Huang, P.; Chen, C.; Bland, K.; Anand, A.; Beier, K.; Liu-Chen, L.-Y.

PVT is involved in stress responses, fear, anxiety, arousal, aversion and reward. Anterior and posterior PVT (aPVT and pPVT) have different neuronal connections, molecular contents, and functional roles. PVT expressed a high level of KOR. Herein we mapped the projection targets of aPVT KOR(+) neurons and explored the behavioral significance of aPVT KOR. Using KOR-iCre mice and Cre-dependent anterograde tracer, we found that KOR(+) glutamatergic neurons in aPVT primarily projected to NAc, CeA, BNST, PFC, and reticular nucleus of the thalamus (RT). 3-D images showed the pathway emanating from aPVT to the ventral RT, through NAc, and out to the other regions, indicating widespread axonal collateralization. We conditionally knock-downed KOR (KOR cKD) in aPVT by injection of AAV-eGFP-Cre or AAV-eGFP (control) into aPVT of Oprk1lox/lox mice. [3H]U69,593 receptor autoradiography revealed substantial KOR cKD in aPVT. In both male and female mice, the KOR cKD in aPVT significantly reduced anxiety-like behaviors in the elevated plus-maze test, cue-induced freezing after fear conditioning and naloxone-precipitated morphine withdrawal-associated jumps. KOR cKD attenuated U50,488H-induced conditioned place aversion in males only, while having no effect on forced swim immobility or the U50,488H-induced visceral analgesic and antipruritic effects in either sex. Thus, our results reveal for the first time that KOR-mediated inhibition of aPVT neurons may mediate morphine withdrawal, anxiety, and cue-induced fear in both sexes but contribute to KOR agonist-induced aversion only in males. Notably, our findings reveal a previously unrecognized role for aPVT in regulating morphine withdrawal, acting in a manner distinct from pPVT.