Chronic stress induces significant gene expression changes in the prefrontal cortex alongside alterations in adult hippocampal neurogenesis

Abstract

Adult hippocampal neurogenesis is involved in stress related disorders such as depression, posttraumatic stress disorders, as well as in the mechanism of antidepressant effects. However, the molecular mechanisms involved in these associations remain to be fully explored. In this study, unpredictable chronic mild stress in mice resulted in a deficit in neuronal dendritic tree development and neuroblast migration in the hippocampal neurogenic niche. To investigate molecular pathways underlying neurogenesis alteration, genome-wide gene expression changes were assessed in the prefrontal cortex, hippocampus and the hypothalamus alongside neurogenesis changes. Cluster analysis showed that the transcriptomic signature of chronic stress is much more prominent in the prefrontal cortex compared to the hippocampus and the hypothalamus. Pathway analyses suggested huntingtin, leptin, myelin regulatory factor, methyl-CpG binding protein and brain derived neurotrophic factor as the top predicted upstream regulators of transcriptomic changes in the prefrontal cortex. Involvement of the satiety regulating pathways (leptin) was corroborated by behavioural data showing increased food reward motivation in stressed mice. Behavioural and gene expression data also suggested circadian rhythm disruption and activation of circadian clock genes such as Period 2. Interestingly, most of these pathways have been previously shown to be involved in the regulation of adult hippocampal neurogenesis. It is possible that activation of these pathways in the prefrontal cortex by chronic stress indirectly affects neuronal differentiation and migration in the hippocampal neurogenic niche via reciprocal connections between the two brain areas.

Sex-Specific Microglial Activation and SARS-CoV-2 Receptor Expression Induced by Chronic Unpredictable Stress

“…Both the hippocampus and the PFC are known key regulators for executive functions associated with social cognition, mood regulation, decision-making, etc. ( Bicks et al, 2015 ) and are the most sensitive brain regions to stress-induced epigenetic and transcriptomic changes ( Hervé et al, 2017 ; Musaelyan et al, 2020 ). This suggests the potential sensitivities of these regions for viral entry or residence in the brain.…”

Modulation of the Hypothalamic Nutrient Sensing Pathways by Sex and Early-Life Stress

“…Thus, ES alters the leptin system at P9, whereas hypothalamic fatty acid metabolism seems unaffected. Interestingly, the leptin signaling pathway has been suggested to be a top upstream regulator of the effects of chronic stress in the prefrontal cortex, indicating leptin could be one of the key mediators by which stress exerts its effect on the brain (Musaelyan et al, 2020). Whether this might be the case also in the context of ES remains to be addressed.…”

Awakening the dormant: Role of axonal guidance cues in stress-induced reorganization of the adult prefrontal cortex leading to depression-like behavior

“…For instance, the polysialylated (PSA) form of N-CAM is involved in the development and migration of neurons in the immature vertebrate brain (Quartu et al, 2008), while also participating in neurite and synaptic remodeling (Varea et al, 2007). Although expressed throughout the lifetime, it is required for synaptogenesis and structural plasticity in adulthood, with multiple studies DCC was one of the top predicted upstream regulators of transcriptomic changes in the PFC after exposed to unpredictable chronic mild stress in adult male mice Musaelyan et al, 2020 Dysregulation of Netrin-1/DCC in mesolimbic DA regions of adolescent male mice susceptible to AcSD, but not in adults; differences in PFC DA connectivity seen between adults and adolescents subjected to AcSD Tochigi et al, 2008;Goswami et al, 2013 Sema3F knock-out male mice show reduced social interaction in SIT and other measures of depression-like behaviors Matsuda et al, 2016 The Sema3A gene is associated with MDD in African American populations Zhou et al, 2017 Frontiers in Neural Circuits 07 frontiersin.org implicating it in the structure and function of the adult male rat PFC (Varea et al, 2005;Castillo-Gómez et al, 2008Rutishauser, 2008). PSA-NCAM mediates synaptic plasticity, neurogenesis, signaling by neurotrophic factors and inflammatory messengers in the brain, all relevant processes in depression-like behaviors (Saini et al, 2020).…”