Neuroscience Graduate Program, Vanderbilt University; Nashville, TN 37232, USA.
College of Arts and Sciences, Vanderbilt University; Nashville, TN 37232, USA.
Neuropharmacology. 2022 Oct 1;217:109201. doi: 10.1016/j.neuropharm.2022.109201. Epub 2022 Jul 30.
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 [Leu, Pro]-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.
社会互动定义了人类的体验，但许多精神障碍都会破坏这些重要的行为。社会行为经过了数千年的演变，而促进无脊椎动物社会行为的神经调质系统也存在于哺乳动物的大脑中。一种保守的神经调质，神经肽 Y（NPY），通过几种受体起作用，包括 Y1r、Y2r 和 Y5r。这些受体存在于控制社会行为的大脑区域，包括伏隔核（NAc）。然而，NPY 是否调节 NAc 神经传递尚不清楚。使用 NAc 神经元的全细胞膜片钳电生理学，我们发现多种 NPY 受体以细胞类型特异性的方式调节兴奋性突触传递。在 D1+MSN 上的兴奋性突触，Y1r 活性增强传递，而 Y2r 抑制传递。在 D1-MSN 上的兴奋性突触，Y5r 活性增强传递，而 Y2r 抑制传递。直接将 NPY 或 Y1r 激动剂 [Leu，Pro]-NPY 注入 NAc 会显著增加与陌生同种动物的社交互动。抑制分解 NPY 的酶，二肽基肽酶 IV（DPP-IV），会使 NPY 对 D1+MSN 的作用转变为 Y1r 主导的表型。总之，这些结果增加了我们对 NPY 如何调节 NAc 中神经传递的理解，并确定了控制社会行为的新机制。此外，它们揭示了一种潜在的策略，以改变 NPY 信号传递以获得治疗收益。
