Acute homeostatic imbalances reinstate sensorimotor dysfunctions in rats with lateral hypothalamic lesions

It has previously been demonstrated that rats recovered from aphagia and adipsia after large bilateral electrolytic lesions of the lateral hypothalamic area do not show the normal feeding response to 2-deoxyglucose or drinking response to polyethylene glyol. The present work reveals that such homeostatic imbalances reinstate the profound sensorimotor impairments that are seen in the immediate postoperative period but abate in parallel with the gradual recovery of ingestive behaviors. Administration of alpha-methyltyrosine or spiroperidol produced sensory and motor dysfunctions in rats with lateral hypothalamic lesions that were similar to those observed after 2-deoxyglucose. These results suggest that the residual feeding and drinking deficits of rats with lateral hypothalamic lesions after apparent recovery of function do not reflect specific loss of putative gluco- and volume-regulatory contributions to ingestive behavior. Instead, they may indicate continued impairments in nonspecific activational components of motivation that normally are mediated, in part, by central dopaminergic neurons.     

Role of activation and sensory stimuli in recovery from lateral hypothalamic damage in the cat

The early stages of recovery from lateral hypothalamic lesions were analyzed in 30 adult cats. In addition to aphagia and adipsia, neurological examination revealed deficits suggestive of deficient endogenous arousal, including somnolence, catalepsy, akinesia, and sensory neglect. Manipulations (tail pinch and injection of amphetamine) that counteracted these deficits also restored feeding. During recovery from aphagia, feeding gradually became activated by sensory stimuli (sight, feel, and smell) associated with food. These data suggest that activation is an important component in the control of normal feeding.     

The Horsley gantt medal address October 11, 1992

The concept of systemic quantization of behavior was used to study the interaction between dominant motivation and reinforcement on brain neurons. Feeding and escape were used as experimental models. Results showed that feeding and escape motivations are based on the mechanisms of ascending activating influences of lateral or ventromedial hypothalamic centers, respectively, on cortical neurons. Feeding and escape motivations evoked by electrical stimulation of hypothalamus, or the ones occurring naturally, modify the responses of single neurons of sensorimotor and insular cortex to sensory stimuli, to microiontophoretic application of neurotransmitters and neuropeptides, and especially to reinforcement. Dominant motivations are reflected in the burst-like activity and in a specific pattern of interpulse intervals of single units in various brain structures. Reinforcement transforms this activity into a regular pattern and also changes the neuronal responses of hypothalamic feeding and escape centers, to electrical stimulation and to microiontophoretic application of oligopeptides. Specific patterns of the unit responses to conditioned stimuli in the course of consecutive reinforcement was determined. After several instances of reinforcement, especially after repetitive reinforcement, the brain neurons influenced by the dominant motivation begin to produce specific protein molecules that are important for organization of an appropriate type of behavior. This process can be blocked by protein synthesis inhibitors.     

Effects of d- versus l-amphetamine, food deprivation, and current intensity on self-stimulation of the lateral hypothalamus, substantia nigra, and medial frontal cortex of the rat.

Intracranial sefl-stimulation (ICSS) was studied in rats with chronically implanted lateral hypothalamic, substantia nigra, or medial frontal cortex bipolar electrodes. A comparison of the effects of d- and l-amphetamine on ICSS response rate indicated that the d isomer had a greater facilitatory effect than the l isomer at lateral hypothalamic and substantia nigra electrode sites but that neither isomer significantly affected medial frontal cortex ICSS. d-Amphetamine resulted in a dose-related increase in motor activity, but the same doses of the l isomer resulted in decreased motor activity. Only lateral hypothalamic ICSS response rates increased significantly in response to food deprivation. Increases in current intensity above the level used for amphetamine and food-deprivation testing facilitated lateral hypothalamic and substantia nigra ICSS response rates but did not significantly affect medial frontal cortex response rates. The responsiveness of ICSS at each electrode site appeared to be correlated with the fiber- and cell-body densities of catecholaminergic systems in the brain.     

Suppression of VMH-lesion-induced reactivity and aggressiveness in the rat by stimulation of lateral septum, but not medial septum or cingulate cortex

Animals made vicious with bilateral ventromedial hypothalamic lesions had bipolar electrodes implanted unilaterally in the lateral septum, medial septum, or cingulate cortex. Four days later, the animals' reactivity and aggressiveness were evaluated 5 min before, during, and 5 min after stimulation at 20 micronA (60 Hz, sine wave). Lateral septal stimulation suppressed reactivity and aggressiveness by almost 80% compared with pre- and poststimulation levels. Stimulation of neither the cingulate cortex nor the medial septum produced a change reliably different from that seen in unstimulated control animals. Further tests with stimulation of the lateral septum at the 20-micronA level showed that neither rewarding self-stimulation nor disruption of ongoing water drinking was produced. These results are congruent with evidence from lesion studies that the lateral septum normally acts to suppress reactivity and aggressiveness in the rat; they do not support previous suggestions that the medial septum is involved in the modulation of these behaviors.     

