Prefrontal–Bed Nucleus Circuit Modulation of a Passive Coping Response Set

Abstract

One of the challenges facing neuroscience entails localization of circuits and mechanisms accounting for how multiple features of stressresponses are organized to promote survival during adverse experiences. The rodent medial prefrontal cortex (mPFC) is generally regarded as a key site for cognitive and affective information processing, and the anteroventral bed nuclei of the stria terminalis (avBST) integrates homeostatic information from a variety of sources, including the mPFC. Thus, we proposed that the mPFC is capable of generating multiple features (endocrine, behavioral) of adaptive responses via its influence over the avBST. To address this possibility, we first optogenetically inhibited input to avBST from the rostral prelimbic cortical region of mPFC and observed concurrent increases in immobility and hypothalamo-pituitary-adrenal (HPA) output in male rats during tail suspension, whereas photostimulation of this pathway decreased immobility during the same challenge. Anatomical tracing experiments confirmed projections from the rostral prelimbic subfield to separate populations of avBST neurons, and from these to HPA effector neurons in the paraventricular hypothalamic nucleus, and to aspects of the midbrain periaqueductal gray that coordinate passive defensive behaviors. Finally, stimulation and inhibition of the prelimbic-avBST pathway, respectively, decreased and increased passive coping in the shock-probe defensive burying test, without having any direct effect on active coping (burying) behavior. These results define a new neural substrate in the coordination of a response set that involves the gating of passive, rather than active, coping behaviors while restraining neuroendocrine activation to optimize adaptation during threat exposure.The circuits and mechanisms accounting for how multiple features of responses are organized to promote adaptation have yet to be elucidated. Our report identifies a prefrontal-bed nucleus pathway that organizes a response set capable of gating passive coping behaviors while concurrently restraining neuroendocrine activation during exposure to inescapable stressors. These data provide insight into the central organization of how multiple features of responses are integrated to promote adaptation during adverse experiences, and how disruption in one neural pathway may underlie a broad array of maladaptive responses in stressrelated psychiatric disorders.

Chemogenetic Inhibition of Infralimbic Prefrontal Cortex GABA-ergic Parvalbumin Interneurons Attenuates Chronic Stress Adaptions in Male Mice

“…Involvement of the PrL is consistent with its prominent role in mediation of coping behavior (Fiore et al, 2015;Johnson et al, 2019;Molendijk and de Kloet, 2019).…”

“…Involvement of the PrL is consistent with its prominent role in mediation of coping behavior (Fiore et al, 2015;Johnson et al, 2019;Molendijk and de Kloet, 2019). As part of our design, we assessed the impact of IL PV IN inhibition acutely following the first stressor in our CVS regimen, the TST, which allows for a behavioral readout (duration of struggling, immobility and latency to immobility).…”

Involvement of P2X2 receptor in the medial prefrontal cortex in ATP modulation of the passive coping response to behavioral challenge

“…In human beings, the symptoms of passive coping response are referred to as hopelessness, which is a core feature of major depressive disorder. It has been shown that mPFC also plays a role in the control of the passive coping response to behavioral challenge 20‐22,29 . By using pharmacological and shRNA interventions, our previous study demonstrates an involvement of P2X2 receptors in the mPFC in the ATP modulation of passive coping response 12 .…”

“…The FST and TST are widely employed to evaluate the despair aspect of depression‐like behavior and screen antidepressants in rodents, 18 but recently researchers prefer to interpret the acquisition of immobility in the FST as behavioral adaptation to the acute stressor which represents an adaptive cognitive process or as passive coping response or inhibition of active coping response 19‐22 . In this study, we used the FST and TST to measure passive coping response to behavioral challenge.…”

MR/GR Signaling in the Brain during the Stress Response

“…In another group of CRH neurons, the BNST input attenuates the sympathetic output. A separate pathway of the BNST projects to the ventrolateral periaqueductal (vl-PAG) where passive coping is promoted at the expense of the initial active coping strategy [89,90]. Active coping refers to fight or flight, which, when the situation is appraised as inescapable, causes a reorganization of prelimbic to infralimbic mPFC circuitry that is aimed to restrain the emotional and autonomic responses [91][92][93][94].…”