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Neural network of glucose monitoring system
Journal of the Autonomic Nervous System, 10 (1984) 359-372 Elsevier
359
JAN 00360
Neural network of glucose monitoring system Yutaka Oomura and Hironobu Yoshimatsu Department of Physiology, Faculty of Medicine, Kyushu University 60, Fukuoka 812 (Japan) (Received September 20th, 1983) (Accepted February 10th, 1984)
Key words: glucose sensor - - hypothalamus - - autonomic nerve -- pancreas -lateral hypothalamic area -- ventromedial hypothalamic nucleus -nucleus of the solitary tract
Abstract
Glucose-sensitive neural elements exist in the hypothalamus, the nucleus of the solitary tract (NTS) and autonomic afferents from visceral organs such as liver and gastrointestinal tract. Glucose affects neural activity through these central and peripheral chemosensors. Glucose is generally suppressive in the liver, the NTS and the lateral hypothalamic area (LHA), and generally excitatory in the small intestine and ventromedial hypothalamic nucleus (VMH). The hypothalamus is involved in the control of pancreatic hormone secretion through autonomic efferent nerves. Stimulation or lesion of the hypothalamus induces various changes in pancreatic autonomic nerve activity. The VMH, the dorsomedial hypothalamic nucleus and the paraventricular nucleus have inhibitory effects on vagal nerve activity and excitatory effects on splanchnic nerve activity. The LHA is excitatory to the vagal nerve, and both excitatory and inhibitory to the splanchnic nerve. These findings suggest that the neural network of the glucose monitoring system, which also analyzes and integrates information concerning other metabolites and peptides in the blood and cerebrospinal fluid, contributes to regulation of peripheral metabolism and endocrine activity as well as feeding behavior. The physiological function and input-output organization of this network are discussed.
Correspondence: Y. Oomura, Dept, of Physiology, Faculty of Medicine, Kyushu University 60, Fukuoka 812, Japan. 0165-1838/84/$03.00 © 1984 Elsevier Science Publishers B.V.
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Introduction The hypothalamus is involved in the control of feeding behavior. Hypothalamic chemosensitive neurons [33] monitor changes in endogenous materials in the blood and cerebrospinal fluid (CSF). A recent study indicates the existence of other monitoring systems outside the hypothalamus such as the nucleus of the solitary tract (NTS) and autonomic afferents from visceral organs [26,29,42]. These monitoring systems, which receive information about metabolites and peptides in the blood and CSF, contribute to feeding behavior. The blood glucose level is maintained constant by insulin, glucagon and catecholamine released from the pancreas and adrenal gland. Secretion of these hormones is considered to be modulated through the autonomic nervous system. This monitoring system also plays an important role in the regulation of peripheral metabolism and endocrine activity by integrating and feeding back information received in the hypothalamus, and other central and peripheral sensors.
(1) Hypothalamie ~ a s o r s Hypothalamic glucose-responsive neurons The existence of glucose-responsive neurons in the lateral hypothalamic area (LHA) and ventromedial hypothalamic nucleus (VMH) was first demonstrated by systemic glucose application. Electrophoretic application of glucose directty on neurons within the hypothalamus delineated those populations of neurons in the hypothalamus that respond to glucose. Glucose-sensitive (GS) neurons in the LHA have their activity suppressed by glucose applied directly to t h ~ surfaces. In the LHA, 20-25~ of the neurons are glucose-sensitive and these are localized in the ventral portion [32,37]. Intracdlular recordings from GS neurons show that the suppressive effect of glucose is a result of hyperpola~'~zation of the membrane without change in the membrane conductance, This is induced by activating the electrogenic Na pump [37]. Glucoreceptor (GR) neurons in the VMH have been defined as those which increase in activity in a dose-responsive manner upon application o f ~ [33,34]. Application of fresh rat VM~ antibody to VMH GR neurons produced large transient activity increase followed by irreversible cessation [34]. This suggests that VMH GR neurons have specific membrane receptor sites. Most of these glucose-respomive neurons are also affected by other blood-borne metabolites and peptides such as free fatty acids (FFA), insulin and glucagon. It is interesting that all of these substances which affect glucose,respons/ve neuron activity have also been shown to influence feeding behavior in~one way or another. Insulin Activity of GR neurons in the VMH is slightly inhibited by insulin alone, but is facilitated by simultaneous application of insulin ami.glacos¢ mine than by alone. Activity of GS neurons in the LHA is facilitated by insulin in a d o ~ -
361 dent manner [39]. Insulin-induced feeding is inhibited by injection of glucose directly into the rat LHA and is also prevented by LHA lesion. These results are consistent with the characteristics of GS neurons in the LHA. Insulin binding sites in the brain have been identified [10,35,44]. They are abundant in the hypothalamus and unaffected by peripheral insulin concentration. The stability of insulin and its binding sites in the brain suggests that constant brain insulin might provide a constant control point against which other materials such as glucose are compared in order to control body weight.
Glucagon Glucagon-like immunoreactivity (GLI) has been identified in the brain although immunoreactive pancreatic glucagon (IRG) was not found in any of the brain regions [13,36,54]. Nerve fibers that reacted with anti-GLI antibody were found in the periventricular region, paraventricular nucleus (PVN), supraoptic nucleus, anterior hypothalamus, dorsomedial hypothalamic nucleus (DMH) and VMH [13,36]. GLI concentration in the VMH has been reported to rise to 1.5 times the control level while it did not change significantly in the LHA during 48 h of deprivation [13]. Intracerebroventricular administration of glucagon causes hyperglycemia and suppresses insulin secretion [1]. There is a possibility that GLI in the brain is related to sugar metabolism as well as to feeding behavior. Neuronal activity of LHA and VMH neurons was recorded during electrophoretic application of glucagon. Glucagon suppressed the activity of GS neurons in the LHA significantly and of G R neurons in the VMH occasionally [13,38]. GLI originating in the brain may act as an inhibitory neurotransmitter or neuromodulator in the hypothalamus.
