Lateral Hypothalamic Syndrome Research Articles

The Lateral Hypothalamic Syndrome in the Weanling Rat: Bone Geometry and Biomechanics

Male weanling Sprague–Dawley rats received bilateral electrolytic lesions in the lateral hypothalamic area (LHAL). One group of sham-operated controls was fed ad lib (CON-ADLIB), another was pair fed to the LHAL group (CON-PF). The experiment was terminated 1 month after surgery. At that time, LHAL rats were 49% and CON-PF rats were 41% lighter than CON-ADLIB. Carcass protein in LHAL rats was significantly reduced in LHAL: versus CON-ADLIB. Linear growth was significantly reduced by 18% in LHAL versus CON-ADLIB, as well as LHAL: versus CON-PF by 6%. Mean caloric intake was significantly reduced by 48% in LHAL versus CON-ADLIB, as was caloric efficiency (body weight gained per calories eaten) by 36%, as well as, in CON-PF versus CON-ADLIB by 20%. LHAL rats showed a significantly shorter (10%), narrower (15%) and thinner (25%) cortex at midshaft of the femur. Resistance to torsional loads was reduced by 25% in both LHAL and CON-PF, but this did not reach statistical significance, in comparison to CON-ADLIB. There was no statistical significance among the groups in stiffness and maximal angular displacement. We conclude that the reduced bone geometrical and biomechanical properties in both LHAL rats and CON-PF versus CON-ADLIB are similar because both former groups of rats were greatly subcaloric. Thus, the changes here observed are not due to a specific neuroendocrine/autonomic lesion effect but may be attributable to the reduced food intake, i.e., nutritional factors.

Gastric mucosal erosions induced by lateral hypothalamic damage: neuronal and dopaminergic mechanisms

Electrolytic lateral hypothalamic (LH) lesions produce numerous disorders including aphagia, gastric mucosal erosions and autonomic and sensorimotor dysfunctions. This series of experiments examined whether damage to LH neurons or dopaminergic fibers of passage produce similar forms and severity of gastric erosions, as well as other disorders. In Experiment 1, LH neurons were destroyed by the excitatory neurotoxin, kainic acid, that presumably leaves axonal fibers of passage intact. Relatively selective damage to LH neurons with kainic acid produced glandular gastric erosions, as well as sensorimotor and autonomic dysfunctions similar to those seen following electrolytic LH lesions. This suggests that direct damage to LH cell bodies may be a primary cause of many of the disorders observed following LH lesions. In Experiments 2 and 3, electrolytic lesions were used to destroy cell bodies in the substantia nigra and their dopaminergic fibers (some of which pass through the LH area). This resulted in the production of gastric erosions in the absence of significant autonomic dysfunctions. Furthermore, atropine methylnitrate prevented the occurence of gastric erosions following substantia nigra lesions, suggesting that the erosion formation is mediated via parasympathetic-vagal activity. In contrast, destruction of the ventral tegmental area (and its associated dopaminergic fibers) had no significant effect on gastric erosion formation. Experiment 4 showed that apomorphine, a central and peripheral dopamine agonist, provided protection against LH lesion-induced gastric erosion formation, whereas domperidone, a peripheral dopamine antagonist, had no effect. Taken together, this study suggests that (a) both LH neurons and fibers of passage provide a potential anatomical basis for the development of gastric mucosal erosions, (b) that an alteration in dopamine levels, either centrally or peripherally, may represent an important neurochemical mechanism for the development of erosions, and (c) that the occurrence of gastric erosion can be dissociated from other symptoms of the LH syndrome.

Metabolic-endocrine correlates of the lateral hypothalamic syndrome: The first 48 hours

