Functional heterogeneity of the monkey lateral hypothalamus in the control of feeding

Regional differences in the effects of electrical (ES) and chemical stimulation on execution of a bar-press feeding task, and in neuronal activity related to feeding, glucose sensitivity, and odor responsiveness were examined in the lateral hypothalamic area (LHA) of monkeys. In satiated animals, ES of the far lateral and ventral LHA induced bar-press feeding. In hungry animals, ES of the dorsal LHA suppressed the feeding task only during the stimulation period, but prolonged feeding suppression that occurred after ES of the ventromedial LHA. Microinjection of Na-glutamate into LHA sites where ES was effective in suppressing feeding had no effect, but it was effective in the medial hypothalamus. Glucose-sensitive (GS) neurons decreased in activity during bar pressing and/or during the ingestion period. Glucose-insensitive (GIS) neurons showed a cue-related excitation more often than GS neurons. Odor-responding GS and GIS cells were localized in ventromedial and lateral LHA sites, respectively. The present study suggests the regional heterogeneity of the LHA in feeding regulation, depending on both hunger and satiety states.     

Internal and external information processing by lateral hypothalamic glucose-sensitive and insensitive neurons during bar press feeding in the monkey

Single neuron activities in the lateral hypothalamic area (LHA) were recorded during bar press feeding task in the monkey. First registered neurons were sorted into 2 groups, glucose-sensitive (GS) and glucose-insensitive (GIS) neurons, depending on their glucose sensitivity. Then firing variations to feeding, electrophoretically applied catecholamines and opiate, and to odor and taste stimuli were investigated. GS neurons responded to dopamine, noradrenaline and morphine more often than GIS neurons. In feeding task GS neurons responded during bar press (BP) and reward (RW) periods with long-lasting inhibition of firing and at cue tone (CT) with transient inhibition, while GIS neurons responded during BP and RW periods mainly with excitation and at cue light (CL) with excitation. A majority of GS neurons responded to both odor and taste stimuli more often than GIS neurons. Data suggest that these two kinds of neurons in the LHA may be involved in different functional aspects of feeding: GS neurons, mainly in internal information processing and reward mechanism, and GIS neurons, in external information processing and motor aspects.     

Glucose-sensitive neurons of the globus pallidus: II. Complex functional attributes

The globus pallidus (GP) is intimately involved in regulation of various aspects of hunger- and thirst-motivated behaviors. Our parallel neurochernical studies demonstrated the existence of GP neurons whose discharge rates are suppressed by glucose applied microelectrophoretically. In the present series of experiments, we aimed to provide complex, feeding-associated functional characterization—similar to that previously accomplished in the case of lateral hypothalamic and amygdabid chemosensitive neurons—of these glucose-sensitive (GS) and the glucose-insensitive (GIS) pallidal cells. To do so, extracellular single neuron activity of the GP was recorded in anesthetized rats and anesthetized or awake rhesus monkeys by means of carbon fiber, multibarreled glass microelectrodes during: a) microelectrophoretic administration of chemicals, b) gustatory, and c) olfactory stimulations. In alert primates, activity changes were also recorded during presentation of food and nonfood objects as well as during the performance of a conditioned, high fixed-ratio bar-press feeding task. The half of pallidal cells examined showed firing rate changes during phases of the conditioned alimentary task. In both species, about 1/7 of all neurons tested proved to be GS, while the proportion of cells responding to gustatory and olfactory stimulations was 19% and 16%, respectively. Task-related and taste- and smell-responsive units were mainly found among the GS neurons of the pallidum. These data, along with previous findings, indicate that chemosensitive cells of the GP, in an apparent overlap with units of the central gustatory representation, are involved in a hierarchically organized glucose-monitoring neural network, through which pallidal neurons exert their integrative functions in the central feeding control.     