(II) Glucose responsive sites outside the hypothalamus
Peripheral glucose sensors There are glucose sensors in the liver which affect vagal afferent nerve fiber activity. These hepatic GS units decrease the discharge rate of vagal afferents when glucose is injected into the hepatic portal vein [29]. Hepatic GS units may also influence the regulation of food intake. Intraportal injection of glucose reduces food consumption in proportion to the glucose concentration, and similar injection of 2-deoxy-D-glucose (2-DG) elicits feeding response [30,31]. The effect of intraportal injection of these substances can be blocked by subdiaphragmatic vagotomy [22]. Hepatic GS units increased in activity following administration of 2-DG into portal vein. Insulin increased and glucagon decreased their activity. These characteristics of hepatic GS units are similar to those of GS neurons in the LHA. To determine relationships between central and peripheral GS elements, changes in LHA neuronal activity due to glucose injections into the portal vein were investigated [50]. As shown in Fig. 1A, GS neurons in the LHA which decreased in activity upon direct application of glucose were also inhibited by portal glucose injections. This inhibition might be mediated through the noradrenaline (NA)
362 A
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Fig. 1. Inhibitory effect of hepatic portal glucose injection on GS neuron in rat LHA. A: continuous from upper to lower. Pulse counter record (discharges/5 s) of LHA neural activity in response to hepatic injection or electrophoretic application o f glucose (Gluc.). Application time represented by horizontal bars. Numbers refer to concentrations of injected solutions or electrophoretic current in n a n t e s (hA). Dose-related inhibitory response to both hepatic portal ( h / p ) injection and direct electrophoretic appficution of glucose is evident. During application of phenoxybenzamine (PBZ) to the neuron, the inhibitory effects due to hepatic portal injection of glucose and to electrophoretic application of NA, but not those due to electrophoretic application of glucose, were blocked. Injection of glucose into jugular vein (jv) had a slight effect. N o detectable reg~0n~ was sce~ when hypertonic saline (0.28 M, 0,3 ml) was injected through the portal vein. Control electrophoretic application of Na + had no effect, thus ruling out current or osmotic effects. B: poststimulus time histogram (PSTH) of discharl~e rate (same neuron as in A) produced by stimulation of ventral N A bundle (0.2 mA, 0.1 ms duration at 1 Hz). PSTH obtained from 200 trials with identical stimulus intensity. Stimulation inhibited neural activity of the neuron for about 20 ms [50].
pathway, since electrophoretic application of NA inhibited GS neuron activity, and tl-ds effect was blocked by applization of phenoxybenzamine (an a-adrenoreceptor blocking agent). In addition, stimulation of the ventral NA bundle inhibited the activity of GS neurons in the LHA (Fig. 1B) [25]. Thus most GS neurons in the LHA seem to receive facilitatory inputs from the hepatic vagal GS units. This afferent neural pathway may be mediated by the NTS and parabrachial nucleus (PBN) as described later. A number of experiments suggest the existence of gastrointestinal ~ e ~ ' p t o r s [23,49]. Glucose infusion into the ~ lumen has reduced food ~ from gastrointestinal glucose sensors are considered to be carried by v~,id~ ~ t s because the effect of glucose on food intake has been prevented by vagotomy [30]. Activity of the vagal afferents from the gastrointestinal tract increased following
363
perfusion of glucose through the canal. These vagal afferents from the gastrointestinal organs also project to the NTS as do those from the liver. N T S glucose-responsioe neurons
Recent study indicates that the NTS has glucose-responsive neurons [26]. In in vitro brain slice experiments, 162 neurons were tested. Among 89 neurons in the caudal NTS, 25 neurons (28%) were glucose-sensitive. There were 7 (8%) G R and 57 non-responsive neurons present in the same region. Of the 73 neurons tested in the rostral part, 8 (11%) were GS and 4 (5%) were G R (Fig. 2). More GS neurons are present in the caudal part of the NTS adjacent to the fourth ventricle, than in the rostral part. This nucleus also has connections with the area postrema which lacks the blood-brain barrier. Thus, chemosensitive neurons in the NTS could directly receive information related to glucose level in the blood a n d / o r cerebrospinal fluid, and also receive signals through vagal afferent nerves from visceral glucose sensors. Therefore, this nucleus might be considered to be an important relay point in the glucose analyzing pathway and to send integrated information to the hypothalamus. A
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Fig. 2. Chemoresponsive neurons in rat nucleus tractus solitarii (NTS). Brain-slice preparation (300/~m thick). A: non-glucose responsive neuron. No response to electrophoretic application of 2-deoxy-D-glucose (2-DG), glucose, or Na ions (Na). Dose-related facilitation by acetylcholine. B: glucose-sensitive neuron. Inhibited dose-responsively by glucose. Na had no effect. Facilitated dose-responsively by 2-DG. C: glucoreceptor neuron. Glucose facilitated and 2-DG inhibited slightly. Horizontal lines: time of electrophoretic application of chemicals expressed in nanoamperes (nA). Vertical calibrations: discharges/s [26].
364 (III) Hypothalamic regulation of the pancreatic autonomic nervous system
A number of studies have revealed that hypothalamic regulation of metabolism and the endocrine system including insulin, glucagon and catecholamine secretion might be mediated by the autonomic nervous system. However, stimulation or lesion of the hypothalamus could produce simultaneous effects on many organs such as the pancreas, liver and adrenal gland which all affect peripheral blood glucose level, so the physiological significance of the hypothalamus in regulating each organ related to glucose metabolism through the autonomic nervous system is still unknown. The effect of the autonomic output from the hypothalamus can be clarified only by determination of activity changes induced in each individual vagal and splanchnic nerve by specific hypothalamic activity. Effects of manipulation of the hypothalamus and autonomic nervous system on insulin secretion The effect of hypothalamic manipulation on pancreatic hormone secretion has been mainly investigated in the VMH and the LHA. Stimulation of the VMH decreased the release of insulin [7]. LHA stimulation produced various insulin secretion responses including excitation and inhibition as well as no effect [4,12,18,28,52]. Lesions of the VMH have been reported to produce hyperinsulinemia [6,11], and this effect has been prevented by vagotomy or denervation of the pancreas [ 1 4 , ~ ] . Lesion o f the paraventricular nucleus o f the h ~ ~ u s also produced h y ~ d n s u t i n e m i a [53]. Peripheral autonomic nerves also influence p a n creatic hormone secretion. Stimulation of the vagal nerve facilitated and that of the splanchnic nerve inhibited the release of insulin [2,8,9,24,55]. These suggest that the effects of the hypothalamic activity on insulin secretion are mediated by the autonomic nervous system. Effect of hypothalamic stimulation on pancreatic autonomic nerve activity Hypothalamic influence o n activity of autonomic nerve effexeats to th¢ pancreas were investigated" by stimulation experiments [15135]. Measurements were m ~ on the efferent cut ends of the respective vagal or splanchnic nerve fiber dissections. In each case recordings were made from only a few of the fibers running in the nerve. Activity of the pancreatic branch of the vagal nerve (VPN) was clearly decreased by VMH stimulation. The response of this nerve to LHA stimulation depended on the stimulating site. Stimulation of the ventral LHA facilitated, and that of the dorsal LHA tended to inhibit vagal nerve activity. As compared with the clearly demonstrated relations between h y p o t ~ l a m i c s t i m l a t i o n ~ V P N activity, the relationship between hypothalamJc stimulation and acti~ty of the pancreatic branch of the splanchnic nerve (SPN) was complicated. The effects did not correlate simply with stimulus sites in the hypothalamus and they changed with stimulus frequency. VMH stimulation both decreased and increased activity of the SPN. LHA stimulation tended to inhibit SPN nerve activity, but in some cases it induced ~increasing response or a brief increase followed by decrease when stimulus f r e q u e n c y was changed. These autonomic nerve responses to hypothalamic stimulation are summarized in Fig. 3 [35].
