Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37232.
Developmental Neuroscience Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027.
Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2403810121. doi: 10.1073/pnas.2403810121. Epub 2024 Nov 25.
During postnatal life, leptin specifies neuronal inputs to the paraventricular nucleus of the hypothalamus (PVH) and activates agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus. Activity-dependent developmental mechanisms impact refinement of sensory circuits, but whether leptin-mediated postnatal neuronal activity specifies hypothalamic neural projections is largely unexplored. Here, we used chemogenetics to manipulate the activity of AgRP neurons during a discrete postnatal critical period and evaluated the development of AgRP inputs to the PVH and descending efferent outflow to the dorsal vagal complex (DVC). In leptin-deficient mice, targeting of AgRP neuronal outgrowth to PVH oxytocin neurons was reduced, and despite the lack of leptin receptors found on oxytocin neurons in the PVH, oxytocin-containing connections to the DVC were also impaired. Activation of AgRP neurons during early postnatal life not only normalized AgRP inputs to the PVH but also oxytocin outputs to the DVC in leptin-deficient mice. Blocking AgRP neuron activity during the same postnatal period reduced the density of AgRP inputs to the PVH of wild type mice, as well as the density of oxytocin-containing DVC fibers, and these innervation deficits were associated with dysregulated autonomic function. These findings suggest that leptin-mediated AgRP neuronal activity is required for the development of PVH connectivity and represents a unique activity-dependent mechanism for specification of neural pathways involved in the hypothalamic integration of autonomic responses.
在出生后生命期间，瘦素指定下丘脑室旁核（PVH）的神经元输入，并激活下丘脑弓状核中的 AgRP 神经元。依赖活动的发育机制影响感觉回路的细化，但瘦素介导的出生后神经元活动是否指定下丘脑神经投射在很大程度上尚未探索。在这里，我们使用化学遗传学在离散的出生后关键期期间操纵 AgRP 神经元的活动，并评估 AgRP 输入到 PVH 和向背侧迷走复合体（DVC）的下行传出的发育。在瘦素缺乏的小鼠中，AgRP 神经元生长到 PVH 催产素神经元的靶向减少，尽管在 PVH 中的催产素神经元上未发现瘦素受体，但催产素与 DVC 的连接也受损。在出生后早期激活 AgRP 神经元不仅使 AgRP 输入到 PVH 正常化，而且使瘦素缺乏的小鼠中的催产素输出到 DVC 正常化。在同一出生后期间阻断 AgRP 神经元活动会降低野生型小鼠 PVH 中的 AgRP 输入密度，以及含有催产素的 DVC 纤维的密度，并且这些神经支配缺陷与自主功能失调有关。这些发现表明，瘦素介导的 AgRP 神经元活动是 PVH 连接发育所必需的，并且代表了涉及自主反应的下丘脑整合的神经通路的独特的依赖活动的机制。