Glucose-sensitive neurons of the globus pallidus: I. Neurochemical characteristics

The lateral hypothalamic area (LHA) and globes pallidtaz (GP) are basically involved in the regulation of feeding and metabolic processes. In the LHA, glucose-sensitive (GS) neurons were described: their activity was found to be specifically suppressed by electrophoretic application of glucose, and these neurons appeared to be also influenced by various feeding-associated neurochemical signals. The main goal of the present experiments was to examine whether similar GS neurons exist in the GP. In addition, neurochemical attributes of the cells were also tested. In anesthetized rats and anesthetized or awake monkeys, single-neuron activity of the GP was recorded by means of carbon fiber multibarreled microelectrodes and the effects of glucose, glutamate (Gt), GABA, dopamine (DA), noradrenaline (NA) and acetylcholine (Ach) were studied. In both the rat and monkey GP, approximately 12% of the neurons examined responded, with inhibition, to glucose. GP neurons, in a high proportion, were also inhibited by GABA and NA. After application of Gt, DA, or Ach, activity increase or decrease occurred. GS neurons exhibited remarkable sensitivity to these neurochemicals previously identified as neurotransmitters of the complex pallidal, extrapyramidel-limbic neuron loops. The results, along with previous data, indicate that GS cells of the GP, while possessing complex neurochemical characteristics, may belong to a hierarchically organized central glucose-monitoring system essential in the regulation of feeding.     

Feeding regulation by endogenous sugar acids through hypothalamic chemosensitive neurons

Analysis of blood of fasted rats revealed two endogenous sugar acids, 3,4-dihydroxybutanoic acid (2-deoxytetronic acid; 2-DTA) and 2,4,5-trihydroxypentanoic acid (3-deoxypentonic acid; 3-DPA), that might be related to food intake control. Injection of 2-DTA into the third cerebral ventricle reduced food intake for 24 hr in 72 hr deprived rats and depressed single neurons activity in the lateral hypothalamus (LHA). The same amounts of 3-DPA elicited feeding in a dose-related fashion, and increased LHA single neuron activity with 6 to 8 min latency. Intravenous injection of 3-DPA, but not 2-DTA, was effective. Liposome encapsulation of 2-DTA enhanced its potency after intraperitoneal injection, probably by allowing passage across the blood-brain barrier. Electrophoretic application of 2-DTA significantly and specifically suppressed, and 3-DPA facilitated activity of glucose-sensitive (GS) neurons in the LHA. Neither affected glucose insensitive LHA neurons. Both sugar acids affected glucoreceptor (GR) neuron activity oppositely in the ventromedial hypothalamic nucleus (VMH). Intracellular recordings verified that the effect of 2-DTA on the GS and GR neurons was the same as glucose. Hyperpolarization of GR neurons with a membrane conductance increase was brought about by 3-DPA. The levels of plasma glucose and insulin changed oppositely by 2-DTA and 3-DPA, respectively when these were applied into the third cerebral ventricle. Feeding behavior and LHA and VMH neuron activity changes after injection suggest 2-DTA may be an endogenous satiety substance and 3-DPA a hunger substance, with effects mediated by GS neurons in LHA and GR neurons in VMH. Effects of 3-hydroxybutyric acid were also verified and discussed.     

Catecholaminergic mechanisms of feeding-related lateral hypothalamic activity in the monkey

The functional role of the catecholaminergic mechanism in the lateral hypothalamus (LHA), in feeding behavior of the monkey was investigated by single neuron activity recording and electrophoretic application of dopamine (DA), noradrenaline (NA) and their antagonists. The feeding paradigm had 4 phases: cue light (CL) signaled start of bar press; bar press (BP, 20-30 times); short cue tone (CT) triggered by last bar press signaled presentation of food; and ingestion-reward (RW). Of 312 neurons tested, 189 (61%) responded in one or more phases of the feeding task. Two types of response were observed: CL- or CT-related transient, and BP- or RW-related long-lasting responses. These feeding-related responses depended on the nature of the food and on the hunger-satiety level. DA excited or inhibited different neurons, while NA mainly inhibited firing. DA-sensitive neurons responded more often in the feeding task than insensitive neurons due mainly to differences in responsiveness to CL on (chi 2 test, P less than 0.01), at motor initiation, and during BP (P less than 0.05). Spiperone blocked the former two responses. NA-sensitive neurons responded more often in the feeding task due to responsiveness during BP and RW (P less than 0.01). Sotalol blocked some BP-related responses, and phenoxybenzamine and sotalol blocked the CT-related responses. The data suggest that dopaminergic and noradrenergic inputs in the LHA are crucial in task initiation and reward processing, respectively. Integration of these catecholaminergic and other inputs in the LHA might be important in accomplishing motivated feeding.     