365 Vag.
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Fig. 3. Sites in the hypothalamus which affect efferent pancreatic vagal (left) and splanchnic (right) activity. Vagal nerve, facilitated by ventral LHA stimulation, but inhibited by VMH and dorsal LHA stimulation. Splanchnic nerve, both facilitated and inhibited in response to VMH stimulation; tendency to inhibition by LHA stimulation. CAI, capsula interna: DMH, dorsomedial hypothalamic nucleus; F, fornix; FMT, fasciculus mamillothalamicus; LHA, lateral hypothalamic area; TO, optic tract; VMH, ventromedial nucleus: ZI, zona incerta [35].
Effect of hypothalamic lesion on pancreatic autonomic nerve activity Fig. 4 shows VPN responses to lesion of various areas of the hypothalamus. VPN activity increased continuously after lesion of the VMH (upper), and decreased rapidly after lesion of the LHA (lower). The directions of the responses are almost opposite to those observed in the stimulation experiments. As in Fig. 5, SPN activity decreased following VMH lesion (upper), while LHA lesion caused both decrease (middle) and increase (lower) in SPN activity [56]. Lesion of other hypothalamic areas have also affected autonomic efferent activity. Lesions of the PVN or D M H vagal nerve VMH lesion D.C. 2mA, 10sec
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Fig. 4. Responses of vagal pancreatic nerve (VPN) to VMH and LHA lesion. Upper: VPN activity gradually increased by VMH lesion. Lower: VPN activity increased following infusion of D-glucose and decreased rapidly following LHA lesion. Modified from [56].
366 tended to produce increasing activity in the VPN and decreasing activity in the SPN [56]. From stimulation and lesion experiments, we can conclude that activity of the VMH, the DMH and the PVN produce vagal inhibition and splanchnic facilitation. The LHA has an excitatory effect on vagal efferents, and both excitatory and inhibitory effects on splanchnic efferents. The evidence clearly demonstrates functional correlation between the hypothalamus and the autonomic nervous system in the regulation of pancreatic hormone secretion. Hyperinsulinemia induced by VMH or PVN lesion is a result of both the increase in vagal activity and the decrease in splanchnic activity, since the peripheral vagal nerve is excitatory and the splanchnic nerve is inhibitory in their effects on insulin secretion. For the same reasons, the inhibitory effect of VMH stimulation on insulin secretion may be produced by vagal inhibition and splanchnic facilitation. The effects of LHA stimulation on insulin secretion are complex, i.e. increase, decrease and no effect. These various responses might be results of complicated relationships between the LHA and the peripheral nerves, i.e. vagal facilitation, and splanchnic facilitation and inhibition in this area.
(IV) Neural circuit-related regulation of feeding behavior and autonomic response
Efferent Anatomical studies using fiber degeneration, autoradiography and horseradish peroxidase staining have revealed the neural pathways which could be involved in the control of metabolism. Fig. 6 shows connections between the h ~ t h a l a m i c nuclei and output from the hyl~thalamus to the autonomic nervous system [36]. The splanchnic nerve VMH lesion D.C. 2mA, 10sec
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D-glucose 150mglkg 0.Sml i.v.
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Fig. 5. Response~of spla_nchn/cpancreaticmwve(SPN) to VMH and LHA lesion. Upper: SPN activity from [56].
367 Hypothalamic pathways to autonomic nervous system
3NI symp.N vag.N Fig. 6. Connections between various nuclei within hypothalamus and pathways from hypothalamus to the autonomic nervous system. CG, central gray: DMH, dorsomedial hypothalamie nucleus; DMV, dorsal motor vagal nucleus; IML, intermediolateral column of spinal cord; LC, locus coeruleus; LHA, lateral hypothalamic area; NTS, nucleus tractus solitarii; PBN, parabrachial nucleus; PVN, paraventricular nucleus; symp. N, efferent sympathetic nerve; vag. N, efferent vagal nerve; VMH, ventromedial hypothalamic nucleus [36]. V M H has intrahypothalamic connections with the D M H and the PVN as has the L H A [3,16,17,21,51]. Since the V M H and the L H A have no direct connections, they connect indirectly through the D M H and the PVN. The VMH, the PVN and the L H A have caudal projections to the central gray (CG), the parabrachial nucleus (PBN) and the locus coeruleus (LC) [5,47,48]. The C G and the PBN project to the sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord (IML) [45,46]. The PBN and the LC project to the NTS and the dorsal motor nucleus of the vagus (DMV) [43,45]. The D M H , the PVN and the L H A have direct connections to the IML, the N T S and the D M V [46]. The NTS also project directly to the I M L [20]. Since the V M H has no direct connection to autonomic preganglionic nuclei (e.g. I M L and DMV), the influence of V M H activity on the autonomic nervous system might be mediated through intrahypothalamic connection to the D M H and the PVN or other polysynaptic pathways relayed in the CG, the PBN and the LC.