Mature (224 g) male Sprague-Dawley rats received bilateral electrolytic (1 mA for 8 sec) lesions in the lateral hypothalamic area (LHAL) or sham operations (CON). One group of CON was allowed to eat ad lib (CON-ADLIB), a second CON group was pair-fed to the LHAL rats (CON-PF). Tap water was available ad lib. Two days after the operation/sham operation all rats were killed by decapitation. Body weight, body weight change, food intake, carcass fat, liver weight, epididymal fat pad weight, in vitro incorporation of U-C 14-glucose into liver total lipid, glycogen and CO 2 (oxidation) (DPM, DPM/mg protein) as well as oxidation in fat pad tissue, plasma glucose and insulin were significantly reduced in LHAL and CON-PF rats compared with CON-ADLIB. Glucose carbon incorporation into epididymal fat pad lipid and glucogen were normal in LHAL and CON-PF. Liver protein and plasma free fatty acids (FFA) were both higher in LHAL and CON-PF than in CON-ADLIB groups. Thus, many of the somatic and metabolic changes that appear in the first few days after lesion production are simply due to hypophagia. However, CON-PF rats also exhibited some significant differences from the LHAL group, i.e., their plasma glucose and incorporation of glucose carbon into liver glycogen (DPM) were significantly lower than in LHAL rats; alternatively, plasma FFA levels were higher in CON-PF than in LHAL rats. Also, liver weight/100 g body weight was lower and fat pad weight/100 g body weight was higher in CON-PF than in LHAL rats. These latter differences suggest that LHAL rats may show a greater peripheral catabolism with enhanced substrate conversion to glucose and glycogen in the liver. Therefore, some of the metabolic manifestations postsurgery are due to lesion-induced changes that appear to be independent of the animals' hypophagia.

Relationship of thyroid hormones and norepinephrine to the lateral hypothalamic syndrome

The role of thyroid hormones and norepinephrine in the elevated thermogenesis seen following lateral hypothalamic (LH) lesions was investigated by measuring serum thyroid hormone levels and urinary norepinephrine excretion during the 24 hours following placement of LH lesions and again one month later when body weight had stabilized at a reduced level. During the first 24 hours following LH lesions, serum thyroxine (T 4) and triiodothyronine (T 3) were significantly depressed. By one month postlesion, both T 4 and T 3 had returned to normal. In contrast, urinary excretion of norepinephrine (NE) was increased 100% during the 24 hours following LH lesions. By one month postlesion, NE had returned to normal levels. These results indicate that the elevated thermogenesis seen shortly following LH lesions does not reflect enhanced thyroid activity, but is probably a consequence of sympathetic nervous system stimulation. The return of NE to normal levels after one month is consistent with the observation that LH-lesioned rats are by one month postlesion no longer hypermetabolic, but display levels of heat production appropriate to the reduced body weight they then maintain.

Control of sensorimotor function by dopaminergic nigrostriatal neurons: Influence on eating and drinking

The literature on the effects of lesions of the lateral hypothalamic area (LHA) on eating and drinking is reviewed in an effort to understand the function of the neural substrate destroyed. The data suggest that damage to the dopaminergic nigrostriatal neurons that course through the LHA results in a decrease in sensorimotor facilitation; that is, an increase in the threshold for responding to stimuli that elicit orientation, approach and consumption. This increase results in decreased consumption of food and water. Evidence is also reviewed suggesting the possibility that striatal dopaminergic activity may mediate a negative feedback signal related to blood glucose level that influences responsiveness to food, and therefore eating. There is no evidence that the nigrostriatal system mediates a similar signal related to water balance and drinking. A second deficit associated with LHA lesions, caused by damage to the pallidofugal neurons that descend through this area, is a dysfunction of motor control of the head and mouth. This results in an increase in the effort required to consume food and water, also leading to decreased consumption. These two behavioral factors: an increased threshold for responding to the sensory properties of food and water and an increase in the effort required to eat and drink are used to explain the symptoms making up the lateral hypothalamic syndrome without postulating changes in physiological regulatory (set point) mechanisms.

We should De-emphasize the Importance of the Role we give Amines in the LH Syndrome

Once amines were implicated in the lateral hypothalamic syndrome, it became accepted that the dominant cause of many of its symptoms was an alteration in amines. We suggest that corticofugal fiber damage may produce some of the behavioral symptoms usually attributed to amine alterations.

A Role for Amine Accumulation in the Syndrome of Ingestive Deficits following Lateral Hypothalamic Lesions

Lesions of the lateral hypothalamus produce ascending catecholamine neuron degeneration which results in terminal depletion and proximal accumulation above the lesions. The occurrence of deficits in ingestive behaviour has been attributed traditionally to the loss of functional dopamine neurotransmitter in the terminal fields. However, release of functional amines may occur in the lateral hypothalamus at areas of accumulation, to produce at least some of the behavioural symptoms characterizing the lateral hypothalamic syndrome. Recovery from behavioural deficits as a result of various pharmacological treatments, after dopamine-depleting lesions, may be mediated by changes in amine release or modified sensitivity of receptors affected by released amines. We conclude that amine accumulation should be considered when interpreting experiments implicating central catecholamine systems in the control of consumatory behaviour and the regulation of body weight.

