The endocrine part of the pancreas plays a central role in blood-glucose regulation. It is well established that an elevation of glucose concentration reduces secretion of the hyperglycaemia-associated hormone glucagon from pancreatic alpha 2 cells. The mechanisms involved, however, remain unknown. Electrophysiological studies have demonstrated that alpha 2 cells generate Ca2+-dependent action potentials. The frequency of these action potentials, which increases under conditions that stimulate glucagon release, is not affected by glucose or insulin. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is present in the endocrine part of the pancreas at concentrations comparable to those encountered in the central nervous system, and co-localizes with insulin in pancreatic beta cells. We now describe a mechanism whereby GABA, co-secreted with insulin from beta cells, may mediate part of the inhibitory action of glucose on glucagon secretion by activating GABAA-receptor Cl- channels in alpha 2 cells. These observations provide a model for feedback regulation of glucagon release, which may be of significance for the understanding of the hypersecretion of glucagon frequently associated with diabetes.
With an antibody specific for L-histidine decarboxylase (HD) in combination with immunohistochemical techniques and retrograde fluorescent tracing, the morphology, distribution, and projections of the histaminergic neurons of the posterior hypothalamus were studied in the adult male rat. Magnocellular neurons, situated on both sides of the mammillary recess and close to the ventral surface of the brain rostral and caudal to the mammillary bodies, were found to contain HD-immunoreactivity (HD-i). In addition to these magnocellular neurons, a substantial number of small and medium-sized neurons were immunostained, as were strands of cells of all sizes bridging the HD-i cell groups. A detailed mapping of the HD-i cells in frontal, sagittal, and horizontal sections showed that these neurons make up one continuous cell group, defined as the tuberomammillary nucleus (TM). This nucleus can be divided into several subgroups. Thus, approximately 600 HD-i neurons situated on each side of the mammillary recess compose the medial subgroup of the TM (TMM). The ventral subgroup of the TM (TMV) consists of some 1,500 neurons situated at the ventral surface of the brain, rostral (TMVr) and caudal (TMVc) to the mammillary bodies. The TMM contains a greater proportion of parvicellular neurons compared to the TMV. About 100 HD-i cells are scattered within the lateral hypothalamic area, the posterior hypothalamic region, the perifornical area, the supramammillary nucleus, and the dorsomedial hypothalamic nucleus. These cells are collectively named the diffuse part of the TM (TMdiff). The morphological differences between the TMM and the TMV did not signal differences in the efferent connections of these subgroups. Thus, single injections of the fluorescent tracer Fast Blue into different regions of the brain, including the spinal cord, resulted in retrograde labeling of HD-i neurons, which were distributed throughout the TM with no discernible topographic pattern. More specifically, each subgroup of the TM contributed projections innervating or passing through a large number of brain regions, including the olfactory bulb, hippocampus, caudate nucleus, paraventricular and supraoptic nuclei of the hypothalamus, cerebellum, tectum, medulla, and spinal cord. The widespread projections of the HD-i neurons contrasted to the more specific projections observed from non HD-i neurons in cell groups situated around the TM. Taken together, these findings suggest that the HD-i cells of the posterior hypothalamus constitute one major nucleus, the TM, and that this nucleus may be subdivided into three components, each of which has diffuse projections throughout the neuraxis.
The excitatory amino acid, L-glutamate, acting through its N-methyl-D-aspartate (NMDA) receptor, may contribute to neuronal death following cerebral vascular occlusion. In support of this hypothesis, NMDA receptor antagonists reduce the volume of infarction produced by occlusion of the middle cerebral artery in vivo and attenuate Ca2+ influx and neuronal death elicited by L-glutamate or NMDA in vitro. A complementary DNA coding for a major component of the NMDA receptor channel complex, a single protein of M(r) 105.5K (NMDA-R1), has been isolated from rat brain. Here we demonstrate that inhibition of the synthesis of NMDA-R1 by treatment with antisense oligodeoxynucleotides selectively reduces the expression of NMDA receptors, prevents the neurotoxicity elicited by NMDA in vitro and reduces the volume of the focal ischaemic infarction produced by occlusion of the middle cerebral artery in the rat.
The origin of afferent connections of the hypothalamic tuberomammillary nucleus has been examined by using retrograde and anterograde tracing techniques. Retrogradely labeled neurons were found in about 70 cell groups of the forebrain and brainstem after injection of tracer into the ventral subgroup of the tuberomammillary nucleus. The majority of the labeled neurons were seen in the forebrain, with particularly large numbers in the infralimbic cortex, lateral septal nucleus, and preoptic region. The anterograde tracing experiments supported the general results of the retrograde tracing experiments. However, we did not observe any single cell group that selectively projected to the cell-rich core of the nucleus. In general, only a few fibers entered the core, whereas many labeled fibers seemed to terminate immediately adjacent to the cell group. Thus the target for the afferents is not primarily the perikarya of the neurons of the tuberomammillary nucleus, but either dendrites radiating out from the nucleus or neurons not belonging to the tuberomammillary nucleus. The results of the present study demonstrate that the histaminergic tuberomammillary nucleus derives its main input from the limbic forebrain. Through their widespread projections, the histaminergic neurons may transmit information originating from the limbic system to most if not all parts of the brain.
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