Study On The Effects And Mechanisms Of Chronic Stress On Medial Prefrontal Cortex Neural Circuits In Mice

Chronic stress exposure can significantly increase the risk of people suffering from mental illnesses such as anxiety and depression.The medial prefrontal cortex(mPFC)plays an important role in mediating high-level brain functions such as emotional regulation,working memory,planning and decision-making.Studies have shown that the mPFC is a core brain area that regulates stress responses and mainly functions by interacting with the limbic system.Among them,two brain areas that are crucial in the limbic system,the basolateral amygdala(BLA)and the nucleus accumbens(NAc),also play important roles in regulating stress responses and both receive a large number of mPFC nerve fibers.Given that the distribution of mPFC projection neurons in different subregions(dorsal medial prefrontal cortex,dmPFC vs.ventral medial prefrontal cortex,vmPFC)and different layers(Layer Ⅱ/Ⅲ vs.Layer Ⅴ)is highly complex,it is currently unclear how chronic stress affects mPFC neurons projecting to BLA and NAc located in different subregions and layers.This study aims to conduct preliminary research on the above issues in order to provide theoretical basis for understanding the occurrence of stress-related diseases regulated by mPFC neural circuits.In this study,we first investigated the distribution of mPFC neurons projecting to BLA and NAc in different subregions and layers using retrograde virus strategy.Then,a classic chronic restraint stress(CRS)model that can induce anxiety disorders in mice was used to investigate the effects of chronic stress exposure on synaptic activity and intrinsic properties of these two groups of neurons.The results showed that mPFC neurons projecting to downstream brain regions have specificity regardless of whether they are located in different subregions(dmPFC vs.vmPFC)or different layers(LayerⅡ/Ⅲ vs.Layer Ⅴ).Next,we validated the effectiveness of the CRS model using open field test and elevated plus maze behavioral tests and found that CRS significantly increased anxiety-like behaviors in mice.Electrophysiological results showed that CRS selectively decreased the inhibitory synaptic transmission efficiency of dmPFC neurons projected to the BLA rather than vmPFC neurons,but had no effect on excitatory synaptic transmission,leading to a shift in the excitation-inhibition balance(E-I balance)towards excitation,and this effect only occurred in Layer Ⅴ.However,the E-I balance of NAc neurons projecting from different subregions or layers did not change significantly after CRS.In addition,we also found that CRS selectively increased the intrinsic excitability of dmPFC neurons projecting to BLA in Layer Ⅴ.However,CRS did not cause significant changes in the intrinsic excitability of NAc neurons projecting from different subregions and layers.In conclusion,the results of our research first found that CRS can significantly increase the activity of mPFC neurons projecting to BLA,and the above effects have subregion and layer selectivity.This provides new insights for how chronic stress affects mPFC neural circuit function and provides potential intervention targets for preventing stress-related mental illnesses.