Hypothalamic agouti-related peptide and neuropeptide Y-expressing (AgRP) neurons have a critical role in both feeding and non-feeding behaviors of newborn, adolescent, and adult mice, suggesting their broad modulatory impact on brain functions. Here we show that constitutive impairment of AgRP neurons or their peripubertal chemogenetic inhibition resulted in both a numerical and functional reduction of neurons in the medial prefrontal cortex (mPFC) of mice. These changes were accompanied by alteration of oscillatory network activity in mPFC, impaired sensorimotor gating, and altered ambulatory behavior that could be reversed by the administration of clozapine, a non-selective dopamine receptor antagonist. The observed AgRP effects are transduced to mPFC in part via dopaminergic neurons in the ventral tegmental area and may also be conveyed by medial thalamic neurons. Our results unmasked a previously unsuspected role for hypothalamic AgRP neurons in control of neuronal pathways that regulate higher-order brain functions during development and in adulthood.

下丘脑刺豚鼠相关肽和神经肽 Y 表达 (AgRP) 神经元在新生、青少年和成年小鼠的进食和非进食行为中具有关键作用，表明它们对大脑功能具有广泛的调节作用。在这里，我们表明 AgRP 神经元的本构性损伤或其围青春期化学遗传学抑制导致小鼠内侧前额叶皮层 (mPFC) 中神经元的数量和功能减少。这些变化伴随着 mPFC 中振荡网络活动的改变、感觉运动门控受损和动态行为改变，这些可以通过服用非选择性多巴胺受体拮抗剂氯氮平来逆转。观察到的 AgRP 效应部分通过腹侧被盖区的多巴胺能神经元转导至 mPFC，也可能由内侧丘脑神经元传递。我们的研究结果揭示了下丘脑 AgRP 神经元在发育和成年期间控制调节高级脑功能的神经元通路的先前未被怀疑的作用。