Influence of sympathectomy on the lateral hypothalamic lesion syndrome.

Sympathetic involvement in the lateral hypothalamic (LH) lesion syndrome was examined. Male rats were surgically or chemically sympathectomized and then given LH lesions. At 24 hr postlesion, lesion-induced hyperglycemia but not hyperthermia was attenuated by splanchnicectomy and celiac ganglionectomy. Hyperthermia but not hyperglycemia was attenuated by adrenal demedullation, adrenalectomy, and neonatal guanethidine treatment. Guanethidine-sympathectomized rats also displayed lower basal temperatures, more perilesion chromatolysis, and severer external symptoms than their controls. No form of sympathectomy affected lesion-induced gastric pathology, plasma gastrin concentrations, or body weight loss. Nor did any sympathectomy influence the recovery of ingestive behavior, daily food intake, the feeding response to 2-deoxy-D-glucose, or body weight maintenance in recovered LH-lesion subjects. These results suggest that sympathetic hyperactivity contributes to some aspects of the acute LH syndrome: Hyperglycemia results from sympathetic outflow to the abdomen, whereas hyperthermia is determined by circulating catecholamines and extraabdominal sympathetic innervation. The results fail to support the hypothesis that chronic increases in sympathetic tone are responsible for the reduced food intake and body weight of the LH-lesion rat.

Influence of sympathectomy on the lateral hypothalamic lesion syndrome.

Influence of sympathectomy on the lateral hypothalamic lesion syndrome.

Body composition and adiposity in LH-lesioned and pair-fed obese Zucker rats.

It has been reported previously that lateral hypothalamic (LH) lesions alter body composition including reducing adipocyte cellularity in lean and obese Zucker rats. The present experiment was designed to determine whether these alterations in body composition and adipose cell number are secondary to the reduced energy consumption of LH-lesioned rats or to a direct effect of the hypothalamic lesion. Groups of lean and obese Zucker rats, sustaining lesions of the lateral hypothalamus at 10 wk of age, maintained body weight at 72% that of nonlesioned controls until killed at 32 wk. Pair-feeding nonlesioned rats to the intakes of lean and obese LH-lesioned rats produced a reduction in adipocyte number similar to that caused by lesions. However, neither the lean nor obese LH-lesioned rats displayed an increase in cell number when fed a palatable diet that markedly increased carcass lipids. This finding suggests that adipocyte number may be constrained in LH-lesioned rats. These and further observations that 1) lean control rats maintained a higher body weight than the LH-lesioned rats to which they were pair fed and 2) in obese rats, food restriction further reduced protein deposition and elevated plasma insulin relative to comparably fed LH-lesioned obese rats suggest that the LH syndrome is mimicked by simple food restriction.

Aphagia, gastric pathology, hyperthermia, and sensorimotor dysfunctions following lateral hypothalamic lesions: Effects of insulin pretreatments

Previous studies have shown that lateral hypothalamic (LH) lesions produce numerous disorders including aphagia, gastric pathology, hyperthermia, and sensorimotor dysfunctions. Because insulin pretreatments shorten the period of aphagia following LH lesions, the present study examined the possibility that insulin might also alter the incidence of other disorders resulting from LH damage. It was found that insulin pretreatments shortened the period of postoperative aphagia and reduced, but did not prevent, the occurrence of glandular gastric pathology. In addition, insulin did not prevent the hyperthermia or attenuate the severity of sensorimotor dysfunctions. Groups of LH damaged rats pretreated with either insulin or saline and allowed to recover initial feeding behaviors displayed significant reductions in core temperature and less gastric pathology than a group of LH rats also pretreated with saline but which was sacrificed while still aphagic. Furthermore, LH animals which ate did so in the presence of rather pronounced sensorimotor abnormalities. These findings suggest that aphagia and sensorimotor dysfunctions induced by LH lesions can be dissociated. They further suggest that viscero-metabolic disroders may play an important role in the initial stages of the LH syndrome, and indicate that insulin may influence recovery of feeding behaviors by affecting peripheral systems as well as central nervous system functions.