Afferent Intestinal visceral signals from hepatic and intestinal glucose sensors, and stomach mechanoreceptors are conveyed afferently to the caudal part of the NTS. Gustatory signals are conveyed to the rostral part of this nucleus. Anatomical study demonstrates that the N T S project directly to the PBN, the D M H and the PVN [41], and the PBN projects directly to the VMH, the D M H , the PVN and the L H A [45]. Hence, the information received by the N T S can proceed rostrally to the hypothalamus either directly or through the PBN. The last important afferent pathway to the hypothalamus is the noradrenergic (NA) bundle. When glucose was infused directly into the rat duodenum, the amount
368
Connections between viscera and brain
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Fig. 7. Hierarchical organization of chemical information processing by central and peripheral nervous systems. Sites of peripheral 81ucose responding nerve elements which have been neur~hyuiok~cally identified. Peripheral sites: visceral--hepatic 81ucose-sens/tive (G$) units, duodenal and intesth~ T8lucoreceptor units; receptors of exoFnous s t i m u l i - - ~ h a ~ l q p a l zeceptors. C~trat sites; lower ~ a i n (medulla)--rostral and caudal NTS 81ucoreceptor (GR) and GS neurons; ~ a i n - ~ ~ v e neurons in SN (not yet confirmed by us); hypothatamus~GR neurons in VI~IH. GS neurons in LHA. DMV, domd motor vasal-nudeus; LHA, lateral hypothalamic area; NTS, ~ s tracfus*~s011tarlus: PBN, parabrachial nucleus; SN, substantia ni8ra; VMH, ventromedial nucleus.
369 of NA in the L H A increased, while it decreased in the V M H [27]. This suggests that signals from duodenal sensors are conveyed to the hypothalamus through the NA pathway. The involvement of the N A in the regulation of feeding behavior has been demonstrated by behavioural study [19]. In addition, glucose-sensitive neurons in the L H A were inhibited by direct application of NA or stimulation of ventral N A bundle described previously [25].
Conclusion
Glucose affects neurons in several peripheral organs and the central nervous system. These glucose-responsive elements might constitute the glucose-analyzing neuronal pathways and feedback loops which efferently affect peripheral metabolism and endocrine activity. Fig. 7 shows glucose-monitoring connections between viscera and the brain [36]. The effect of glucose is inhibitory in the liver, the NTS and the LHA, and excitatory in the small intestine and the VMH. Glucose affects neural central activity through peripheral sensors in the liver and small intestine. The information from these sensors as well as stomach mechanoreceptor is conveyed to the NTS through vagal afferent nerves. NTS neurons themselves have chemosensitivity which directly monitors the level of glucose in the blood and CSF. Taste signals from the tongue also project to this nuclei. The first step in the integration of visceral and glucose-related information might occur in the NTS. Since this nucleus has connection with autonomic preganglionic nuclei, the information could return caudally in the autonomic efferent nerves as a reflex from the level of the brainstem. Integrated information from the NTS also can proceed rostrally to the hypothalamus directly or through the PBN. The second step in the integration of peripheral signals and direct information of blood-borne chemicals could occur at the hypothalamic level. Since hypothalamic activity also influences the autonomic efferent nerve system, the hypothalamus is considered to be involved in a reflex loop which regulates metabolism and the endocrine system from a higher point, in the forebrain. The information received by the hypothalamic chemosensitive neurons themselves or through afferent neural pathways is further integrated in association cortices such as the orbitofrontal cortex (OBF). The prefrontal cortex and the OBF are known to have active pathways of communication with the hypothalamus [34]. This communication between the association cortices and the hypothalamus may contribute to higher functions such as memory and motivation during feeding behavior.
References
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371 28 Natelson, B.H., Smith, G.P., Stokes, P.E. and Root, A.W., An analysis of emotional hyperglycemia in monkeys, Neurology, 22 (1972) 433. 29 Niijima, A., Glucose-sensitive afferent nerve fibers in the hepatic branch of the vagus nerve in the guinea pig, J. Physiol. (Lond.), 332 (1982) 315-323. 30 Novin, D., Rogers,R.C. and Hermann, G., Visceral afferent and efferent connections in the brain, Diabetologia, 20 (1981) 331-336. 31 Novin, D., Vanderweele, D.A. and Rezek, M., Infusion of 2-deoxy-D-glucose into the hepatic-portal system causes eating: evidence for peripheral glucoreceptors, Science, 181 (1973) 858-860. 32 Oomura, Y., Central mechanism of feeding. In M. Kotani (Ed.), Advance in Biophysics, Univ. of Tokyo Press, Tokyo, 1973, pp. 65-142. 33 Oornura, Y., Significance of glucose, insulin and free fatty acid on the hypothalamic feeding and satiety neurons. In D. Novin, W. Wyrwicka and G.A. Bray (Eds.), Hunger: Basic Mechanisms and Clinical Implications, Raven Press, New York, 1976, pp. 145-157. 34 Oomura, Y., Input-output organization in hypothalamus. In P.J. Morgane and J. Panksepp (Eds.), Handbook of the Hypothalamus, Vol. 2, Dekker, New York, 1980, pp. 557-620. 35 Oomura, Y. and Kita, H., Insulin acting as a modulator of feeding through the hypothalamus, Diabetologia, 20 (1981) 290-298. 36 Oomura, Y. and Niijima, A., Chemosensitive neurons and neural control of pancreatic sectretion. In Eric, N. Nngola (Ed.), Diabetes, 1982, Excerpta Medica, Amsterdam, 1983, pp. 201-211. 37 Oomura, Y., Ooyama, H., Sugimori, M., Nakamura, T. and Yamada, Y., Glucose inhibition of the glucose-sensitive neurone in the rat lateral hypothalamus, Nature (Lond.), 247 (1974) 284-286. 38 Oomura, Y., Shimizu, N., Miyahara, S. and Hattori, K., Chemosensitive neurons in the hypothalamus. Do they relate to feeding behavior? In B.G. Hoeble, D. Novin (Eds.), The Neural Basis of Feeding and Reward, Haer Institute Electrophysiological Research, Brunswick, ME, 1982, pp. 551-566. 39 Oomura, Y., Sugimori, M., Nakamura, T. and Yamada, Y., Contribution of electrophysiological techniques to the understanding of central control systems. In G.J. Mogenson, F.R. Calaresu (Eds.), Neural Integration of Physiological Mechanisms and Behavior, Univ. Tronto Press, Toronto, (1975) pp. 375-395. 40 Powley, T.L. and Opsahl, C.A., Ventromedial hypothalamic obesity abolished by subdiaphragmatic vagotomy, Amer. J. Physiol., 226, (1974) 25-33. 41 Ricard, J.A. and Koh, E.T., Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat, Brain Res., 153 (1978) 1-26. 42 Rogers, R.C., Novin, D. and Butcher, L.L., Electrophysiological and neuroanatomical studies of hepatic portal osmo- and sodium-receptive afferent projections within the brain, J. auton. Nerv. Syst., 1 (1979) 183-202. 43 Ruggiero, D.A., Ross, C. and Reis, D.J., Central afferents to the intermediate nucleus tractus solitarius and the commissural nucleus of the vagus: a retrograde transport study in rat and rabbit, Soc. Neurosci. Abstr., 6 (1980) 275. 44 Sakamoto, Y., Oomura, Y., Kita, H., Shibata, S., Suzuki, S., Kuzuya, T. and Yoshida, S., Insulin content and insulin receptors in the rat brain. Effect of fasting and streptozotocin treatment, Biomed. Res., 1 (1980) 334-340. 45 Saper, C.B. and Loewy, A.D., Efferent connections of the parabrachial nucleus in the rat, Brain Res., 197 (1980) 291-317. 46 Saper, C.B., Loewy, A.D., Swanson, L.W. and Cowan W.M., Direct hypothalamic autonomic connections, Brain Res., 117 (1976) 305-312. 47 Saper, C.B., Swanson, L.W. and Cowan, W.M., The efferent connections of the ventromedial nucleus of the hypothalamus of the rat, J. comp. Neurol., 169 (1976) 409-442. 48 Saper, C.B., Swanson, L.W. and Cowan, W.M., An autoradiographic study of the efferent connections of the lateral hypothalamic area in the rat, J. comp. Neurol., 183 (1979) 689-706. 49 Sharma, K.N. and Nasset, E.S., Electrical activity in mesenteric nerve after perfusion of gut lumen, Amer. J. Physiol., 202 (1962) 725-730. 50 Shimizu, N., Oomura, Y., Novin, D., Grijalva, C.V. and Cooper, P.H., Functional correlations between lateral hypothalamic glucose-sensitive neurons and hepatic portal glucose sensitive units in rat, Brain Res., 265 (1983) 49-54.
