Vagal afferent neuron (VAN) signaling sends information from the gut to the brain and is fundamental in the control of feeding behavior and metabolism [1]. Recent findings reveal that VAN signaling also plays a critical role in cognitive processes, including affective motivational behaviors and hippocampus (HPC)-dependent memory [2, 3, 4, 5]. VANs, located in nodose ganglia, express receptors for various gut-derived peptide signals; however, the function of these receptors with regard to feeding behavior, metabolism, and memory control is poorly understood. We hypothesized that VAN-mediated processes are influenced by ghrelin, a stomach-derived orexigenic hormone, via communication to its receptor (GHSR) expressed on gut-innervating VANs. To examine this hypothesis, rats received nodose ganglia injections of an adeno-associated virus (AAV) expressing short hairpin RNAs targeting GHSR (or a control AAV) for RNAi-mediated VAN-specific GHSR knockdown. Results reveal that VAN GHSR knockdown induced various feeding and metabolic disturbances, including increased meal frequency, impaired glucose tolerance, delayed gastric emptying, and increased body weight compared to controls. Additionally, VAN-specific GHSR knockdown impaired HPC-dependent contextual episodic memory and reduced HPC brain-derived neurotrophic factor expression, but did not affect anxiety-like behavior or general activity levels. A functional role for endogenous VAN GHSR signaling was further confirmed by results revealing that VAN signaling is required for the hyperphagic effects of ghrelin administered at dark onset, and that gut-restricted ghrelin-induced increases in VAN firing rate require intact VAN GHSR expression. Collective results reveal that VAN GHSR signaling is required for both normal feeding and metabolic function as well as HPC-dependent memory.

迷走神经传入神经元 (VAN) 信号将信息从肠道发送到大脑，是控制进食行为和新陈代谢的基础 [1]。最近的研究结果表明，VAN 信号在认知过程中也起着关键作用，包括情感动机行为和海马体 (HPC) 依赖性记忆 [2、3、4、5]。VANs 位于结状神经节，表达各种肠道衍生肽信号的受体；然而，人们对这些受体在进食行为、新陈代谢和记忆控制方面的功能知之甚少。我们假设 VAN 介导的过程受到 ghrelin 的影响，ghrelin 是一种胃源性促食激素，通过与其在肠道神经 VAN 上表达的受体 (GHSR) 的通讯。为了验证这个假设，大鼠接受腺相关病毒 (AAV) 的结状神经节注射，该病毒表达靶向 GHSR（或对照 AAV）的短发夹 RNA，用于 RNAi 介导的 VAN 特异性 GHSR 敲低。结果表明，与对照组相比，VAN GHSR 敲低会导致各种进食和代谢紊乱，包括进餐频率增加、葡萄糖耐量降低、胃排空延迟和体重增加。此外，VAN 特异性 GHSR 敲低损害了 HPC 依赖性情景情景记忆并降低了 HPC 脑源性神经营养因子表达，但不影响焦虑样行为或一般活动水平。结果进一步证实了内源性 VAN GHSR 信号的功能作用，结果表明 VAN 信号是在黑暗开始时施用的生长素释放肽的过度吞噬作用所必需的，并且肠道限制性生长素释放肽诱导的 VAN 放电率增加需要完整的 VAN GHSR 表达。综合结果表明，正常进食和代谢功能以及 HPC 依赖性记忆都需要 VAN GHSR 信号。