Prediction of Learned Resistance or Helplessness by Hippocampal-Prefrontal Cortical Network Activity during Stress.

The perception of control over a stressful experience may determine its impacts and generate resistance against future stressors. Although the medial prefrontal cortex (PFC) and the hippocampus (HPC) are implicated in the encoding of stressor controllability, the neural dynamics underlying this process are unknown. Here, we recorded HPC and PFC neural activities in male rats during the exposure to controllable, uncontrollable, or no shocks and investigated electrophysiological predictors of escape performance upon exposure to subsequent uncontrollable shocks. We were able to accurately discriminate stressed from non-stressed animals and predict resistant (R) or helpless (H) individuals based on hippocampal-cortical oscillatory dynamics. Remarkably, R animals exhibited an increase in theta power during CS, while H exhibited a decrease. Furthermore, R exhibited higher HPC to PFC theta synchronization during stress. Notably, HPC-PFC theta connectivity in the initial stress exposure showed strong correlations with escape performance evaluated days later. R rats also showed stronger theta coupling to both gamma oscillations and neuronal firing in the PFC. Finally, we found that these distinct features of network dynamics collectively formed a pattern that accurately predicted learned resistance and was lacking in helpless individuals. Our findings suggest that hippocampal-prefrontal network theta activity supports cognitive mechanisms of stress coping, whose impairment may underlie vulnerability to stress-related disorders.SIGNIFICANCE STATEMENT:The appraisal of adversities as controllable or uncontrollable is key in determining resilience or risk for stress-related disorders. Here we performed the first electrophysiological investigation during controllable or uncontrollable stress. Pharmacological studies showed that the prefrontal cortex (PFC) and the hippocampus (HPC) encode stressor controllability, and here we identified the neural activity underlying this process. This 'neural signature of stressor controllability' accurately predicted resistance to future stressors and was characterized by increased HPC-PFC oscillatory activity in the theta frequency (4-10 Hz). Our findings suggest a new role of frontal theta oscillations in adaptive stress coping, integrating its emotional and cognitive functions. We also endorse the potential of this biomarker to guide neurophysiologically-informed and rhythm-based stimulation therapies for depression.