372 51 Silverman, A.J., Hoffman, D.L. and Zimmerman, E.A., The descending afferent connections of the paraventricular nucleus of the hypothalamus (PVN), Brain Res. Bull., 6 (1981) 47-61. 52 Steffens, A.B., Mogenson, G.J. and Stevenson, J.A.F., Blood glucose, insulin and free fatty acids after stimulation and lesions of the hypothalamus, Amer. J. Physiol., 222 (1972) 1446-1452. 53 Steves, J.P. and Lorden, J.F., Effects of lesions of the paraventricular nucleus of the hypothalamus on plasma insulin levels in the rat, Soc. Neurosci. Abstr., 8, part 2 (1982) 904. 54 Tager, H., Hohenboken, M., Markese, J. and Dinerstein, R.J., Identification and localization of glucagon related peptides in rat brain, Proc. natl. Acad. Sci. U.S.A. 77 (1980) 6229-6233. 55 Uvn~-Wallensten, K. and Nilsson, G., A quantitative study of the insulin release induced by vagal stimulation in anesthetized cats, Acta Physiol. Scand., 102 (1978) 137-142. 56 Yoshimatsu, H., Niijima, A., Oomura, Y., Yamabe, K. and Katafuchi, T., Effects of hypothalamic lesion on pancreatic autonomic nerve activity in the rat, Brain Res., submitted.
359
JAN 00360
Neural network of glucose monitoring system Yutaka Oomura and Hironobu Yoshimatsu Department of Physiology, Faculty of Medicine, Kyushu University 60, Fukuoka 812 (Japan) (Received September 20th, 1983) (Accepted February 10th, 1984)
Key words: glucose sensor - - hypothalamus - - autonomic nerve -- pancreas -lateral hypothalamic area -- ventromedial hypothalamic nucleus -nucleus of the solitary tract
Abstract
Glucose-sensitive neural elements exist in the hypothalamus, the nucleus of the solitary tract (NTS) and autonomic afferents from visceral organs such as liver and gastrointestinal tract. Glucose affects neural activity through these central and peripheral chemosensors. Glucose is generally suppressive in the liver, the NTS and the lateral hypothalamic area (LHA), and generally excitatory in the small intestine and ventromedial hypothalamic nucleus (VMH). The hypothalamus is involved in the control of pancreatic hormone secretion through autonomic efferent nerves. Stimulation or lesion of the hypothalamus induces various changes in pancreatic autonomic nerve activity. The VMH, the dorsomedial hypothalamic nucleus and the paraventricular nucleus have inhibitory effects on vagal nerve activity and excitatory effects on splanchnic nerve activity. The LHA is excitatory to the vagal nerve, and both excitatory and inhibitory to the splanchnic nerve. These findings suggest that the neural network of the glucose monitoring system, which also analyzes and integrates information concerning other metabolites and peptides in the blood and cerebrospinal fluid, contributes to regulation of peripheral metabolism and endocrine activity as well as feeding behavior. The physiological function and input-output organization of this network are discussed.
Correspondence: Y. Oomura, Dept, of Physiology, Faculty of Medicine, Kyushu University 60, Fukuoka 812, Japan. 0165-1838/84/$03.00 © 1984 Elsevier Science Publishers B.V.
360
Introduction The hypothalamus is involved in the control of feeding behavior. Hypothalamic chemosensitive neurons [33] monitor changes in endogenous materials in the blood and cerebrospinal fluid (CSF). A recent study indicates the existence of other monitoring systems outside the hypothalamus such as the nucleus of the solitary tract (NTS) and autonomic afferents from visceral organs [26,29,42]. These monitoring systems, which receive information about metabolites and peptides in the blood and CSF, contribute to feeding behavior. The blood glucose level is maintained constant by insulin, glucagon and catecholamine released from the pancreas and adrenal gland. Secretion of these hormones is considered to be modulated through the autonomic nervous system. This monitoring system also plays an important role in the regulation of peripheral metabolism and endocrine activity by integrating and feeding back information received in the hypothalamus, and other central and peripheral sensors.
