J.C. Orsini

Characteristics of glycemia-sensitive neurons in the nucleus tractus solitarii: Possible involvement in nutritional regulation

Single unit responses to moderate glycemic variations were extracellularly recorded in the caudal division of the nucleus tractus solitarii of rats anesthetized by i.v. infusion of ketamine. As previously observed, a majority of recorded neurons (70%) were either activated or depressed by moderate hyperglycemia. Responses were consistently reproducible and amplitude was dependent on the maximum level of hyperglycemia. All glycemia-sensitive neurons responded in opposite directions to induced hyperglycemia and hypoglycemia, and almost all displayed the same type of response to local and i.v. glucose administration. Most glycemia-sensitive neurons were depressed by iontophoresis of clonidine, suggesting that they were adrenergic or noradrenergic. Based on these findings, we speculate that glycemia-sensitive neurons in the caudal nucleus tractus solitarii may act as glucose sensors that transmit glycemic information corresponding to different nutritional states, as well as other relevant signals toward hypothalamic structures involved in feeding and metabolic regulation via ascending adrenergic and noradrenergic pathways.

Solitary tract nucleus sensitivity to moderate changes in glucose level.

Many neurons in the caudal nucleus tractus solitarii (NTS) recorded in vivo respond to moderate glycemic fluctuations through the local action of glucose molecules. To investigate this sensitivity in vitro, the extracellular activity of 112 neurons was recorded in hindbrain slices: 57 changed in firing rate when the glucose level in the bathing medium was increased by 2 mM. Since the glucose-responding neurons were located in catecholaminergic regions and depressed by the alpha-2 adrenoceptor agonist clonidine, they were likely to be adrenergic or noradrenergic. A comparison of the responses to glucose and 2-deoxy-D-glucose suggested that the bioenergetic metabolism is involved in NTS sensitivity to glucose.

Involvement of adenosine triphosphate-sensitive K+ channels in glucose-sensing in the rat solitary tract nucleus

The presence of adenosine triphosphate-sensitive (ATP-sensitive) K+ channels (K(ATP) channels) in the caudal nucleus tractus solitarii (NTS), and their possible involvement in glucose-sensing, were assessed by extracellular recording of neuronal activity in rat hindbrain slices. In 21 out of 36 recorded cells, firing was increased by sulfonylureas and decreased by K+ channel opener (KCO), indicating the existence of K(ATP) channels in the caudal NTS. In seven out of the nine neurons activated by a 2 mM increase in the glucose level, the effects of sulfonylureas and KCO were consistent with the involvement of K(ATP) channels in the glucose response. Conversely, the mechanism(s) underlying the response of glucose-depressed neurons remains to be clarified. Finally, the presence of K(ATP) channels was also detected in some neurons that were unresponsive to a 2 mM change in the glucose level. Thus, K(ATP) channels were pharmacologically identified in the caudal NTS, where they may be partly involved in glucose sensing.

Changes in lateral hypothalamic neuronal activity accompanying hyper- and hypoglycemias

Blood glucose level and forebrain unit activity were simultaneously recorded in rats anesthetized with a ketamine IV infusion. Slight and transient fluctuations in glycemia, occurring either spontaneously or after IV injections of glucose or phlorizin, were observed. The spike frequency of more than 1/3 of the neurons tested in the lateral hypothalamic area was affected by these fluctuations. A majority of the responsive cells displayed either an activation during hypoglycemia or a depression during hyperglycemia. These neurons might mediate the effects of a drop in blood glucose on either meal initiation or neuroendocrine or autonomic events related to nutritional functions.

Sensitivity of nucleus tractus solitarius neurons to induced moderate hyperglycemia, with special reference to catecholaminergic regions

Extracellular single-unit recordings have been carried out in the caudal part of the nucleus tractus solitarius of male rats anesthetized by i.v. infusion with Ketamine. The sensitivity of 38 cells to 0.2 ml of 0.55 M glucose i.v. administration has been studied. The spike frequency of 75% of these cells was affected by the induced moderate hyperglycemia and a majority of them was activated. Immunohistochemical data on 9 glycemia-sensitive neurons showed that all recording sites were within TH-immunoreactive regions of the caudal part of the nucleus (either in the A2 noradrenergic group, or the C2 adrenergic group). These results confirm the existence of glycemia-sensitive neurons in the nucleus tractus solitarius, and suggest that these cells might mediate the effects of physiological fluctuations in blood glucose level on the control of food intake and metabolic regulations. The localization of these cells in catecholaminergic regions suggests that adrenaline and/or noradrenaline efferents might convey feeding relevant information concerning glycemic level or satiety signal from the nucleus tractus solitarius to forebrain structures involved in food intake, such as the perifornical lateral hypothalamic area and the paraventricular nucleus.