Lateral hypothalamic modulation of oral sensory afferent activity in nucleus tractus solitarius neurons of rats

This study was designed to examine whether the sensory afferents from the anterior part of the tongue are modulated by activity of the lateral hypothalamic area (LHA) at the level of the nucleus tractus solitarius (NTS) in rats. The electrical activity of the NTS neurons was recorded extracellularly, and they were classified as gustatory, thermal, or mechanical neurons in accordance with their responsiveness to tongue stimulation by taste solutions, by warm and cool water, and by stroking the tongue surface. Sixty-two percent of the neurons were polysynaptically activated by electrical stimulation of the LHA. When a single conditioning stimulus of the LHA was applied prior to the test electrical stimulation of the tongue at various conditioning-test intervals, the activity of the gustatory neurons was facilitated by 30 to 80% of their control level for a period of approximately 20 to 150 msec. The activity of the mechanical and thermal neurons was suppressed for a 50- to 300-msec period. These results demonstrate the existence of modulatory effects from the LHA on the NTS neurons, which receive sensory information from the tongue.     

Inhibitory effects of lipopolysaccharide on hypothalamic nuclei implicated in the control of food intake

The arcuate nucleus (Arc) and the lateral hypothalamic area (LHA), two key hypothalamic nuclei regulating feeding behavior, express c-Fos, a marker of neuronal activation in fasted animals. This is reversed by refeeding. In the present study we tested whether an anorectic dose of lipopolysaccharide (LPS), the cell wall component of Gram-negative bacteria, also inhibits fasting-induced c-Fos expression in these hypothalamic nuclei. This would suggest that they are involved in anorexia during bacterial infections as well. We also studied whether LPS modulates the activity of orexin-A positive (OX+) LHA neurons. Food deprived BALB/c mice were injected with LPS or saline and were sacrificed 4 or 6h later. Four hours after injection, LPS reduced the number of c-Fos positive cells in the Arc and in the LHA, but had no effect on c-Fos in OX+ neurons. Six hours after injection, LPS reduced c-Fos expression in the LHA, both in the OX- and OX+ neurons, but not in the Arc. These results show that LPS modulates neuronal activity in the Arc and LHA similar to feeding-related stimuli, suggesting that the observed effects might contribute to the anorectic effect of LPS. Thus, physiological satiety signals released during refeeding and anorexia during bacterial infection seem to engage similar neuronal substrates.     

Feeding and diurnal related activity of lateral hypothalamic neurons in freely behaving rats

Activity of 64 single neurons in the lateral hypothalamus (LHA) was recorded for 1-8 days in freely behaving rats. The activity of 26 (40.6%) neurons varied with circadian rhythm and in relation to feeding. Activity of 23 of these neurons decreased during consumption of each pellet, and that of one increased. The activity of two other neurons increased intermittently, at night, prior to and during eating and drinking episodes. All changed activity with sleep-wake changes; increasing in the dark or upon arousal, and decreasing in the light or during slow wave sleep, but the activity was independent of individual movement, except feeding. The activity of 29 (45.3%) neurons varied only diurnally. Of these, 26 neurons also had sleep-wake responses and activity changes that corresponded to behavior. The firing rate of the other 3 neurons was independent of sleep-wake condition or individual feeding activity, but gradually increased in the dark to a maximum in the early morning, then subsided rapidly in 1-2 h. Four (6.3%) neurons were related only to feeding and not to diurnal rhythm, and 5 (7.8%) neurons were not related to either. Of the 5 neurons that were unrelated to either diurnal rhythm or feeding acts, 3 increased activity at light on and decreased it at light off for 4-13 min. These data suggest LHA neuronal involvement in control of short term feeding or individual feeding episodes, and long term feeding or circadian feeding rhythm.     

