Role of locus coeruleus-paraventricular thalamic projections in social threat processing

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SUMMARY The paraventricular nucleus of the thalamus (PVT) regulates motivated behaviors including behaviors induced by stress exposure. The PVT receives extensive projections from the locus coeruleus (LC), an important component of the stress response system that mediates arousal and cognitive aspects of the stress response and the primary source of norepinephrine (NE) in the brain. Thus, both the PVT and the LC play important roles in arousal and attention during stress, thus contributing to positive and negative valence states, RDoC constructs important in multiple psychopathologies. However, the role of LC projections to the PVT in mediating responses to stress has received little to no attention. Our previous work on the PVT in rats showed that the posterior division of the PVT (pPVT) preferentially regulates responses to repeated stress. Further, preliminary data suggest that neuronal activity in the pPVT is higher in animals susceptible to repeated social defeat compared to resilient and control animals. Susceptibility to defeat is associated with greater stimulatory inputs to LC cells. These data suggest that activity of LC projections to pPVT are enhanced in individuals susceptible to the effects of repeated social defeat. Based on preliminary and published data, the central hypothesis of this exploratory/developmental proposal is that elevations in activity of LC/NE projections to pPVT lead to susceptibility to social defeat. Both male and female mice will be studied. Experiments will use the GRABNE sensor to assess NE release through fiber photometry in the pPVT during repeated social defeat and will use chemogenetics to inhibit pPVT-projecting LC cells in DBH-cre mice. We expect that NE release in the pPVT will be highest after defeat in mice that go on to be socially avoidant/susceptible and that inhibition of pPVT-projecting LC-NE cells during social defeat will reduce social avoidance thereby reducing susceptibility to defeat. We further expect greater NE release and less of an impact of LC-pPVT inhibition in female compared to male mice. The completion of these studies will provide the first information on how LC-NE inputs to the PVT regulate stress responses and the first information on sex differences in functions of these inputs. Elucidating the impact of NE release in the pPVT and of activity in pPVT-projecting LC cells will provide new mechanistic insights into individual differences in the response to stress.