BDNF receptor balance gates AgRP-to-PVH fiber density and stimulation evoked feeding across caloric states

Abstract

Agouti-related peptide (AgRP) neurons show opposite pairings of anatomy and output across caloric states. In mice, 24-h caloric restriction (CR) increases AgRP-to-paraventricular hypothalamus (PVH) fiber density without increasing stimulation-evoked feeding, whereas 5-day high-fat diet (HFD) reduces fiber density yet increases stimulation-evoked feeding, including during PVH terminal stimulation. PVH Bdnf rises acutely under both challenges and remains elevated with sustained HFD. Receptor expression shifts with state: in AgRP neurons, CR increases TrkB transcripts, whereas HFD increases p75NTR transcripts. AgRP-specific deletions define directional roles: TrkB loss reduces AgRP-to-PVH fiber density and yields larger stimulation-evoked feeding, whereas p75NTR loss increases fiber density and limits responses. Thus, a TrkB/p75NTR balance in AgRP neurons provides rheostat-like control over the relationship between circuit structure and stimulation-evoked feeding across caloric states, identifying TrkB and p75NTR as tractable molecular handles for probing state-dependent control of AgRP circuit output. HighlightsO_LICR increases AgRP[->]PVH fibers without boosting evoked feeding C_LIO_LIHFD retracts AgRP[->]PVH fibers and amplifies evoked feeding C_LIO_LIPVH Bdnf rises acutely in response to CR or HFD; elevation persists only with HFD C_LIO_LIAgRP TrkB{uparrow} with CR, p75NTR{uparrow} with HFD; AgRP specific knockouts of these receptors define floor and ceiling PVH axon innervation/evoked feeding C_LI