Trial measurement of brain activity underlying olfactory–gustatory synchrony perception using event-related potentials from five female participants

Temporal synchrony between odor and taste plays an important role in flavor perception. When we investigate temporal synchrony between odor and taste, it is necessary to pay attention not only to physical simultaneity of the presentation of olfactory and gustatory stimuli, but also to the perceptual simultaneity between the two stimuli. In this study, we examined short-latency brain activity underlying synchrony perception for olfactory–gustatory combinations. While five female participants performed a simultaneity judgment (SJ) task using soy sauce odor and salt solution, single-channel event-related potentials (ERPs) were recorded at the position of Cz. In each trial, the participant was asked whether olfactory and gustatory stimuli were perceived simultaneously or successively. Based on the judgment responses acquired from participants (i.e., simultaneous or successive), ERP data were classified into two datasets. The means of ERPs from each participant were calculated for each type of judgment response, considering the onset of olfactory or gustatory stimuli (OERPs or GERPs, respectively) as the starting point. The latencies of the P1 component of GERPs were very similar between simultaneous and successive judgment responses, whereas the P1 amplitudes differed significantly. These results indicated that neural activity affecting SJ for an olfactory–gustatory combination is generated during a period of about 130 ms from the onset of gustatory stimulus. Thus, olfactory and gustatory information processing related to flavor perception (more specially, synchrony perception between odor and taste) might be initiated at a relatively early stage of the central pathway.     

Hypothalamic control of gastric acid secretion

Study of hypothalamic control of gastric acid scretion (GAS) has revealed GAS-related neurons, their location in the lateral hypothalamic area (LHA), their characteristics, and implications of their relations to feeding and other functions. Some LHA glucose-sensitive neurons are referred to as gastric type because of their effects on gastric oxyntic cells via specific gastric related neurons of the medulla oblongata and the vagus. The 2-deoxy-D-glucose (2-DG), or insulin induced GAS was completely abolished by bilateral subdiaphragmatic vagotomy, or micro-lesions in specific sites of the LHA. These gastric type glucose-sensitive neurons were thus believed to contribute to control of GAS. The paraventricular nucleus (PVN) was also found to affect GAS. GAS-related PVN neurons were observed in the rostral PVN. Electrophoretic application of various chemicals, especially glucose, also affected neurons in the rostral PVN. Electrophoretically applied norepinephrine (NE) increased PVN single neuron activity and suppressed GAS. Results suggest that the rostral PVN may be another site to modulate LHA control of GAS, and NE may be a transmitter or modulator.     

Competence of nerve tissue as distal insert promoting nerve regeneration in a silicone chamber

In some medial forebrain bundle (MFB) sites, self-stimulation is often modulated by hunger or satiety. With electrodes in the nucleus accumbens (NAC) such modulation rarely occurs. The influence of food deprivation on MFB self-stimulation is the main basis for the hypothesis that electrical stimulation of the MFB can mimic the rewarding effect of food for hungry animals. To investigate this hypothesis, unit activity was recorded from the lateral hypothalamic area (LHA) of freely moving rats during rewarding stimulation at loci in both MFB and NAC, and during food ingestion. Of 63 neurons tested during MFB stimulation, 41 were inhibited, 19 were activated, and 3 were not influenced. NAC stimulation suppressed 8 of the 31 neurons tested, excited 16, and elicited no response in the remaining 7. During ingestion, 29 of the 63 neurons tested were inhibited and one was facilitated. Of 29 neurons suppressed by food, 20 were also inhibited by rewarding MFB stimulation, but 10 of 13 neurons inhibited by food were excited by rewarding NAC stimulation. Thus, most LHA neurons inhibited during feeding were also inhibited by rewarding MFB stimulation. Rewarding NAC stimulation, however, does not inhibit most LHA neurons that are inhibited by food. This result suggests that LHA neurons which are inhibited by food might be involved in mediation of the rewarding effect of electrical stimulation at some sites in the MFB. Nevertheless, self-stimulation may occur by activating reward processes other than those related to food, because rewarding NAC stimulation does not inhibit LHA neurons which are suppressed by food.     