(1) Hypothalamie ~ a s o r s Hypothalamic glucose-responsive neurons The existence of glucose-responsive neurons in the lateral hypothalamic area (LHA) and ventromedial hypothalamic nucleus (VMH) was first demonstrated by systemic glucose application. Electrophoretic application of glucose directty on neurons within the hypothalamus delineated those populations of neurons in the hypothalamus that respond to glucose. Glucose-sensitive (GS) neurons in the LHA have their activity suppressed by glucose applied directly to t h ~ surfaces. In the LHA, 20-25~ of the neurons are glucose-sensitive and these are localized in the ventral portion [32,37]. Intracdlular recordings from GS neurons show that the suppressive effect of glucose is a result of hyperpola~'~zation of the membrane without change in the membrane conductance, This is induced by activating the electrogenic Na pump [37]. Glucoreceptor (GR) neurons in the VMH have been defined as those which increase in activity in a dose-responsive manner upon application o f ~ [33,34]. Application of fresh rat VM~ antibody to VMH GR neurons produced large transient activity increase followed by irreversible cessation [34]. This suggests that VMH GR neurons have specific membrane receptor sites. Most of these glucose-respomive neurons are also affected by other blood-borne metabolites and peptides such as free fatty acids (FFA), insulin and glucagon. It is interesting that all of these substances which affect glucose,respons/ve neuron activity have also been shown to influence feeding behavior in~one way or another. Insulin Activity of GR neurons in the VMH is slightly inhibited by insulin alone, but is facilitated by simultaneous application of insulin ami.glacos¢ mine than by alone. Activity of GS neurons in the LHA is facilitated by insulin in a d o ~ -
361 dent manner [39]. Insulin-induced feeding is inhibited by injection of glucose directly into the rat LHA and is also prevented by LHA lesion. These results are consistent with the characteristics of GS neurons in the LHA. Insulin binding sites in the brain have been identified [10,35,44]. They are abundant in the hypothalamus and unaffected by peripheral insulin concentration. The stability of insulin and its binding sites in the brain suggests that constant brain insulin might provide a constant control point against which other materials such as glucose are compared in order to control body weight.
Glucagon Glucagon-like immunoreactivity (GLI) has been identified in the brain although immunoreactive pancreatic glucagon (IRG) was not found in any of the brain regions [13,36,54]. Nerve fibers that reacted with anti-GLI antibody were found in the periventricular region, paraventricular nucleus (PVN), supraoptic nucleus, anterior hypothalamus, dorsomedial hypothalamic nucleus (DMH) and VMH [13,36]. GLI concentration in the VMH has been reported to rise to 1.5 times the control level while it did not change significantly in the LHA during 48 h of deprivation [13]. Intracerebroventricular administration of glucagon causes hyperglycemia and suppresses insulin secretion [1]. There is a possibility that GLI in the brain is related to sugar metabolism as well as to feeding behavior. Neuronal activity of LHA and VMH neurons was recorded during electrophoretic application of glucagon. Glucagon suppressed the activity of GS neurons in the LHA significantly and of G R neurons in the VMH occasionally [13,38]. GLI originating in the brain may act as an inhibitory neurotransmitter or neuromodulator in the hypothalamus.
(II) Glucose responsive sites outside the hypothalamus
Peripheral glucose sensors There are glucose sensors in the liver which affect vagal afferent nerve fiber activity. These hepatic GS units decrease the discharge rate of vagal afferents when glucose is injected into the hepatic portal vein [29]. Hepatic GS units may also influence the regulation of food intake. Intraportal injection of glucose reduces food consumption in proportion to the glucose concentration, and similar injection of 2-deoxy-D-glucose (2-DG) elicits feeding response [30,31]. The effect of intraportal injection of these substances can be blocked by subdiaphragmatic vagotomy [22]. Hepatic GS units increased in activity following administration of 2-DG into portal vein. Insulin increased and glucagon decreased their activity. These characteristics of hepatic GS units are similar to those of GS neurons in the LHA. To determine relationships between central and peripheral GS elements, changes in LHA neuronal activity due to glucose injections into the portal vein were investigated [50]. As shown in Fig. 1A, GS neurons in the LHA which decreased in activity upon direct application of glucose were also inhibited by portal glucose injections. This inhibition might be mediated through the noradrenaline (NA)
362 A
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Fig. 1. Inhibitory effect of hepatic portal glucose injection on GS neuron in rat LHA. A: continuous from upper to lower. Pulse counter record (discharges/5 s) of LHA neural activity in response to hepatic injection or electrophoretic application o f glucose (Gluc.). Application time represented by horizontal bars. Numbers refer to concentrations of injected solutions or electrophoretic current in n a n t e s (hA). Dose-related inhibitory response to both hepatic portal ( h / p ) injection and direct electrophoretic appficution of glucose is evident. During application of phenoxybenzamine (PBZ) to the neuron, the inhibitory effects due to hepatic portal injection of glucose and to electrophoretic application of NA, but not those due to electrophoretic application of glucose, were blocked. Injection of glucose into jugular vein (jv) had a slight effect. N o detectable reg~0n~ was sce~ when hypertonic saline (0.28 M, 0,3 ml) was injected through the portal vein. Control electrophoretic application of Na + had no effect, thus ruling out current or osmotic effects. B: poststimulus time histogram (PSTH) of discharl~e rate (same neuron as in A) produced by stimulation of ventral N A bundle (0.2 mA, 0.1 ms duration at 1 Hz). PSTH obtained from 200 trials with identical stimulus intensity. Stimulation inhibited neural activity of the neuron for about 20 ms [50].
pathway, since electrophoretic application of NA inhibited GS neuron activity, and tl-ds effect was blocked by applization of phenoxybenzamine (an a-adrenoreceptor blocking agent). In addition, stimulation of the ventral NA bundle inhibited the activity of GS neurons in the LHA (Fig. 1B) [25]. Thus most GS neurons in the LHA seem to receive facilitatory inputs from the hepatic vagal GS units. This afferent neural pathway may be mediated by the NTS and parabrachial nucleus (PBN) as described later. A number of experiments suggest the existence of gastrointestinal ~ e ~ ' p t o r s [23,49]. Glucose infusion into the ~ lumen has reduced food ~ from gastrointestinal glucose sensors are considered to be carried by v~,id~ ~ t s because the effect of glucose on food intake has been prevented by vagotomy [30]. Activity of the vagal afferents from the gastrointestinal tract increased following
363
perfusion of glucose through the canal. These vagal afferents from the gastrointestinal organs also project to the NTS as do those from the liver. N T S glucose-responsioe neurons
Recent study indicates that the NTS has glucose-responsive neurons [26]. In in vitro brain slice experiments, 162 neurons were tested. Among 89 neurons in the caudal NTS, 25 neurons (28%) were glucose-sensitive. There were 7 (8%) G R and 57 non-responsive neurons present in the same region. Of the 73 neurons tested in the rostral part, 8 (11%) were GS and 4 (5%) were G R (Fig. 2). More GS neurons are present in the caudal part of the NTS adjacent to the fourth ventricle, than in the rostral part. This nucleus also has connections with the area postrema which lacks the blood-brain barrier. Thus, chemosensitive neurons in the NTS could directly receive information related to glucose level in the blood a n d / o r cerebrospinal fluid, and also receive signals through vagal afferent nerves from visceral glucose sensors. Therefore, this nucleus might be considered to be an important relay point in the glucose analyzing pathway and to send integrated information to the hypothalamus. A
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Fig. 2. Chemoresponsive neurons in rat nucleus tractus solitarii (NTS). Brain-slice preparation (300/~m thick). A: non-glucose responsive neuron. No response to electrophoretic application of 2-deoxy-D-glucose (2-DG), glucose, or Na ions (Na). Dose-related facilitation by acetylcholine. B: glucose-sensitive neuron. Inhibited dose-responsively by glucose. Na had no effect. Facilitated dose-responsively by 2-DG. C: glucoreceptor neuron. Glucose facilitated and 2-DG inhibited slightly. Horizontal lines: time of electrophoretic application of chemicals expressed in nanoamperes (nA). Vertical calibrations: discharges/s [26].
