Neuromodulatory Regulation of Synaptic Transmission in the ARC AgRP→PVN Circuit Revealed by Optogenetics

Abstract

Aim: This study aimed to investigate how dopamine, leptin, kappa opioid receptor signaling, and melanocortin receptors modulate synaptic transmission in the ARC AgRP→PVN pathway. Materials and Methods: We combined optogenetic stimulation with whole-cell electrophysiological recordings to directly assess synaptic strength and connectivity. ARC AgRP neurons were selectively activated using AAV-FLEX-ChR2-mediated expression of channelrhodopsin, and postsynaptic responses were recorded in PVN neurons. The effects of dopamine, leptin, and cannabinoid receptor agonists and antagonists on synaptic transmission were evaluated, allowing precise analysis of modulatory influences on this hypothalamic feeding circuit. Results: Leptin and a kappa opioid receptor agonist significantly reduced the synaptic strength of the ARC AgRP→PVN pathway, as reflected by a decrease in the peak amplitude of optogenetically evoked synaptic responses in PVN neurons. In contrast, neither dopamine nor MTII produced significant changes in synaptic strength or neurotransmitter release at this connection (*p<0.05). Conclusion: These findings demonstrate that leptin and kappa opioid receptor activation suppress synaptic transmission in the ARC AgRP→PVN circuit, whereas dopamine and melanocortin receptor activation with MTII have minimal effects on this pathway. Collectively, these results provide new insights into the neuromodulatory mechanisms regulating hypothalamic feeding circuits and highlight potential targets for interventions aimed at controlling appetite and energy balance.