Department of Biological Sciences, Human and Evolutionary Biology Section, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Institute of Diabetes, Obesity and Metabolism, Graduate Groups of Psychology and Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA.
Curr Biol. 2020 Nov 16;30(22):4510-4518.e6. doi: 10.1016/j.cub.2020.08.069. Epub 2020 Sep 17.
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 [2-5]. 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.
迷走传入神经元（VAN）信号将来自肠道的信息发送到大脑，并在控制进食行为和代谢中起着至关重要的作用[1]。最近的发现表明，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（HPC）依赖性记忆[2-5]。VAN 位于结状神经节，表达各种源自肠道的肽信号受体；然而，这些受体在进食行为、代谢和记忆控制方面的功能知之甚少。我们假设，通过与表达于肠道传入 VAN 的受体（GHSR）进行通讯，源自胃的食欲激素ghrelin 会影响 VAN 介导的过程。为了检验这一假设，大鼠接受了表达短发夹 RNA（shRNA）靶向 GHSR 的腺相关病毒（AAV）（或对照 AAV）的结状神经节注射，以进行 RNAi 介导的 VAN 特异性 GHSR 敲低。结果表明，与对照相比，VAN GHSR 敲低会引起各种进食和代谢紊乱，包括增加进食频率、葡萄糖耐量受损、胃排空延迟以及体重增加。此外，VAN 特异性 GHSR 敲低会损害 HPC 依赖性情景性 episodic 记忆并降低 HPC 脑源性神经营养因子表达，但不会影响焦虑样行为或一般活动水平。VAN GHSR 信号的内源性作用进一步通过以下结果得到证实：在黑暗开始时给予 ghrelin 会引起过度摄食，而肠道限制的 ghrelin 引起的 VAN 放电率增加需要完整的 VAN GHSR 表达，这表明 VAN 信号是必需的。集体研究结果表明，VAN GHSR 信号对于正常的进食和代谢功能以及 HPC 依赖性记忆都是必需的。