The lateral hypothalamic syndrome: Comparison with the syndrome of anorexia nervosa

The lateral hypothalamic syndrome of feeding disorders may not involve the hypothalamus per se, nor is it simply an impairment of feeding behavior. Recent work has forced revisions in traditional concepts regarding the role of the hypothalamus in the control of feeding. At present, it seems clear that hypothalamic damage disrupts nonspecific contributions to feeding behavior, by damaging dopaminergic and other fibers of passage coursing through the ventral diencephalon, and that the resultant aphagia reflects a general disruption of all voluntary behavior that includes feeding but is not restricted to it. Neurological dysfunctions such as akinesia, catalepsy, and sensory neglect are prominent and indicate a broad activational disorder reminiscent of Parkinson's disease. In the absence of a clear notion of how feeding is controlled by the brain, it seems premature to consider animals with experimental lesions in the hypothalamus (or elsewhere in the brain) as appropriate models of anorexia nervosa.

Cortical activity and sleep in the rat lateral hypothalamic syndrome

Continuous EEG recordings were performed in lateral hypothalamic (LH) damaged rats from day 1 post-lesion when totally aphagic and adipsic until complete recovery of their feeding and drinking. During the early post-operative stage (days 1–3 post-lesion), LH rats showed a complete disorganization of their basal EEG which was characterized by two superimposed activities, a constant rapid low voltage activity modulated by high voltage low frequency waves. Except in the case of intense illumination, several arousing stimuli did not affect this activity. By day 4 post-lesion, the two overlapping activities were replaced by less abnormal waves on top of which the first normal sleep spindles appeared. Sleep increased gradually and normal amounts of both slow-wave and paradoxical sleep were observed during ‘stage 4’ of recovery when rats again ate food and drank water. During this stage, and contrary to normal rats, meal size was correlated only with sleep events occurring within the intermeal interval following the next meal, when most of the ingested nutrients reached the systematic compartment. The effect on sleep of intragastric or intravenous caloric repletion was, at least in part, in agreement with the view of indirect effect of LH lesions on sleep through metabolic impairment. Whatever the mechanism underlying sleep deficits, these are one of the major symptoms of the lateral hypothalamic syndrome.

Meal-induced decreases in serum corticosterone in the lateral hypothalamic syndrome

Decreases in serum corticosterone levels were used to quantify positive emotional responses to meals in rats that survived bilateral lateral hypothalamic lesions (n=9), intraventricular 6-hydroxydopamine injections with pargyline pretreatment (n=3), or without it (n=8) and operated controls that were fed either ad lib (n=19) or were pair-fed with brain-damaged rats throughout the study (n=11). Meals of dry powdered chow and tap water, offered in the evening after 8 hr of food and water deprivation, did not reliably reduce corticosterone levels within 30 min. When the rats were forced to eat their entire daily food ration during a 1-hr morning period for over 2 weeks, corticosterone levels were lower within 10 min of meal onset than they were prior to feeding. Placement of the rats into chambers in which they had received their daily meals was also effective in reducing corticosterone levels. Lateral hypothalamic or 6-hydroxydopamine lesions did not affect the magnitude of the corticosterone decreases, but did affect changes in glucose levels associated with meals. The data were discussed in terms of mechanisms involved in the permanent hypophagia of the lateral hypothalamic syndrome.

Changed cortical activation and the lateral hypothalamic syndrome: a study in the split-brain cat

Changed cortical activation and the lateral hypothalamic syndrome: a study in the split-brain cat

Biochemical and pharmacological basis for the lateral hypothalamic syndrome

The lateral hypothalamic (LH) syndrome characterized by impairment of the ability to regulate food and water intake has been reported to occur after injections of 6-hydroxydopamine (6-OHDA) into this region. In the present experiment the fluorescence histochemical technique was used to assess monoamine depletion of noradrenaline and dopamine containing neurons following intrahypothalamic injection of 6-OHDA. Results show that the intensity and area of monoamine accumulation in axons served by 6-OHDA is correlated with the severity of behavioral deficits but that actual catecholamine depletion of either the corpus striatum or the hypothalamus is unrelated to the syndrome. Possible mechanisms of action of this accumulation in producing behavioral deficits are discussed.

