Infusion of neurotoxic doses of N-methyl-D-aspartate into the lateral hypothalamus in rats produces stomach erosions, hyperthermia, and a disruption in eating behavior.

The present study examined whether damage to intrinsic lateral hypothalamic (LH) neurons induced by microinfusions of N-methyl-D-aspartate (NMDA) would produce effects similar to those seen after electrolytic LH lesions. In Experiment 1, rats receiving electrolytic (1.2 mA anodal current, 10 s) LH lesions displayed motor impairments, whereas those receiving NMDA (20 microg/microl) infusions did not. Both electrolytic lesions and NMDA infusions were associated with eating deficits, hyperthermia, and gastric erosion formation 24 hr after surgery. In Experiment 2, either 20 microg/microl or 10 microg/microl NMDA destroyed LH cells and produced dose-dependent gastric mucosal erosions as well as similar increases in body temperature. These results indicate that an alteration in the acute activity of intrinsic LH neurons plays a role in the production of gastric mucosal injury and hyperthermia and lend support to other studies implicating a role of LH neurons in eating behavior.

Gastric mucosal erosion produced by NMDA microinfusions in the lateral hypothalamus: effect of selective knife cuts.

Bilateral infusions of N-methyl-D-aspartate (NMDA) into the lateral hypothalamus (LH) produce gastric erosions in rats. The present study attempted to determine the neural pathways that mediate this effect. In order to interrupt axonal transmission, knife cuts (KC) were made in different planes adjacent to the LH. In separate groups of rats, KC were made anterior, posterior or lateral to the LH just prior to bilateral NMDA infusions (20 micrograms/microliter). The incidence of gastric erosions was measured 24 h after NMDA infusions. Animals receiving sham KC and infused with NMDA exhibited significantly more gastric erosions than those infused with vehicle. Lateral parasagittal KC blocked the occurrence of gastric erosions produced by NMDA, whereas anterior coronal KC significantly increased the incidence of erosions produced by NMDA. Posterior coronal KC did not alter the incidence of gastric erosions produced by NMDA infusions into the LH. These results suggest that intrinsic LH neurons with gastric function project axons laterally and probably descend through the internal capsule to brainstem medullary nuclei. The results of the anterior KC suggest that the LH sends and/or receives inhibitory projections from neural structures (possibly the amygdaloid complex) anterior to the plane of the KC.

Body temperature and wheel running predict survival times in rats exposed to activity-stress.

The relationship between restricted feeding, core body temperature (Tb), wheel running, survival, and gastric erosion formation was examined in female rats exposed to activity-stress. Core body temperature and gross motor activity were telemetrically monitored in four groups of rats that had free access to running wheels and in one group that was not allowed to run on the wheels. Twenty-four hours prior to the onset of hypothermia and predicted mortality, different groups were left undisturbed, warmed with a heat lamp, denied access to running wheels, or euthanized. Length of survival in wheel-running rats varied from 2 to 12 days. During the first day of food deprivation, premorbid changes in the variability of Tb during the diurnal period and the mean number of wheel revolutions during the nocturnal period were strongly predictive of length of survival. Warming rats with a heat lamp or preventing rats from ever running on the wheel increased the length of survival and attenuated gastric erosion formation. Only rats that were warmed had a greater likelihood of survival. Gastric pathology was also reduced in rats that were euthanized prior to becoming moribund. Rats that were left undisturbed or locked from the running wheel over the last 24 h of testing became moribund and had extensive gastric mucosal damage. These results indicate that thermoregulatory disturbances induced by restricted feeding and not wheel running alone are critical in determining survival and the degree of gastric mucosal injury in rats exposed to activity-stress. Results further suggest that predisposing factors may put some rats at risk for the development of activity-stress-induced mortality.

Lateral hypothalamic lesions cause gastric injury by stimulating gastric contractility.

Changes in gastric contractility following lateral hypothalamic (LH) lesions with and without bilateral cervical vagotomy were measured in urethan-anesthetized rats. LH lesions were induced with direct current passed through stereotaxically placed electrodes. Gastric contractility was recorded continuously for 4 h with acutely implanted strain gauge force transducers and analyzed by computer. LH lesions consistently stimulated gastric contractility and caused more gastric mucosal injury than control conditions. Vagotomy blocked both gastric mucosal injury and high-amplitude gastric contractions. In rats with LH lesions and exogenously infused intragastric hydrochloric acid, atropine methyl nitrate inhibited high-amplitude gastric contractions and gastric erosions. These findings indicate that LH lesions stimulate vagally mediated high-amplitude gastric contractions, which, in the presence of hydrochloric acid, cause gastric mucosal erosions.