Neuronal responses to cannabinoid receptor ligands in the solitary tract nucleus

Our previous study showed many neurons in the subpostremal division of the nucleus tractus solitarii to be cannabinoid-sensitive. In order to further investigate this sensitivity, single unit activity was recorded extracellularly in rat hindbrain slices, and the effects of bath application of delta9-tetrahydrocannabinol and of two synthetic cannabinoid receptor agonists were analysed and compared to each other. Approximately half the recorded neurons responded to agonists, and most of the neurons exposed to two of the agonists reacted similarly to both. The involvement of cannabinoid CB receptors in neuronal sensitivity to delta9-tetrahydrocannabinol is supported by these data and by the effects of N-piperidin-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-p yrazole-carboxamide, hydrochloride (SR 141716A), a compound which is considered to be a selective antagonist and/or a selective inverse agonist of this receptor type.

Neuronal responses to Δ9-tetrahydrocannabinol in the solitary tract nucleus

Abstract The effects of Δ 9 -tetrahydrocannabinol on single-unit activity in the subpostremal division of the nucleus tractus solitarii were investigated by extracellular recording in rat brain slices. The spontaneous firing rate of 54.8% of the recorded neurons was significantly changed after bath applications of Δ 9 -tetrahydrocannabinol. Putative nutrition-related neurons responding to a moderate increase in glucose concentration were selectively sensitive to Δ 9 -tetrahydrocannabinol. The Δ 9 -tetrahydrocannabinol-sensitive neurons were depressed by clonidine and are therefore likely to be adrenergic or noradrenergic. These observations suggest that some catecholaminergic, glucose-responsive neurons in the subpostremal nucleus tractus solitarii might mediate the influence of cannabinoids on feeding behaviour. Furthermore, most Δ 9 -tetrahydrocannabinol-sensitive neurons in the nucleus tractus solitarii showed opposite responses to Δ 9 -tetrahydrocannabinol and the 5-HT 3 receptor agonist 1-phenylbiguanide, and might therefore be involved in the nausea-reducing effects of cannabinoids.

Catecholaminergic projections from the solitary tract nucleus to the perifornical hypothalamus

The source of adrenergic and other catecholaminergic fibers innervating the perifornical lateral hypothalamus was localized in the medulla after combination of Fluoro-Gold retrograde tracing and immunohistochemistry for either tyrosine-hydroxylase or phenylethanolamine-N-methyltransferase. Following perifornical injections, Fluoro-Gold-labeled neurons were observed mainly in regions including the noradrenergic and adrenergic cell groups. In the caudal solitary tract nucleus, two kinds of doubly labeled neurons were found: a) numerous noradrenergic neurons in the A2 group at the level of, or caudal to the area postrema; b) some adrenergic neurons in the C2 group at a level immediately rostral to the area postrema. These catecholaminergic neurons connecting the caudal solitary tract nucleus to the perifornical hypothalamus might convey feeding relevant information such as glycemic level or satiety signals.

BASIC-language software for simultaneous monitoring of blood glucose level and neuronal firing frequency

We have designed software for an Apple II GS microcomputer allowing simultaneous on-line monitoring of blood glucose level and neuronal firing frequency in experimental rats. Blood glucose level in the carotid blood was continuously measured by a glucose analyzer and digitized through an A/D board. The firing rate of a brain neuron, recorded by a classical technique, was counted by a versatile interface adapter. Both parameters are graphically displayed on the screen. They can also be exported to another computer for off-line analysis. This software is adaptable to other experimental applications in electrophysiology, involving the monitoring of glycemia or other biological parameters.

Neuronal responses to systemic nicotine in the solitary tract nucleus : Origin and possible relation with nutritional effects of nicotine

Single-unit activity was recorded extracellularly in the caudal part of the solitary tract nucleus of anesthetized rats. Of 60 recorded neurons, 44 (73.3%) responded to intravenous (I.V.) nicotine. The incidence of response was significantly greater in the cells sensitive to moderate changes in blood glucose level, suggesting that the effects of nicotine on food intake and body weight are partly mediated by the glycemia-sensitive neurons in the caudal nucleus tractus solitarius. Only one-fourth of the neurons affected by I.V. nicotine responded in the same direction to iontophoretic nicotine application, suggesting that sensitivity to systemic nicotine results mainly from an indirect mechanism. Based on the observed effects of nicotinic agonists and antagonists unable to cross the blood-brain barrier, a majority of indirect unit responses to I.V. nicotine might be mediated by peripheral receptors, while the remaining ones might involve central or both central and peripheral receptors.