Inhibition of adult neurogenesis reduces avoidance behavior in male, but not female, mice subjected to early life adversity

Abstract

Early life adversity (ELA) increases the risk of developing neuropsychiatric illnesses such as anxiety disorders. However, the mechanisms connecting these negative early life experiences to illness later in life remain unclear. In rodents, plasticity mechanisms, specifically adult neurogenesis in the ventral hippocampus, have been shown to be altered by ELA and important for buffering against detrimental stress-induced outcomes. The current study sought to explore whether adult neurogenesis contributes to ELA-induced changes in avoidance behavior. Using the GFAP-TK transgenic model, which allows for the inhibition of adult neurogenesis, and CD1 littermate controls, we subjected mice to an ELA paradigm of maternal separation and early weaning (MSEW) or control rearing. We found that mice with intact adult neurogenesis showed no behavioral changes in response to MSEW. After reducing adult neurogenesis, however, male mice previously subjected to MSEW had an unexpected decrease in avoidance behavior. This finding was not observed in female mice, suggesting that a sex difference exists in the role of adult-born neurons in buffering against ELA-induced changes in behavior. Taken together with the existing literature on ELA and avoidance behavior, this work suggests that strain differences exist in susceptibility to ELA and that adult-born neurons may play a role in regulating adaptive behavior.

Sex Differences in the Spatial Behavior Functions of Adult-Born Neurons in Rats

“…This discrepancy could be because of methodological differences, including potential strain-related, neurogenesis-independent alterations in stress and emotional regulation ( Groves et al, 2013 ). Another study found that blocking adult neurogenesis selectively reduced anxiety-like behavior in male mice that were subjected to early life stress ( Waters et al, 2022 ), highlighting the need to consider sex in future studies of adult neurogenesis. Moreover, these and other data indicate that neurogenesis is often dispensible for behavior in naive animals but can contribute when animals are faced with additional stressors before, or during, testing ( Snyder et al, 2011 ; Glover et al, 2017 ; Anacker et al, 2018 ).…”

“…One study reported sex differences in neurogenic modulation of the hypothalamic-pituitary-adrenal (HPA) response ( Silveira‐Rosa et al, 2021 ), although this rat model is confounded by neurogenesis-independent effects on emotion ( Groves et al, 2013 ). A second study found that adult neurogenesis buffers the effects of early life stress on subsequent anxiety-like behavior, selectively in male mice ( Waters et al, 2022 ). Whether adult neurogenesis differentially regulates behavior across the sexes in learning situations, however, remains unknown.…”

Early Life Adversity and Neuropsychiatric Disease: Differential Outcomes and Translational Relevance of Rodent Models

“…A newer model than maternal separation alone, maternal separation and early weaning, which may be a more cumulative model of ELA, has produced results that seem to show increased “depressive-like” behavior ( George et al, 2010 ; Montalvo-Ortiz et al, 2016 ; Sun et al, 2021 ) as well as increased behavioral avoidance ( George et al, 2010 ; Carlyle et al, 2012 ; Murthy et al, 2019 ; Sun et al, 2021 ), perhaps reflecting the high comorbidity between MDD and anxiety disorders, but there are still reports showing inconsistent results ( Tan et al, 2017 ; Waters et al, 2022 ). Maternal separation and early weaning studies have generally shown effects in male mice and rats ( George et al, 2010 ; Montalvo-Ortiz et al, 2016 ; Murthy et al, 2019 ; Sun et al, 2021 ), with studies either not examining females or, if so, finding no effects ( Murthy et al, 2019 ; Sun et al, 2021 ).…”

Inhibition of Hippocampal Neurogenesis Starting in Adolescence Increases Anxiodepressive Behaviors Amid Stress

“…We chose male rats to maximize sample size in our litter group due to unbalanced male and female generation and wanting to avoid using multiple litter groups at different times ( Lazic and Essioux, 2013 ). This exclusion of females though is particularly important as sex differences have been reported on the effects of developmental stress on adult anxiodepressive behavior ( Goodwill et al, 2019 ; Lovelock and Deak, 2019 ), stress effects on new neuron generation, survival, and activation ( Yagi and Galea, 2019 ; O’Leary et al, 2022 ), and behavioral consequences following neurogenesis ablation ( O’Leary et al, 2022 ; Silveira-Rosa et al, 2022 ; Waters et al, 2022 ). Other studies have shown comparable effects of neurogenesis ablation across sexes ( Huckleberry et al, 2018 ; Seib et al, 2018 ; Cope et al, 2020 ), and it is unknown how our adolescent manipulations would have affected adult anxiodepressive behaviors in female rats.…”

“…Transgenic (TK) mice with ablated adult hippocampal neurogenesis show impaired negative feedback to acute stress and display more anxiety-like and depressive behaviors in stressful conditions ( Snyder et al, 2011 ), suggesting a role for new neurons of the hippocampus in stress reactivity. Relatedly, recent experiments demonstrate that reduction of new hippocampal neurons in adulthood prevents rodents from exhibiting behavioral flexibility from stress either naturally or following antidepressant treatment ( Alves et al, 2017 ; Schoenfeld et al, 2019 ; Waters et al, 2022 ), despite different methods of neurogenesis suppression. Together, research suggests that adult neurogenesis in the hippocampus is most important for regulating emotional behavior amid changing environments ( Cameron and Schoenfeld, 2018 ).…”