364 (III) Hypothalamic regulation of the pancreatic autonomic nervous system
A number of studies have revealed that hypothalamic regulation of metabolism and the endocrine system including insulin, glucagon and catecholamine secretion might be mediated by the autonomic nervous system. However, stimulation or lesion of the hypothalamus could produce simultaneous effects on many organs such as the pancreas, liver and adrenal gland which all affect peripheral blood glucose level, so the physiological significance of the hypothalamus in regulating each organ related to glucose metabolism through the autonomic nervous system is still unknown. The effect of the autonomic output from the hypothalamus can be clarified only by determination of activity changes induced in each individual vagal and splanchnic nerve by specific hypothalamic activity. Effects of manipulation of the hypothalamus and autonomic nervous system on insulin secretion The effect of hypothalamic manipulation on pancreatic hormone secretion has been mainly investigated in the VMH and the LHA. Stimulation of the VMH decreased the release of insulin [7]. LHA stimulation produced various insulin secretion responses including excitation and inhibition as well as no effect [4,12,18,28,52]. Lesions of the VMH have been reported to produce hyperinsulinemia [6,11], and this effect has been prevented by vagotomy or denervation of the pancreas [ 1 4 , ~ ] . Lesion o f the paraventricular nucleus o f the h ~ ~ u s also produced h y ~ d n s u t i n e m i a [53]. Peripheral autonomic nerves also influence p a n creatic hormone secretion. Stimulation of the vagal nerve facilitated and that of the splanchnic nerve inhibited the release of insulin [2,8,9,24,55]. These suggest that the effects of the hypothalamic activity on insulin secretion are mediated by the autonomic nervous system. Effect of hypothalamic stimulation on pancreatic autonomic nerve activity Hypothalamic influence o n activity of autonomic nerve effexeats to th¢ pancreas were investigated" by stimulation experiments [15135]. Measurements were m ~ on the efferent cut ends of the respective vagal or splanchnic nerve fiber dissections. In each case recordings were made from only a few of the fibers running in the nerve. Activity of the pancreatic branch of the vagal nerve (VPN) was clearly decreased by VMH stimulation. The response of this nerve to LHA stimulation depended on the stimulating site. Stimulation of the ventral LHA facilitated, and that of the dorsal LHA tended to inhibit vagal nerve activity. As compared with the clearly demonstrated relations between h y p o t ~ l a m i c s t i m l a t i o n ~ V P N activity, the relationship between hypothalamJc stimulation and acti~ty of the pancreatic branch of the splanchnic nerve (SPN) was complicated. The effects did not correlate simply with stimulus sites in the hypothalamus and they changed with stimulus frequency. VMH stimulation both decreased and increased activity of the SPN. LHA stimulation tended to inhibit SPN nerve activity, but in some cases it induced ~increasing response or a brief increase followed by decrease when stimulus f r e q u e n c y was changed. These autonomic nerve responses to hypothalamic stimulation are summarized in Fig. 3 [35].
365 Vag.
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Fig. 3. Sites in the hypothalamus which affect efferent pancreatic vagal (left) and splanchnic (right) activity. Vagal nerve, facilitated by ventral LHA stimulation, but inhibited by VMH and dorsal LHA stimulation. Splanchnic nerve, both facilitated and inhibited in response to VMH stimulation; tendency to inhibition by LHA stimulation. CAI, capsula interna: DMH, dorsomedial hypothalamic nucleus; F, fornix; FMT, fasciculus mamillothalamicus; LHA, lateral hypothalamic area; TO, optic tract; VMH, ventromedial nucleus: ZI, zona incerta [35].
Effect of hypothalamic lesion on pancreatic autonomic nerve activity Fig. 4 shows VPN responses to lesion of various areas of the hypothalamus. VPN activity increased continuously after lesion of the VMH (upper), and decreased rapidly after lesion of the LHA (lower). The directions of the responses are almost opposite to those observed in the stimulation experiments. As in Fig. 5, SPN activity decreased following VMH lesion (upper), while LHA lesion caused both decrease (middle) and increase (lower) in SPN activity [56]. Lesion of other hypothalamic areas have also affected autonomic efferent activity. Lesions of the PVN or D M H vagal nerve VMH lesion D.C. 2mA, 10sec
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Fig. 4. Responses of vagal pancreatic nerve (VPN) to VMH and LHA lesion. Upper: VPN activity gradually increased by VMH lesion. Lower: VPN activity increased following infusion of D-glucose and decreased rapidly following LHA lesion. Modified from [56].
366 tended to produce increasing activity in the VPN and decreasing activity in the SPN [56]. From stimulation and lesion experiments, we can conclude that activity of the VMH, the DMH and the PVN produce vagal inhibition and splanchnic facilitation. The LHA has an excitatory effect on vagal efferents, and both excitatory and inhibitory effects on splanchnic efferents. The evidence clearly demonstrates functional correlation between the hypothalamus and the autonomic nervous system in the regulation of pancreatic hormone secretion. Hyperinsulinemia induced by VMH or PVN lesion is a result of both the increase in vagal activity and the decrease in splanchnic activity, since the peripheral vagal nerve is excitatory and the splanchnic nerve is inhibitory in their effects on insulin secretion. For the same reasons, the inhibitory effect of VMH stimulation on insulin secretion may be produced by vagal inhibition and splanchnic facilitation. The effects of LHA stimulation on insulin secretion are complex, i.e. increase, decrease and no effect. These various responses might be results of complicated relationships between the LHA and the peripheral nerves, i.e. vagal facilitation, and splanchnic facilitation and inhibition in this area.