Non-interaction of ventromedial and lateral hypothalamic mechanisms in the regulation of feeding and hoarding behaviour in the rat

Lesions of the hypothalamic ventromedial nucleus (VMN) led to an immediate increase in food intake but not to any increase in hoarding activity. Later, when subjects were very obese, they failed to hoard even in response to a 16-hr. deprivation schedule, although this schedule did produce hoarding if body weights were held at, or were brought down to, preoperative levels. These results indicate that the lateral hypothalamic mechanism responsible for hoarding and feeding responds to long-term nutritional factors, and that it is not directly affected by the short-term satiety mechanisms in the VMN. These findings support the hypothesis (a) that even “non-physiological” activities (e.g. hoarding, exploration) are motivated by physiological needs, and (b) that the reason these activities do not ordinarily covary with physiological drives is that, unlike the physiological drives, they are not subject to inhibition by the hypothalamic satiety mechanisms.     

Ontogeny of meal patterning in rats and its recapitulation during recovery from lateral hypothalamic lesions.

The development of feeding patterns was investigated in weanling rats and in rats with lateral hypothalamic lesions. From 16 to 25 days of age, the weanlings demonstrated a preprandial intake pattern, i.e., a positive correlation between meal size and time since the preceding meal. This subsequently declined while the postprandial relationship (correlation with time until subsequent meal) began to emerge such that by 30-35 days of age a full adult pattern was observed. Rats recovering from lateral hypothalamic lesions, for a brief period, also demonstrated a preprandial intake pattern. The postprandial relationship was abolished by the lesions. These results suggest that the development of adult meal patterning results from maturation of lateral hypothalamic mechanisms governing meal initiation.     

Motivated behaviors elicited from hypothalamus, midbrain, and pons of the guinea pig (Cavia porcellus).

Eating, drinking, biting attack, male mating behavior, and gnawing were elicited by electrical stimulation through electrodes located predominantly in a region extending from the preoptic area through the lateral hypothalamus into the ventral midbrain. Escape and digging were elicited from a parallel but more medial region that overlapped the lateral zone only in the preoptic-anterior hypothalamic area. Several differentiable vocalizations were produced from sites distributed through most, although not all, areas explored. Sites yielding painlike responses were located principally in the vicinity of the presumed pain pathway traced after anterolateral cordotomy in other species. Reward was obtained from widespread sites that were generally congruent with catecholaminergic systems as described in the rat. Although there was considerable overlap of the effective zones for many responses, their underlying mechanisms were differentiated anatomically by localized differences in their distribution or functionally by the elicitation of pure responses from some electrodes. Response mechanisms localized in the brain stem of the guinea pig generally resembled those in the rat, although there were differences in details, especially in the posterior midbrain and pons.     

Leupeptin, a thiol proteinase inhibitor, causes a selective impairment of spatial maze performance in rats

The effects of chronic intraventricular infusion of leupeptin, a potent inhibitor of thiol proteinases, were tested on ingestive behaviors, escape and avoidance conditioning, and spatial memory in rats. The drug did not detectably influence feeding, drinking, body temperature, or the latency to escape from a mild footshock or inhibitory avoidance behavior. However, rats treated with leupeptin made numerous errors ( reentries ) in an eight-arm spatial maze. These results are interpreted as supporting the hypothesis that calcium-activated thiol proteinases are involved in the formation of certain types of memory.     

Time-shared feeding and drinking

Barbary doves were tested in an operant situation in which they characteristically alternate between feeding and drinking. The experimental findings may be summarized as follows: (1) the cumulative distribution of the intervals between feeding bouts is little affected by reward rates; (2) a lock-on index is correlated with reward rate, but is not affected by altering reward rate per se, as long as the overall rate of ingestion remains the same; (3) when a primarily hungry animal is interrupted while feeding, or a primarily thirsty animal while drinking, the behaviour is resumed after the interruption; (4) when a primarily hungry animal is interrupted while drinking, or a primarily thirsty animal while feeding, the behaviour is resumed after a short interruption, but changes to the alternative behaviour following a long interruption; (5) titration of interruption period in the dominant region of the motivational state space is always stable, but becomes unstable if the dominance changes, or if the titrating criteria are reversed. From this evidence it is concluded that feeding and drinking can be time-shared in a manner analogous to that found in computers.     