Body weight and regulatory deficits following unilateral nigrostriatal lesions

Unilateral nigrostriatal lesions were performed in rats by punctate injection of 6-hydroxydopamine. Lesioned animals exhibited anorexia and weight loss for 7–11 days after surgery. These animals then displayed normal rate of weight gain. However there was a chronic depression of body weight in the lesioned animals relative to sham controls, evident for over two months after 6-hydroxydopamine administration. Unilateral nigrostriatal damage also produced major deficits in the animals' water intake in tests of prandial drinking, response to water deprivation, and response to osmotic challenge. The relationship of nigrostriatal damage to the “lateral hypothalamic syndrome” and the role of dopaminergic neurons in regulation and ingestive behaviors are discussed.

Effects of lateral hypothalamic lesions on schedule dependent and schedule induced behavior

Rats were reduced to 80 percent body weight and were exposed to an FI 1 min food reinforcement schedule for 30 min daily until lever presses, licks and water consumption stabilized for at least 10 days. Six animals were subjected to bilateral mid lateral hypothalamic (LH) lesions and 6 animals to bilateral posterior LH lesions. Animals were tested for 50 days following the lesions at 80 percent body weight, were permitted to recover body weight, and were tested for an additional 30 days under ad lib feeding and after body weight recovered. Animals were then subjected to the following four home cage tests: food consumption following food deprivation; drinking following water deprivation; insulin induced eating; and salt arousal of drinking. On the basis of the data collected in these tests and lesion locus and size, the 12 experimental animals were divided into 3 groups--asymmetrical, typical and posterior bilateral LH lesion and were compared to a sham lesion control group of 4 animals. The asymmetrical LH lesion group was similar to the sham lesion group except lever pressing was significantly depressed. Typical bilateral lesion animals displayed the usual LH syndrome with prolonged depression of both schedule dependent lever pressing and schedule induced licking and drinking. Posterior bilateral LH lesions produced the most drastic effects on both schedule dependent and schedule induced behavior. Results indicate that the neural mechanism which is involved in schedule induced polydipsia is destroyed by posterior bilateral LH lesions.

Body weight and gastric acid secretion in rats with subdiaphragmatic vagotomy and lateral hypothalamic lesions.

In an experiment to investigate the role of the vagus in the lateral hypothalamic (LH) syndrome of body weight loss, male albino rats were divided into four groups: (a) animals with bilateral LH lesions that were subsequently given a bilateral subdiaphragmatic vagotomy, (b) LH animals that received a control vagotomy operation, (c) nonlesion animals that were given a subdiaphragmatic vagotomy operation, (c) nonlesion animals that were given a subdiaphragmatic vagotomy, and (d) nonlesion animals that received a control vagotomy operation. Both LH lesions and vagotomy reduced body weight levels, though the effects differed in terms of the length of time required to reach initial maximal loss, the time required to reach chronic levels of maintenance, and the severity of body weight reduction. Fasting gastric acid secretion was lowered by LH lesions, and the extent of this reduction was positively correlated with the reduction in body weight. Finally, gastric contents after a 24-hr fast were greater in vagotomized rats than in nonvagotomized animals. These data are discussed in relation to the changes in gastric functioning after LH lesions and vagotomy.

Recovery of regulatory drinking following lateral hypothalamic lesions: Nature of residual deficits analyzed by NaCl and water infusions

Traditional views that thirst is no longer experienced by rats which have recovered spontaneous ingestion after lateral hypothalamic lesions have been questioned by a number of recent observations which emphasize the non-specific stressful aspects of dipsogenic challenges. These issues have now been examined in some detail using novel and nonstressful drinking tests. During long-term intravenous and intragastric NaCl infusions, five out of eight rats with lesions in the lateral hypothalamus increased oral drinking. These five rats, and two of the nondrinkers, decreased oral drinking during complementary experiments in which water was infused. All animals with lesions selected for study showed complete failure to drink within 6 hr of intraperitoneal NaCl injection. It is therefore suggested that previous studies have failed to characterize completely the nature of the drinking impairments in these animals. The implications and difficulties of interpretation of these findings in terms of regulatory deficits are discussed, as well as more general issues relating to recovery of function after central nervous system damage. There may be qualitative differences between animals with larger and smaller lesions, and it appears unwise to posit global explanations for the lateral hypothalamic syndrome.