(IV) Neural circuit-related regulation of feeding behavior and autonomic response
Efferent Anatomical studies using fiber degeneration, autoradiography and horseradish peroxidase staining have revealed the neural pathways which could be involved in the control of metabolism. Fig. 6 shows connections between the h ~ t h a l a m i c nuclei and output from the hyl~thalamus to the autonomic nervous system [36]. The splanchnic nerve VMH lesion D.C. 2mA, 10sec
!
D-glucose 150mglkg 0.Sml i.v.
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LHA lesion D.C. 2mA, lOeec
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Fig. 5. Response~of spla_nchn/cpancreaticmwve(SPN) to VMH and LHA lesion. Upper: SPN activity from [56].
367 Hypothalamic pathways to autonomic nervous system
3NI symp.N vag.N Fig. 6. Connections between various nuclei within hypothalamus and pathways from hypothalamus to the autonomic nervous system. CG, central gray: DMH, dorsomedial hypothalamie nucleus; DMV, dorsal motor vagal nucleus; IML, intermediolateral column of spinal cord; LC, locus coeruleus; LHA, lateral hypothalamic area; NTS, nucleus tractus solitarii; PBN, parabrachial nucleus; PVN, paraventricular nucleus; symp. N, efferent sympathetic nerve; vag. N, efferent vagal nerve; VMH, ventromedial hypothalamic nucleus [36]. V M H has intrahypothalamic connections with the D M H and the PVN as has the L H A [3,16,17,21,51]. Since the V M H and the L H A have no direct connections, they connect indirectly through the D M H and the PVN. The VMH, the PVN and the L H A have caudal projections to the central gray (CG), the parabrachial nucleus (PBN) and the locus coeruleus (LC) [5,47,48]. The C G and the PBN project to the sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord (IML) [45,46]. The PBN and the LC project to the NTS and the dorsal motor nucleus of the vagus (DMV) [43,45]. The D M H , the PVN and the L H A have direct connections to the IML, the N T S and the D M V [46]. The NTS also project directly to the I M L [20]. Since the V M H has no direct connection to autonomic preganglionic nuclei (e.g. I M L and DMV), the influence of V M H activity on the autonomic nervous system might be mediated through intrahypothalamic connection to the D M H and the PVN or other polysynaptic pathways relayed in the CG, the PBN and the LC.
Afferent Intestinal visceral signals from hepatic and intestinal glucose sensors, and stomach mechanoreceptors are conveyed afferently to the caudal part of the NTS. Gustatory signals are conveyed to the rostral part of this nucleus. Anatomical study demonstrates that the N T S project directly to the PBN, the D M H and the PVN [41], and the PBN projects directly to the VMH, the D M H , the PVN and the L H A [45]. Hence, the information received by the N T S can proceed rostrally to the hypothalamus either directly or through the PBN. The last important afferent pathway to the hypothalamus is the noradrenergic (NA) bundle. When glucose was infused directly into the rat duodenum, the amount
368
Connections between viscera and brain
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L H A glucole
8lnsltlve
nouronl
l Midbrain
Pens
PBN glucose e.en~JUveneurone
i
Medulla
NTS rostral caudal
/
Tongue
DMV
G,S,N
"
Viscera
InlAtutlngl g l u c o r o c q q i 4 0 r units
Fig. 7. Hierarchical organization of chemical information processing by central and peripheral nervous systems. Sites of peripheral 81ucose responding nerve elements which have been neur~hyuiok~cally identified. Peripheral sites: visceral--hepatic 81ucose-sens/tive (G$) units, duodenal and intesth~ T8lucoreceptor units; receptors of exoFnous s t i m u l i - - ~ h a ~ l q p a l zeceptors. C~trat sites; lower ~ a i n (medulla)--rostral and caudal NTS 81ucoreceptor (GR) and GS neurons; ~ a i n - ~ ~ v e neurons in SN (not yet confirmed by us); hypothatamus~GR neurons in VI~IH. GS neurons in LHA. DMV, domd motor vasal-nudeus; LHA, lateral hypothalamic area; NTS, ~ s tracfus*~s011tarlus: PBN, parabrachial nucleus; SN, substantia ni8ra; VMH, ventromedial nucleus.
369 of NA in the L H A increased, while it decreased in the V M H [27]. This suggests that signals from duodenal sensors are conveyed to the hypothalamus through the NA pathway. The involvement of the N A in the regulation of feeding behavior has been demonstrated by behavioural study [19]. In addition, glucose-sensitive neurons in the L H A were inhibited by direct application of NA or stimulation of ventral N A bundle described previously [25].
Conclusion
Glucose affects neurons in several peripheral organs and the central nervous system. These glucose-responsive elements might constitute the glucose-analyzing neuronal pathways and feedback loops which efferently affect peripheral metabolism and endocrine activity. Fig. 7 shows glucose-monitoring connections between viscera and the brain [36]. The effect of glucose is inhibitory in the liver, the NTS and the LHA, and excitatory in the small intestine and the VMH. Glucose affects neural central activity through peripheral sensors in the liver and small intestine. The information from these sensors as well as stomach mechanoreceptor is conveyed to the NTS through vagal afferent nerves. NTS neurons themselves have chemosensitivity which directly monitors the level of glucose in the blood and CSF. Taste signals from the tongue also project to this nuclei. The first step in the integration of visceral and glucose-related information might occur in the NTS. Since this nucleus has connection with autonomic preganglionic nuclei, the information could return caudally in the autonomic efferent nerves as a reflex from the level of the brainstem. Integrated information from the NTS also can proceed rostrally to the hypothalamus directly or through the PBN. The second step in the integration of peripheral signals and direct information of blood-borne chemicals could occur at the hypothalamic level. Since hypothalamic activity also influences the autonomic efferent nerve system, the hypothalamus is considered to be involved in a reflex loop which regulates metabolism and the endocrine system from a higher point, in the forebrain. The information received by the hypothalamic chemosensitive neurons themselves or through afferent neural pathways is further integrated in association cortices such as the orbitofrontal cortex (OBF). The prefrontal cortex and the OBF are known to have active pathways of communication with the hypothalamus [34]. This communication between the association cortices and the hypothalamus may contribute to higher functions such as memory and motivation during feeding behavior.
References
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