Effects of amygdaloid lesions on gastric erosion formation during exposure to activity-stress.

To examine the role of the amygdala in the production of gastric ulcers induced by activity-stress, electrolytic lesions were placed in the centromedial (CENT) and medial (MED) amygdaloid nuclei, as well as in the intra-amygdaloid division of the bed nucleus of the stria terminalis (BNST). As compared to sham-operated controls (CONT), gastric ulceration was attenuated in rats with CENT lesions and exacerbated in rats with lesions located in the BNST or MED. Wheel running did not differ significantly between control animals and lesioned rats, but did differ within lesioned groups. Rats with MED lesions ran more than rats with CENT or BNST lesions. Results support the view that the integrity of the centromedial amygdala is critical for the maintenance of the viscera and demonstrate that neurogenic factors contribute to the development of gastric erosions during exposure to activity-stress.

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 occurrence 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.

Destruction of different fiber tracts underlies development of lateral hypothalamic lesion-induced hyperthermia and loss of bombesin-induced hypothermia.

The relative roles of lateral hypothalamic cell bodies and fibers of passage were assessed in the development of lesion-induced hyperthermia and bombesin-induced hypothermia. Electrolytic lesions or discrete fiber transections were combined with intracisternal bombesin injection to show that each of these two thermoregulatory effects involves fibers crossing the borders of the lateral hypothalamus; however, the two effects primarily involve fibers crossing different borders. Thus, the hyperthermia and the abolition of bombesin-induced hypothermia which follow lateral hypothalamic damage appear to result from disruption of separate thermoregulatory pathways.

Gastric mucosal damage induced by lateral hypothalamic lesions in female rats: influence of age and ovariectomy.

Male rats given lateral hypothalamic (LH) lesions exhibit an acute increase in gastric acid secretion and develop erosions of the glandular portion of the stomach within 24 h. Since this process has been examined predominantly in male rats, the present experiments were devised to study the effects of LH lesions on the gastric mucosa of female rats. In Experiment 1, 1-year-old Sprague-Dawley female rats given LH lesions exhibited erosions in the rumenal portion of the stomach, a pattern unlike that found in both young and old male rats. Although the glandular mucosa lacked evidence of gross defects, the mucosa appeared blanched and covered with a mucus-like secretion. Experiment 2 demonstrated that, like male rats, LH lesions produced gastric hypersecretion in 1-year-old females. The results of the first two experiments indicate that the dissimilar patterns of gastric mucosal injury between males and older females cannot be accounted for on the basis of differences in gastric acid secretion. Experiment 3 demonstrated that, unlike older females but like males, 4-month-old female rats given LH lesions developed gastric erosions in the glandular mucosa only. Additionally, ovariectomy had no significant effect in altering the extent of gastric pathology. Taken together, these results suggests that (1) age and gender are important variables in neurogenic gastric mucosal injury, (2) differences in the type of gastric ulceration cannot be accounted for by differences in acid secretion, (3) ovarian hormones do not appear to play a significant role in gastric ulceration following brain damage.

Contrasting effects of centromedial and basolateral amygdaloid lesions on stress-related responses in the rat.

The effects of lesions in the centromedial and basolateral amygdala were examined using three different tests sensitive to the following stress-related responses: exploratory behavior, pain reactivity, and immune responses. The most clear-cut results were found with exploratory behavior. Rats with lesions of the centromedial amygdala tended to explore a radial-arm maze more quickly and entered more novel arms of the maze than controls. Those with lesions of the basolateral amygdala were generally too hesitant to explore at all. No significant differences were found between groups on measurements of natural killer cell activity. In tests of pain perception, rats in the control group displayed an analgesic response on the hot plate following an injection of the anxiogenic drug, RO 15-1788, whereas rats with centromedial lesions tended to exhibit a blunted response. These findings provide modest support for the view that the central and lateral regions of the amygdala play complementary roles in aversively motivated behaviors and in stress-related response patterns.

The role of the hypothalamus and dorsal vagal complex in gastrointestinal function and pathophysiology.