Separate neural sites for d-amphetamine suppression of mouse killing and feeding behavior in rats

The present study was conducted to investigate several possible neural sites for d-amphetamine's effect on mouse killing and feeding behaviors. d-Amphetamine (10, 20, and 30 μg) injected into each lateral ventricle, suppressed mouse kiling, food, and water intake in a dose-dependent manner. Bilateral adminstration of d-amphetamine (20 μg) into the central amygdaloid nucleus abolished mouse killing behavior but did not affect feeding and drinking. By contrast, bilateral amphetamine injections into the substantia nigra, or into the ventral region of the caudate nucleus, did not suppress mouse killing behavior, but significantly decreased food and water intake. The lateral hypothalamus was sensitive to d-amphetamine injections, which suppressed mouse killing and food intake as well as water intake. d-Amphetamine injections into the nucleus accumbens produced inconsistent effects on mouse killing and feeding. Our observations suggest a differentiation of the neural sites that mediate feeding from those underlying mouse killing behavior.     

Gastric pathology and feeding deficits induced by hypothalamic damage in rats: effects of lesion type, size, and placement.

Three doses each of cathodal or anodal direct current were delivered to coagulate lateral hypothalamic tissue bilaterally in rats. Increases in hypothalamic tissue damage were associated with more instances of aphagia, greater amounts of glandular, but not rumenal, gastric pathology, and greater weight loss. Both anodal and cathodal lesions produced aphagia and similar amounts of gastric pathology, but anodal lesions also appeared to facilitate weight loss independently of the tissue damage. Extensive chromatolysis surrounding anodal lesion cavities may be importantly related to the postoperative effects. In additional experiments, anodal electrolytic lesions or cortical suction ablations were used to vary the location of neural damage. Fedding deficits and gastric pathology resulted from the destruction of several brain areas. In particular, eating of dry food in the presence of high gastric pathology was observed in rats with lesions ventral and medial to an area in the dorsolateral hypothalamus that was associated with aphagia. When aphagia was accompained by severe gastric pathology, the brain lesions typically encroached extensively on more ventromedial areas. Moreover, aphagia sometimes was observed with only negligible gastric pathology. It is suggested that gastric pathology is not primary to the expression of the aphagia that follows lateral hypothalamic damage.     

Insulin and glucagon as determinants of body weight set point and microregulation in rats

Seven adult male rats were observed for body weight and microregulation (feeding, drinking, and running patterns) after manipulation of insulin and glucagon levels. They received three injections per day for 3 days each week of 3 U of protamine zinc insulin, .25 mg of zinc glucagon, 50 microgram of protamine zinc somatostatin (SRIF), or protamine zinc vehicle. Diabetes was then induced with an iv injection of streptozotocin (65 mg/kg), and the injection schedule was repeated after the full diabetic syndrome emerged. In all rats whose insulin levels were increased relative to glucagon levels, body weight increased; in those whose glucagon levels were increased relative to insulin levels, body weight decreased. All injections except vehicle reduced meal sizes in both normal and diabetic rats, but only insulin increased the frequency of feeding. These effects could be predicted by the glucostatic theory of food intake regulation and are thus interpreted as supportive of this theory. These results also support the hypothesis that the relative concentration of insulin to glucagon is a regulator of body weight set point.     

Modifications in basal and stress-induced hypothalamic AMP-activated protein kinase (AMPK) activity in rats chronically treated with an angiotensin II receptor blocker

5' adenosine monophosphate-activated protein kinase (AMPK) plays a prominent role as a metabolic stress sensor. The role of hypothalamic AMPK in response to restraint and surgical stress has not been previously investigated. It has been recently suggested that the renin-angiotensin system, in addition to its role in stress regulation, may play a significant role in regulating metabolic pathways including the regulation of the AMPK system. This study was thus aimed to evaluate the effects of candesartan, an angiotensin II AT1 receptor blocker drug, on hypothalamic AMPK activity under basal conditions and after restraint in conscious rats or after surgical stress under general anesthesia. Male Wistar rats were treated with 5 mg/kg/day candesartan in the drinking water for 2 weeks. The hypothalamic AMPK activity was determined under basal and stress conditions, using a kinase activity assay. Chronic administration of candesartan significantly increased hypothalamic AMPK activity. Hypothalamic AMPK activity was also increased by restraint stress whereas no change was observed during surgical stress under anesthesia. The high levels of hypothalamic AMPK activation observed in candesartan-treated rats were not changed by restraint stress but were reduced to control levels by anesthesia and surgery. In conclusion, chronic candesartan treatment and restraint stress in conscious rats stimulate the hypothalamic AMPK activity, whereas surgical stress under anesthesia inhibits pathways regulating the AMPK activity even in candesartan-treated rats.     

