Adaptation to stress switches stress-evoked network disconnection to a new forebrain network state.

Stress adaptation is critical to maintaining mental and physical health. If acute stress is associated with changes in neuronal activity in many brain regions, how neuronal activity itself is coordinated across regions during stress, and how neuronal networks are modified during stress adaptation, are unknown. In male rats, we recorded local field potentials (LFPs) from stress-responsive regions, including the prelimbic cortex, anterior cingulate cortex, basolateral amygdala, lateral habenula, and dorsal hippocampus, in rats during repeated stress exposure in a within-subjects design. We characterized network activity by computing cross-region coherence, Granger causality, and phase-amplitude coupling on bipolar derivatives of LFPs. We established a stress-adaptation model in rats: the behavioral response to acute 10-minute restraint stress returned to baseline after a second restraint 3 hours later. The pre-stress state was characterized by robust global network interactions in the theta and gamma bands. The first exposure induced widespread disconnection, whereas following the second one, when rats showed an adaptive response, the connectivity pattern appeared different than this from the pre-stress state. Finally, baseline, stressed, and adaptive states was predicted (> 90 % accuracy) from network activity. Overall, we showed that the acutely stressed brain state was primarily a state of network disconnection, while stress adaptation was a new network state rather than a return to baseline.Significance statement Upon repeated stress exposure individuals can adapt and cope. Such responses can be observed at the cerebral level through investigation of communication among a network of key regions involved in the stress response, using local field potential recordings and coherence and causality analyses. Here we demonstrate that rats exposed to two consecutive stressful experiences show behavioral signs of adaptation during the second and that stress and adaptive states are associated with distinct network activity; while the stress state is accompanied by widespread disconnections among the network, the adaptive state is associated with a a distinct network configuration compared to the pre-stress baseline. Network communication could therefore hold translational potential for understanding stress and adaptive states and help deliniate stress-related disorders.