A foregone conclusion is that central neural and endocrine control of gastrointestinal functions is based on a complex array of interconnecting brain structures, neurochemical systems, and hormonal modulators. As might be expected, a considerable degree of redundancy is seen not only in the manner in which certain brain structures appear to participate in the regulation of GI functions, but also in the extent to which certain neurotransmitters or brain-gut peptides, when injected centrally, alter these functions. Despite the seemingly ambiguous nature of brain-gut interactions, a picture is beginning to unfold that suggests that GI properties are based on certain reflexes (e.g., vago-vagal). These reflexes, in turn, appear to be influenced by brain structures in a hierarchical manner, not all that dissimilar to the system described by Papez and expanded on by MacLean several years ago. For example, the perceptual or cognitive aspects of both external and internal stimuli are monitored at various brain levels, but obviously higher cortical processes are intimately involved. Aversive events provide sensory information, which is integrated primarily by the limbic system (e.g., amygdala) and translated into the expression of emotional behavior and associated autonomic response patterns. Various hypothalamic structures, in turn, appear most strongly to influence physiological changes associated with aversive events by virtue of the direct connections to the autonomic and endocrine systems. Ultimately, the visceral outcome can be seen as being based on the integrated convergence of information from cortical, limbic, and hypothalamic structures onto medullary nerve nuclei as well as other efferent systems. With respect to animal models of neurogenic or stress ulcer, activity of the dorsal vagal complex and vagal efferents appears to be the final common pathway for pathologic changes in the gut.

Flavor-illness aversions: the role of the amygdala in the acquisition of taste-potentiated odor aversions.

In the present experiments the role of the amygdaloid complex and its specific nuclei were tested in the conditioning of taste potentiated odor aversions. In the first experiment two groups of rats were given either large electrolytic lesions in the amygdala (AMX) or sham operations (SH). Postoperatively, these rats were trained to avoid either a taste, an odor, or a taste-odor compound using LiCl illness. Subsequent tests with odor and taste alone showed that the SH group developed strong taste and odor aversions; however, the AMX group failed to display either an odor or taste aversion. In the second experiment, another four groups of rats received either lesions in the medial and basomedial nuclei (M), central nuclei (C), lateral and basolateral (L), or sham operations (SH). The results from postoperative conditioning showed that all groups had strong taste and odor aversions, except group L which displayed a significant disruption of odor aversion learning. In conclusion, these data indicate that the amygdala is involved in the acquisition of taste, odor and potentiated odor aversions learning. Moreover, it is demonstrated that the lateral and/or basolateral nuclei are particularly involved in the development of potentiated odor aversions learning.

Amygdaloid lesions attenuate neurogenic gastric mucosal erosions but do not alter gastric secretory changes induced by intracisternal bombesin.

Bilateral lesions of the lateral hypothalamus in rats produce glandular gastric mucosal damage. The results of the first experiment demonstrated that the severity of the neurogenic gastric erosions is attenuated by prior lesions of the centromedial amygdala. In a second experiment it was shown that fasting gastric acidity is significantly reduced following chronic amygdaloid lesions and this may be the mechanism involved in the protective nature of the amygdaloid lesions against gastric mucosal damage. In addition, it was found that gastric secretory changes induced by intracisternal injection of bombesin are unaffected by amygdaloid damage. The present results are consistent with the view that the centromedial amygdaloid region may influence gastric functions by modulating the activity of the preoptic-anterolateral hypothalamic areas or by directly influencing lower brain stem autonomic control areas.

Neurobiologic and psychobiologic mechanisms in gastric function and ulceration.

The initiation and termination of feeding behavior are not fully understood. The stomach has been implicated as one source of signals regulating food intake. The sight and smell of food are potent stimuli to gastric acid secretion and contraction. The mouth, upper gastrointestinal tract and liver contain receptors regulating food intake; afferent information passes into the brain stem and into the brain areas. Lateral hypothalamic lesions abolish feeding, raise the body temperature and basal gastric acid secretion and produce gastric erosions. Vagotomy and administering propantheline bromide abolish the increased acid secretion after such lesions; they also alter the mucosal barrier permitting diffusion of protons into mucosal cells. Several of the neuropeptides via the central nervous system stimulate or inhibit gastric acid secretion through modulation of the autonomic nervous system. Most animal models of gastric erosions are associated with a reduced body temperature. Unknown is whether or not this association is the result of increased levels of thyrotropin-releasing hormone-a potent stimulus to gastric acid secretion and erosion formation when injected intracisternally.

Ingestive responses to homeostatic challenges in rats with ablations of the anterolateral neocortex.