Sociodemographic factors,religiosity, academic performance,and substance use among first-year university students in South Africa

The purpose of this study was to identify the relationships among sociodemographic variables, family background, religiosity, course of study, academic performance, and substance use. The sample included 799 first-year students in the age range of 16 to 49 years (M age 20.1 yr., SD = 3.2) chosen at random from the University of the North in South Africa. A Model Core Questionnaire from the WHO on Substance use was administered. Analysis indicated that women smoked tobacco or cannabis and drank less than men, while women took more stimulants and other opiate type drugs than men. Low scores on religiosity was a predictor for past-month tobacco use alcohol use, binge drinking, cannabis use, and having a drinking or drug problem now. Being a member of a Protestant denominational church or a Roman Catholic was a predictor for past-month tobacco and alcohol use. A family history of drinking or drug problems and being a social science or humanities student were predictive for a current alcohol or drug problem. Economic status, education of parents. living arrangement. and rural-urban differences were not associated with substance use. Findings have implications for prevention programmes.     

Developmental flavor experience affects utilization of odor, not taste in toxiphobic conditioning

Feeding experiences were varied in developing rats and the effects upon flavor neophobia and lithium chloride-induced flavor aversions were observed. In Experiment 1, nursing experience of neonate rats was reduced by artificial feeding via intragastric cannula; the rats then were tested with apple juice paired with lithium chloride injection at weaning or maturity. Conditioned aversions were not affected, but neophobia to novel apple juice was attenuated in artificially-reared rats tested at maturity. In Experiment 2, rats received enriched feeding experience after weaning, which consisted of (a) obtaining many complex flavors, a few of which were paired with poisoning, effortlessly in the home cage, or (b) foraging for various foods on an elevated maze. No dramatic effects on neophobia or conditioned taste aversion for saccharin water were apparent. In Experiment 3, rats were given experience after weaning with vanilla-scented water either paired or unpaired with quinine water, and then tested with the odor of almond or that odor compounded with saccharin water for neophobia and lithium-induced aversions. Flavor-experienced rats exhibited more pronounced odor conditioning and more resistance to extinction of the odor aversion after both simple and compound conditioning. In contrast, saccharin taste aversions were relatively unchanged. Apparently, enriched feeding and drinking experience facilitates the utilization of odor more than taste cues.     

Thiamin deprivation in ventromedial hypothalamic hyperphagic rats: anorexia, specificity of food aversion, and a dietary consideration.

The anorexic consequence of thiamin deprivation was investigated in ventromedial hypothalamic (VMH) hyperphagic rats under either high-fat or low-fat thiamin-free diet conditions. The low-fat diet maintained feeding significantly longer in thiamin-deprived VMH rats than in intact rats, whereas the hig-fat diet sustained feeding in thiamin-deficient intact rats and accelerated anorexia onset in vitamin B1 deprived VMH rats. This effect was noted under both ad lib and pair-feeding conditions. Thiamin-deprived VMH rats subjected to weight control developed anorexia sooner than intact subjects regardless of the diet employed. The VMH rats fed a high-fat diet failed to resume feeding after thiamin readministration, which was interpreted as a permanent aversion to this diet. The relation between dietary intake and conditioned taste aversion is discussed with reference to the VMH and intact rat.     

Neocortex and feeding behavior in the rat.

Consummatory behavior and weight-regulation capacity were measured in 12 normal rats and in 43 rats that survived complete (C), sequential unilateral (U), anterolateral (A), or posterior (P) neocortical ablations. Groups C and A displayed aphagia and adipsia followed by a sequence of recovery stages gualitatively identical to, but shorter than, recovery typically seen following lateral hypothalamic lesions. After recovery, Group C displayed long-term effects of finickiness and pradial drinking. These effects as well as a measure of recovery of body-weight-regulation capacity were significantly intercorrelated with lesion size, and body-weight set point remained significantly lower than normal. Group U was relatively unaffected by the first unilateral ablation and showed, relative the second ablation but displayed the long-term effects. Group P, though significantly affected by the lesion, did not display the pattern or intensity of effects described for the other bilaterally ablated groups.     

Drinking by rats after lateral hypothalamic lesions: a new look at the lateral hypothalamic syndrome.

Rats that have recovered from aphagia and adipsia following lateral hypothalamic lesions are believed to be incapable of experiencing thirst and to drink water simply to facilitate the consumption of dry food. However, the present results indicate that these animals will drink in response to dehydration of the intracellular or intravascular fluid compartments and to hyperangiotensinemia, if testing continues beyond a few hours. Comparable effects also were obtained in rats with mesencephalic brain damage, which appeared to destroy portions of the substantia nigra and the ascending nigrostriatal dopaminergic projections. These findings, when placed in the context of a recent neurochemical model for recovery of function, provide the basis for a new interpretation of the lateral hypothalamic syndrome.