CNS CONTROL OF GASTROINTESTINAL FUNCTION

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This proposal sets forth plans for the study of the dorsal motor nucleus of the vagus (DMV), the single most important group of neurons in the brain for the control of gastrointestinal (G.I.) function. To understand how the brain exerts control over G.I. function, it is mandatory to understand how neurons in the DMV "operate" in terms of their intrinsic membrane currents and in terms of how they respond to incoming signals, and convey specific information to targeted areas of the G.I. tract. During the previous grant we have used whole cell patch-clamp recordings of single DMV neurons of the rat brain slice preparation to document the presence and distribution of ionic currents, especially hyperpolarization- activated currents I/H and I/XIR, and how the electrophysiological properties of DMV neurons are influenced by neuroactive substances (e.g. TRH, 5-HT, nitric oxide, norepinephrine, nicotine). We have established the existence of a glutamatergic neural pathway from the commissural sub- nucleus of the nucleus tractus solitarius (comNTS), and are in the process of describing how the DMV receives incoming signals form blood-borne chemicals in the area postrema (AP). Studies proposed in this continuing renewal application will build on our thesis that neurons of the DMV are functionally heterogenous and this is largely due to the specific array of intrinsic membrane currents contained within them. Our recent work has documented that neurons in the medial aspect of the DMV exhibit a more than 2-fold faster firing rate than neurons in the lateral aspect of the DMV. The reason(s) for this, the significance of differences in firing rate in response to incoming signals, and the peripheral targets affected by "fast" and "slow" discharging DMV neurons will be explored. Our hypothesis is that the different firing rates is due to the non-uniform distribution of I/H, I/XIR and the after depolarization current, I/AHP, in the medial and lateral column neurons. Work of others suggests that the I/KATP channel is also distributed non-uniformly among DMV neurons, and our hypothesis is that this channel is associated with medial column DMV neurons rather than lateral column neurons, and the presence of the I/KATP channel determines whether DMV neurons respond to blood-borne substances such as glucose. While our proposal is focused on comparing the electrophysiological behavior of medial and lateral column DMV neurons, we will also compare DMV neurons containing both acetylcholine and dopamine in the medial column with neurons in the medial column and do not contain dopamine. Furthermore, DMV neurons that do not exist the brain with the vagus will be compared electrophysiologically with those DMV neurons that do exist the brain with the vagus. Finally, we will determine whether findings made from the in vitro brain slice preparation can be confirmed and extended in an in vivo rat model. Our overall goal is to understand how information processing occurs in the DMV, and to relate this knowledge to how the brain controls G.I. function in health and disease.