Because rats with either anterolateral neocortical or lateral hypothalamic (LH) damage initially display similar feeding and drinking deficits and recovery patterns, the possibility that anterolateral neocortical ablations would also produce similar chronic ingestive impairments to glucoprivic and hydrational challenges was examined. In general, rats with anterolateral neocortical ablations exhibited normal feeding responses to food deprivation and glucoprivation induced by insulin or moderate doses of 2-deoxy-D-glucose (2-DG), but their response to a high dose (500 mg/kg) of 2-DG was impaired. These animals also drank normally in response to hypertonic saline injections and following water deprivation, but only if food was available during the test session, results indicating that they drank prandially. Results indicate that although the anterolateral neocortex and LH are anatomically related, these brain regions appear to be functionally dissimilar in terms of the regulation of ingestion.

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.

Fatty acid mobilization to 2-deoxyglucose is blocked by globus pallidus lesions.

Lesions of the lateral hypothalamus or discrete bilateral transections on the lateral border of the lateral hypothalamus disrupt the mobilization of metabolic fuels to intraperitoneal administration of the glucose analog 2-deoxyglucose. To better define the pathways involved in these responses, the effects of globus pallidus lesions on body fuel mobilization were investigated. Globus pallidus lesions blocked the increase in plasma free fatty acids normally caused by 2-deoxyglucose, but did not diminish the concomitant hyperglycemia. The data indicate that a pathway running through the globus pallidus, crossing the dorsoanterolateral hypothalamic border, and turning caudally in the dorsolateral hypothalamus is important in the immediate release of free fatty acids following 2-deoxyglucose administration.

Lateral hypothalamic mediation of hypergastrinemia induced by intracisternal bombesin.

Electrolytic lesions of the lateral hypothalamus (LH), but not of the lateral thalamus, prevented the elevation of serum gastrin induced by intracisternal injection of bombesin in rats. Knife cuts through the lateral or the posterior LH border largely abolished the rise in circulating gastrin induced by intracisternal bombesin. Cuts through the medial LH border partly inhibited the response, whereas cuts through the anterior LH border did not modify peptide action. None of the transections altered basal gastrin levels nor the rise in gastric pH and inhibition of gastric acid output induced by intracisternal bombesin. LH lesions did not modify the rise in serum gastrin induced by intravenous bombesin. These results demonstrate that the gastrin-releasing effect of intracisternal bombesin requires the integrity of fibers crossing the posterior, lateral, and medial borders of the LH and is independent of changes in gastric pH. The LH area is not itself necessary for the expression of the inhibitory action of bombesin on gastric acid secretion.

Lateral hypothalamic lesions or transections block bombesin hyperglycemia in rats.

The peptide bombesin-14 causes hyperglycemia when injected into the cisterna magna of rats. We report that acute lateral hypothalamic lesions block bombesin hyperglycemia. Lateral thalamic lesions do not have this effect. We further report that transections on the lateral or posterior borders of the lateral hypothalamus also block bombesin hyperglycemia. Cuts on the medial border also somewhat diminish this hyperglycemia, while cuts on the anterior border are not reliably effective. These results suggest that fibers traversing the lateral hypothalamus are involved in the hyperglycemic response to intracisternal bombesin-14.

Gastric mucosal damage induced by lateral hypothalamic lesions in rats: the potential contribution of bile.

The present study was conducted to investigate the potential contribution of bile to gastric mucosal damage induced by lesions of the lateral hypothalamic area in rats. In two separate experiments it was found that (1) lateral hypothalamic lesions did not alter the rate of bile flow in the acute preparation, but (2) bile duct ligation significantly reduced the incidence of gastric mucosal damage. Based on these and previous findings it is suggested that the reflux of bile interacts with the weakened gastric mucosal barrier to elicit ulceration.

Functional correlations between lateral hypothalamic glucose-sensitive neurons and hepatic portal glucose-sensitive units in rat.

The effects of glucose injection into the hepatic portal vein on neural activity of the lateral hypothalamic area (LHA) were studied in rats. A majority of identified glucose-sensitive neurons in the LHA were inhibited by portal injection of glucose. This was found to be mediated through the alpha-noradrenergic pathways. Most of the glucose-insensitive neurons did not respond to the same procedure. Portal injection of hypertonic saline increased neural activity of some glucose-insensitive neurons but no glucose-sensitive neurons responded. Convergence of hepatic vagal afferent glucose-sensitive units on LHA glucose-sensitive neurons was clarified by this study.