Biddinger Jessica E, Elson Amanda E T, Fathi Payam A, Sweet Serena R, Nishimori Katsuhiko, Ayala Julio E, Simerly Richard B
bioRxiv. 2024 Jun 3:2024.06.02.592838. doi: 10.1101/2024.06.02.592838.
During postnatal life, the adipocyte-derived hormone leptin is required for proper targeting of neural inputs to the paraventricular nucleus of the hypothalamus (PVH) and impacts the activity of neurons containing agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Activity-dependent developmental mechanisms are known to play a defining role during postnatal organization of neural circuits, but whether leptin-mediated postnatal neuronal activity specifies neural projections to the PVH or impacts downstream connectivity is largely unexplored. Here, we blocked neuronal activity of AgRP neurons during a discrete postnatal period and evaluated development of AgRP inputs to defined regions in the PVH, as well as descending projections from PVH oxytocin neurons to the dorsal vagal complex (DVC) and assessed their dependence on leptin or postnatal AgRP neuronal activity. In leptin-deficient mice, AgRP inputs to PVH neurons were significantly reduced, as well as oxytocin-specific neuronal targeting by AgRP. Moreover, downstream oxytocin projections from the PVH to the DVC were also impaired, despite the lack of leptin receptors found on PVH oxytocin neurons. Blocking AgRP neuron activity specifically during early postnatal life reduced the density of AgRP inputs to the PVH, as well as the density of projections from PVH oxytocin neurons to the DVC, and these innervation deficits were associated with dysregulated autonomic function. These findings suggest that postnatal targeting of descending PVH oxytocin projections to the DVC requires leptin-mediated AgRP neuronal activity, and represents a novel activity-dependent mechanism for hypothalamic specification of metabolic circuitry, with consequences for autonomic regulation.
Hypothalamic neural circuits maintain homeostasis by coordinating endocrine signals with autonomic responses and behavioral outputs to ensure that physiological responses remain in tune with environmental demands. The paraventricular nucleus of the hypothalamus (PVH) plays a central role in metabolic regulation, and the architecture of its neural inputs and axonal projections is a defining feature of how it receives and conveys neuroendocrine information. In adults, leptin regulates multiple aspects of metabolic physiology, but it also functions during development to direct formation of circuits controlling homeostatic functions. Here we demonstrate that leptin acts to specify the input-output architecture of PVH circuits through an activity-dependent, transsynaptic mechanism, which represents a novel means of sculpting neuroendocrine circuitry, with lasting effects on how the brain controls energy balance.
在出生后的生命过程中，脂肪细胞衍生的激素瘦素对于神经输入正确靶向下丘脑室旁核（PVH）是必需的，并且会影响下丘脑弓状核中含有刺鼠相关肽（AgRP）的神经元的活性。已知活动依赖性发育机制在神经回路的出生后组织过程中起决定性作用，但瘦素介导的出生后神经元活动是否确定了向PVH的神经投射或影响下游连接性在很大程度上尚未得到探索。在这里，我们在出生后的一个离散时期阻断了AgRP神经元的活动，并评估了AgRP向PVH中特定区域的输入的发育情况，以及从PVH催产素神经元到背迷走神经复合体（DVC）的下行投射，并评估了它们对瘦素或出生后AgRP神经元活动的依赖性。在瘦素缺乏的小鼠中，AgRP向PVH神经元的输入显著减少，以及AgRP对催产素特异性神经元的靶向作用也减弱。此外，尽管在PVH催产素神经元上未发现瘦素受体，但从PVH到DVC的下游催产素投射也受损。在出生后早期特异性阻断AgRP神经元活动会降低AgRP向PVH的输入密度，以及从PVH催产素神经元到DVC的投射密度，并且这些神经支配缺陷与自主神经功能失调有关。这些发现表明，出生后PVH催产素向DVC的下行投射的靶向需要瘦素介导的AgRP神经元活动，并且代表了一种新的活动依赖性机制，用于下丘脑对代谢回路的特化，对自主神经调节有影响。
下丘脑神经回路通过协调内分泌信号与自主反应和行为输出以维持体内平衡，以确保生理反应与环境需求保持一致。下丘脑室旁核（PVH）在代谢调节中起核心作用，其神经输入和轴突投射的结构是其接收和传递神经内分泌信息方式的一个决定性特征。在成年人中，瘦素调节代谢生理学的多个方面，但它在发育过程中也发挥作用，以指导控制体内平衡功能的回路的形成。在这里，我们证明瘦素通过一种活动依赖性跨突触机制来确定PVH回路的输入 - 输出结构，这代表了一种塑造神经内分泌回路的新方式，对大脑控制能量平衡的方式有持久影响。
