Research On Neural Circuit Rewiring In The Frontal Association Cortex Of Mice Based On Chronic Social Defeat Stress Paradigm

Depression is a common and life threatening mental disorder, contributing substantially to global social burden. The etiology mechanisms of depression is complicated, involving abnormal changes and dysfunctions on the level of molecular, cellular and neural circuit. To date, the depression etiology mechanism is unclear and the understanding of depression pathological progression is far to complete. Depression is often described as a stress-related disorder, and chronic stress can lead to depressive-like pathological disorders and behaviors, increasing the risk of depression and precipitating depression. Investigating chronic stress induced pathological progression could help us understand and reveal the etiological and pathological mechanisms of depression. Previous study about chronic stress induced abnormal alterations in neural circuits mostly focused on brain areas like medial prefrontal cortex (mPFC), hippocampus, amygdala, et al. and some progresses have been achieved, like that chronic stress can also induce a volume reduction and structural and functional recession of medial prefrontal cortex (mPFC), otherwise inducing a volume increase and structural and functional enhancement of amygdala. However, rare study prospects the role of dorsolateral part of prefrontal cortex, frontal association cortex (FrA), in etiology and pathology of depression. FrA, which is large (-20%) in the whole prefrontal cortex and connects with mPFC and amygdala, is supposed to be implicated in higher brain functions as investigation results have showed that FrA is involved in dementia pathology and contributes to memory formation in associative learning. What changes of FrA neural circuits will be caused by chronic stress? Whether and how is FrA involved in the regulation of chronic stress response? To address these questions, in this article, we adopt chronic social defeat stress paradigm and combine open-skull surgery with two-photon in vivo microscopy, imaging apical dendritic spines of layer V pyramidal neurons in FrA of Thy1-YFP H line transgenic mice and tracing the fate of same spines in the same YFP mice, to analyze the rewiring of FrA neural circuit after chronic stress.The results in this article show that, using cholera toxin subunit B Alexa Fluor 647 conjugate (CTB-647) for retrograde labeling, we confirmed that FrA receives neural inputs directly from mPFC and amygdala; chronic social defeat stress leads to depressive-like behaviors in defeated mice, including social avoidance and anhedonia (decreased sucrose preference); simultaneously, chronic social defeat stress induces abnormal changes to FrA spine dynamics, including formation but elimination of FrA spines has a mild but significant decrease, FrA spine density decreases, otherwise the survival rate of FrA newly formed spines is elevated and the contribution of newly formed spines to FrA neural circuit is increased. The decrease of FrA spine formation rate induced by chronic social defeat stress suggests that synaptic plasticity of FrA neural circuit is influenced by chronic stress, accompanied with depressive-like behaviors. This implies that adaptive alteration of synaptic dynamics in FrA may underlie the depressive-like behaviors. On the other hand, after chronic social defeat stress, the increased survival rate newly formed spines in FrA and elevated contribution of newly formed spines to FrA neural circuit, suggest that chronic stress causes more newly formed spines integrate into FrA neural circuit, resulting in the rewiring of neural circuit in FrA. The rewiring of neural circuit in FrA is accompanied with persistent depressive-like behaviors, indicating that this adaptive rewiring of FrA neural circuit may be related to a certain negative memory associated with the experience of chronic stress.