Neuropeptide Y modulates excitatory synaptic transmission and promotes social behavior in the mouse nucleus accumbens

Social interactions define the human experience, but these integral behaviors are disrupted in many psychiatric disorders. Social behaviors have evolved over millennia, and neuromodulatory systems that promote social behavior in invertebrates are also present in mammalian brains. One such conserved neuromodulator, neuropeptide Y (NPY), acts through several receptors including the Y1r, Y2r, and Y5r. These receptors are present in brain regions that control social behavior, including the nucleus accumbens (NAc). However, whether NPY modulates NAc neurotransmission is unknown. Using whole-cell patch-clamp electrophysiology of NAc neurons, we find that multiple NPY receptors regulate excitatory synaptic transmission in a cell-type specific manner. At excitatory synapses onto D1+ MSNs, Y1r activity enhances transmission while Y2r suppresses transmission. At excitatory synapses onto D1- MSNs, Y5r activity enhances transmission while Y2r suppresses transmission. Directly infusing NPY or the Y1r agonist [Leu³¹, Pro³⁴]-NPY into the NAc significantly increases social interaction with an unfamiliar conspecific. Inhibition of an enzyme that breaks down NPY, dipeptidyl peptidase IV (DPP-IV), shifts the effect of NPY on D1+ MSNs to a Y1r dominated phenotype. Together, these results increase our understanding of how NPY regulates neurotransmission in the NAc and identify a novel mechanism underlying the control of social behavior. Further, they reveal a potential strategy to shift NPY signaling for therapeutic gain.