Interoceptive accuracy and its impact on neuronal responses to olfactory stimulation in the insular cortex

The insular cortex plays a key role in the integration of multimodal information and in interoceptive and exteroceptive processing. For instance, neurons in the central dorsal insula that are active during interoceptive tasks, also show an adaptation to gustatory stimulation. We tested the link between interoception and exteroception for the olfactory system (i.e., the second domain of chemosensation). In a sample of 31 participants, olfactory function was assessed in a two dimensional approach while the Heartbeat Perception Task served as a measurement for cardiac interoceptive accuracy. Subsequent fMRI sessions were performed on a 3‐Tesla MR scanner containing 12–15 olfactory stimulation trials with a mildly pleasant food‐related odor (coffee). Persons scoring high in the cardiac interoceptive accuracy task presented stronger smelling abilities as well as enhanced BOLD responses following olfactory stimulation. The olfactory stimulation triggered enhanced insular activation patterns in the central dorsal insular cortex. Consistent with prior findings on the coherence of gustatory and interoceptive processing in the central dorsal insula, these results base the insula as a common region for the integration of interoception and exteroception. We propose an explanatory model of how exteroception triggers the integration of intero‐ and exteroceptive sensations in the central dorsal insular cortex.     

Response properties of lateral hypothalamic neurons during ingestive behavior with special reference to licking of various taste solutions

Activity of 58 single neurons in the lateral hypothalamic area (LHA) was recorded while Wistar male rats were drinking water and various taste solutions in a test box. A cue tone was presented before opening of a shutter for access to a drinking spout. Except 8 neurons which were non-responsive in the present experimental paradigm, 50 neurons were classified into 3 types according to their response properties: (1) 10 neurons changed their activity with arousal state or circadian rhythm, (2) 10 neurons responded to specific sensory stimuli, i.e. 2 were classified as taste-responsive neurons, which responded excitatory to sodium salts, 3 neurons responded to olfactory stimulation, 5 to somatosensory stimulation applied to the perioral region, and (3) the remaining 30 decreased their activity during licking of liquids regardless of their qualities. Besides this classification, activity of 28 of 58 LHA neurons was altered after onset of the cue tone (or before start of licking), i.e. 24 increased their activity (learned anticipatory response), and 3 modulated their tonic activity into burst discharges corresponding to sniffing, and 1 increased its activity in relation to stepping toward the drinking spout. These data suggest that about half of the LHA neurons increased their activity in anticipatory (searching or approaching) periods just before ingestion, and decreased activity in rewarding periods during ingestion of water or sapid solutions.     

High-affinity cAMP phosphodiesterase and adenosine localized in sensory organs

Odorant-stimulated formation of cAMP in olfactory receptor neurons may mediate olfactory signal transduction. The response is short and desensitization occurs rapidly, possibly by induction of cyclic necleotide phosphodiesterase (PDE) activity. Previously, we showed that two low K_{m PDEs} regulate hydrolysis of cAMP in olfactory cilia. One PDE is Ca²⁺/ calmodulin-dependent and non-selective for both cAMP-PDE and cGMP; the other is Ca²⁺/ calmodulin-independent, sensitive to rolipram and selective for cAMP. We have localized cAMP-selective PDE in olfactory, gustatory and retinal sensory systems by autoradiography with the selective inhibitor [³H]rolipram. We observe dense binding over olfactory neurons, particularly over olfactory nerve bundles and olfactory cilia. In the tongue apical regions of taste buds of the circumvallate papillae are strongly labeled as well as portions of the glossopharyngeal nerve. Retinal binding is most dense over the inner plexiform layer, ganglion cells and the optic nerve but is also substantial over the inner nuclear layer. The pattern of [³H]rolipram-binding in retina is reminiscent of adenosine localization. Accordingly, adenosine was immunohistochemically localized in olfactory, gustatory and retinal tissues. Adenosine immunoreactivity is observed in olfactory neurons, in the basal regions of taste buds and in retinal ganglion cells.     

Direct effects of 3,4-dihydroxybutanoic acid gamma-lactone and 2,4,5-trihydroxypentanoic acid gamma-lactone on lateral and ventromedial hypothalamic neurons

The mechanism of central actions of endogenous sugar acids, 3,4-dihydroxybutanoic acid gamma-lactone (3,4-DB) and 2,4,5-trihydroxypentanoic acid gamma-lactone (2,4,5-TP) which have been newly identified as satiety and hunger substances respectively, was investigated. Intracellular recordings were made from neurons in the lateral hypothalamic area (LHA) of rats and ventromedial hypothalamic nucleus (VMH) of guinea pigs, brain areas referred to as feeding and satiety centers, respectively. The LHA neurons hyperpolarized by 3,4-DB show no change in membrane input resistance while the depolarized VMH neurons are associated with an increase in membrane resistance. The mechanisms related to the action of 3,4-DB on these hypothalamic neurons are similar to those in case of glucose on the glucose-sensitive neuron in the LHA and the glucoreceptor neuron in the VMH. 2,4,5-TP depolarized LHA neurons but hyperpolarized VMH neurons with a decrease in the membrane resistance. Our findings indicate that 3,4-DB and 2,4,5-TP have reciprocal effects on each LHA and VMH neurons, with regard to neuronal excitability.     

