine can be bidirectionally modified via targeted manipulations of the DG and suggest that molecular- and neural circuit-based modulations of DG may provide a new therapeutic avenue for more effective antidepressant treatments.

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Chronic non-discriminatory social defeat is an effective chronic stress paradigm for both male and female mice

Cited by 56 publications

References 48 publications

Adult-Born Neurons in the Hippocampus Are Essential for Social Memory Maintenance

Adult-Born Neurons in the Hippocampus Are Essential for Social Memory Maintenance

Chronic non-discriminatory social defeat stress reduces effort-related motivated behaviors in male and female mice

Dentate gyrus activin signaling mediates the antidepressant response

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