BRAINSTEM CIRCUITS CONTROLLING GASTROINTESTINAL FUNCTION

点击翻译按钮获取中文摘要

DESCRIPTION: The nucleus of the tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) are essential components of a circuit responsible for the coordination of vago-vagal reflexes such as gastric receptive relaxation and the ileal brake. Recently, it has been proposed that there are discreet nodes where sensory information is transmitted from specific neurons in the NTS to distinct populations of DMV neurons. Though this concept has been discussed and examined by a number of investigators, there is no electrophysiologic evidence to support it, likely because of substantial technical difficulties associated with any in vivo experiments that would attempt to determine the interactions between individual NTS and DMV neurons. On the other hand, slice paradigms are ideally suited to this type of investigation. The studies we describe in this application are based on the following hypotheses: Hypothesis 1: The NTS-DMV circuitry is organized in a manner that allows specific neurons in the NTS to interact with selected neuronal subsets in the DMV. In particular, we propose that neurons in the medial DMV receive a fast excitatory input from neurons in the cen-NTS (an interactions that could provide the anatomical substrate for the receptive relaxation reflex), while neurons in the lateral DMV receive a "slower or longer lasting inhibitory input from neurons in the com-NTS (an interaction that could play a role in the ileal brake phenomenon). Hypothesis 2: The medullary raphe nuclei integrate GI reflex activity by providing a selective modulation of NTS-DMV synapses. It is proposed that this modulation is accomplished by medullary raphe neurons that excite of subset of DMV neurons and/or inhibit a subpopulation of NTS neurons via the release of 5-HT, TRH and/or SP. The hypotheses will be tested using whole cell patch clamp recordings in brainstem slices that include the NTS, the DMV and the raphe nuclei. The slices will be taken from rats that have undergone placement of fluorescent tracers in isolated branches of the subdiaphragmatic vagus nerve or select regions of the GI tract. This protocol will label a subset of the terminals of visceral afferents that terminate on NTS neurons as well as the somata of DMV neurons that project to the region of the GI tract that received the injection of the fluorescent tracer. Synaptic currents and potentials will be evoked from the NTS and will be recorded in DMV and/or NTS; the modulation of the DMV-NTS synapses will be analyzed upon stimulation of the adjacent raphe medullary nuclei and upon perfusion with 5-HT, TRH and/or SP. Data obtained from pursuing these specific aims will reveal the synaptic currents underlying the behavior of discrete NTS and DMV neuronal populations. Furthermore, the fundamental circuitry of the vago-vagal reflex will be elucidated. These data will increase our understanding of how the interaction between NTS and DMV neurons can result in the pattern of neuronal activity controlling vago-vagal reflexes such as gastric receptive relaxation and ileal brake.