Cortical mechanisms of stress-induced cognitive impairment

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PROJECT SUMMARY / ABSTRACT Stress profoundly impacts mental health via impaired cognitive function and increased risk of neuropsychiatric disorders, resulting in loss of lives, tremendous healthcare costs and reduced economic productivity. Central to the mechanism of stress-induced cognitive impairment is loss of excitatory synapses and consequently, disrupted connectivity of key brain areas, including those involved in decision-making. Decisions rely on this connectivity to combine sensory clues with internal factors like attention, memories and outcome predictions. In the neocortex, sensory information is provided by bottom-up inputs while internal factors are conveyed via top- down systems. The capacity of the posterior parietal cortex (PPC) to integrate these various information streams is fundamental to decision-making. There is emerging evidence from human studies that the parietal circuit is affected by chronic stress. Yet, there is a critical gap in our knowledge regarding the mechanistic role the PPC circuit may play in mediating the link between stress and impaired decision-making. Our preliminary findings indicate that repeated exposure to multiple concurrent stressors (combining physical, visual and auditory stresses, RMS for short) destroys excitatory synapses in the PPC. Specifically, synaptic inputs corresponding to the sensory modalities (visual and auditory) conveying the stress are lost while top- down inputs from frontal brain regions are preserved. These findings motivate our central hypothesis that stress impedes decision-making by disrupting the integration of sensory and top-down information streams in the PPC circuit. We will test this hypothesis at the behavioral, circuit and synaptic level. First, utilizing quantitative behavioral analysis, we will determine which aspects of decision-making are affected by RMS. We will use chemogenetic circuit manipulation (DREADDs) to link our behavioral findings to sensory and top-down inputs of the PPC. Next, we will use in vivo two-photon calcium imaging and signal detection theory to directly test the effect of RMS on information transfer between cortical regions. Finally, we will use dual-color optogenetics and whole-cell patch clamp recordings in acute brain slices to determine the effect of RMS on the integration of sensory and top-down synaptic inputs in PPC neurons. Successful completion of the proposed studies will establish an important mechanistic link between the PPC circuit and stress-induced deficits in decision-making. The generated insights will pave the way towards identifying novel targets for prevention and intervention strategies to address stress-related neuropsychiatric disorders.