Olfactory and gustatory capacities of alcoholic Korsakoff patients

The psychophysical method of magnitude estimation was used to assess the olfactory, gustatory, visual and auditory capacities of alcoholic Korsakoff patients. The Korsakoffs were most impaired in their scaling of olfactory and gustatory stimuli but did evidence some mild impairments on two of the three visual tasks. In contrast, right-hemisphere lesion patients were impaired on all three visual tasks and on an auditory task, but they scaled olfactory and gustatory stimuli in a normal manner. This dissociation indicates that the Korsakoffs difficulties with the chemical senses cannot be attributed to the complexity of the tests.     

Feeding pattern in obese Zucker rats after dopaminergic and serotonergic LHA grafts.

To study the role of the lateral hypothalamic area (LHA) dopamine and serotonin in the regulation of feeding pattern during obesity, embryonic dopaminergic and serotonergic neurons from mesencephalon and rombencephalon of lean rats were grafted into the LHA of adult obese Zucker rats. Compared to the pregrafting period, a smaller increase in meal size occurred in both serotonin-grafted (9%) and dopamine-grafted (31%) rats vs control rats (51%). There was also a smaller decrease in meal number in both serotonin-grafted (3%) and dopamine-grafted (13%) rats vs control rats (28%). Although the changes in feeding pattern resulted in a decrease in total food intake in serotonin-grafted rats (5%) vs control rats, no differences in body weight gain were observed in grafted vs control rats for the duration of the study. Since adult obese Zucker rats are known to have an increased meal size and decreased meal number relative to lean rats, the data indicate the involvement of LHA dopamine and serotonin in the regulation of feeding pattern during obesity.     

Concurrent measurement of serotonin metabolism and single neuron activity changes in the lateral hypothalamus of freely behaving rat.

To further investigate the activity of serotonin neurons in relation to feeding behavior, the metabolic activity of the serotonergic system and single neuron activity changes in the lateral hypothalamic area (LHA) were investigated concurrently in freely behaving rats. The extracellular concentration of 5-hydroxyindoleacetic acid (5-HIAA), a metabolic product of serotonin in the LHA, began to increase concomitantly with the early stage of nocturnal eating. The increased 5-HIAA returned to the basal level within 3 or 4 h. In conjunction with the increase in serotonin metabolism, activity of 12 out of 30 LHA neurons (40%) increased, whereas it decreased in 7 (23%), and in 11 (37%) it showed no change. An intracerebroventricular injection of lisuride suppressed the increased activity in 7 of the 12 neurons, but had no effect on the others. These results suggest that the concurrent increase in serotonin metabolism and neuron activity changes in the LHA may occur in the early portion of the nocturnal eating period, and may be important in controlling feeding behavior.     

Modulation of lateral hypothalamic activity by olfactory bulb and sciatic stimulation.

Lateral hypothalamic area (LHA) single unit activity (extracellular) was studied in response to electrical stimulation of the olfactory bulb (OB) or sciatic nerve in adult albino rats (n = 39) anesthetized with dialurethane. Olfactory stimulation resulted in a greater proportion of LHA units showing inhibitory rather than excitatory responses, while sciatic nerve stimulation resulted in similar proportions of units showing inhibitory and excitatory responses. Of the 76 LHA units tested with both OB and sciatic nerve stimulation, 36% responded to both stimulation sites, 18% responded only to OB stimulation, 26% responded only to sciatic nerve stimulation, and 20% were unresponsive to either stimulation. The locations of responsive units were diffuse throughout the LHA sampled. The response characteristics of LHA neurons to external sensory stimulation are consistent with the anatomy and putative integrative functions of this brain region.