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.     

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.     

Approach and withdrawal analysis of the effects of hypothalamic stimulation and lesions in rats.

In a paradigm in which rats would both initiate and terminate hypothalamic stimulation, "purely" rewarding lateral hypothalamic and "purely" aversive medial hypothalamic electrodes were identified. Subjects were then given a series of tests designed to assess the effects of brain stimulation on approach and withdrawal behaviors. Lateral hypothalamic stimulation facilitated approach behavior and suppressed withdrawal behaviors, whereas medial hypothalamic stimulation produced largely the opposite effects. No serious motor deficits due to stimulation were detected with either type of electrode. In a second experiment, the approach-withdrawal effects of bilateral lateral hypothalamic lesions were tested and found to suppress approach behaviors and facilitate withdrawal behaviors. Other neurological examinations revealed motor deficits, but these deficits do not account for the specific pattern of results observed on the approach-withdrawal tests. These approach-withdrawal phenomena are interpreted in terms of altering a natural balance between approach and withdrawl behavior facilitating systems in the lateral and medial hypothalamus, respectively.     

Gastric pathology and aphagia following lateral hypothalamic lesions in rats: effects of preoperative weight reduction.

The body weights of male albino rats were reduced gradually to 80% of normal body weight by resricting food intake (dieting), and then the rats were given lateral hypothalamic (LH) lesions. Compared with rats of normal body weight sustaining similar brain lesions, the dieted group displayed a shorter period of postoperative aphagia and less gastric pathology. In a second experiment, a group of rats was reduced to 80% of normal body weight by withholding all food (fasting) and then given LH lesions. Compared with dieted rats sustaining similar brain damage, the fasted group displayed a longer period of post operative aphagia and greater gastric pathology. Since the duration of aphagia could be shortened or lengthened by simple manipulations of preoperative body weight, the adequacy of sensorimotor or motivational hypotheses to account for aphagia is questioned. The results are more consistent with the suggestion that gastric abnormalities produced by LH lesions inhibit eating.     

Role of fatty acid oxidation in control of meal pattern

To characterize the role of fatty acid oxidation in the control of food intake, we investigated the effect of 2-mercaptoacetate, which inhibits fatty acid oxidation, on meal patterns and cumulative food intake in rats. Rats were fed either a medium fat (MF, 18% fat) or a low fat (LF, 3.3% fat) diet. Mercaptoacetate (400 mumole/kg body wt), intraperitoneally injected in the middle of the bright or at the onset of the dark phase of the diurnal lighting cycle, increased cumulative food intake in MF rats by shortening the latency to eat after injection and the duration of the subsequent intermeal interval (IMI) without affecting the size of the first meal. Mercaptoacetate, injected in the middle of the bright phase, reduced the latency to eat but did not affect the duration of the subsequent IMI or cumulative food intake in LF rats. A higher dose of mercaptoacetate (600 mumole/kg body wt), initially increased and later decreased cumulative food intake in MF rats. The initial increase in food intake was due to shorter IMIs; the subsequent decrease in food intake was due to smaller meals after mercaptoacetate injection than after control injection. The results indicate that a drop in fatty acid oxidation caused by mercaptoacetate triggers a meal. This implicates fatty acid oxidation in the maintenance of postprandial satiety.     

Facilitation of a Distributed Shuttle-Box Conditioning with Posttraining Intracranial Self-Stimulation in Old Rats

Old Wistar rats (16–17 months) were trained in a two-way active avoidance task for 5 consecutive days (10 trials/day). Immediately after each training session a lateral hypothalamic intracranial self-stimulation session (ICSS group) or a sham-treatment session (Control group) was given to the animals. Long-term retention was tested 7 days after the last acquisition session. ICSS treatment led to a significant improvement in acquisition. In the long-term retention session the level of avoidance in both groups was similar to that achieved in the last acquisition session, although differences among groups failed to reach statistical significance. These results are compared with those obtained in previous experiments with young adult rats. While ICSS facilitated the process of acquisition in both young and old rats (however, it was much more powerful in young animals), further experiments are needed to elucidate whether this effect is long-lasting in old rats, as occurs in young adult subjects.     

Central noradrenergic neurons: differential effects on body weight of electrolytic and 6-hydroxydopamine lesions in rats.

The ventral noradrenergic bundle (VB) of the rate brain has been proposed as the substrate for the hyperphagia and obesity produced by ventromedial hypothalamic lesions. To determine the relationship between body weight and damage to the VB, the effects of bilateral electrolytic and 6-hydroxy-dopamine (6-OHDA) lesions of the VB were compared. When rats were fed only a standard laboratory diet, no significant differences were found between groups. When a high-fat diet supplement was introduced, the group with electrolytic lesions became significantly heavier than the control group; however, the 6-OHDA group did not differ from the controls. Norepinephrine depletion was significantly greater following the 6-OHDA than the electrolytic lesions. Both lesions reduced telencephalic dopamine and serotonin only slightly. A second study in which both types of lesions were placed at a rostral ventromedial hypothalamic site yielded the same pattern of results. Diet-dependent increases in body weight were attributed to the destruction of a non-noradrenergic system, which was spared by the relatively selective 6-OHDA lesion but damaged by the nonselective electrolytic lesion.     

Changes in feeding and foraging patterns as an antipredator defensive strategy: a laboratory simulation using aversive stimulation in a closed economy.

The effects of the risk of electric shock on the meal patterns of rats living in an operant chamber were investigated. Rats could obtain food by working on a response lever that provided reinforcement according to chained fixed-ratio continuous reinforcement schedules that allowed the animals control over meal size. Using a two-compartment operant chamber with a safe nesting area and manipulanda area with a grid floor, shock could be correlated with responding on the schedule. Shocks (less than or equal to 1.25 per hour) were scheduled to occur randomly throughout the day, independent of the rat's behavior. Shock caused a reorganization of meal patterns such that the animals took less frequent but larger meals. This pattern reduced the time the animals spent at risk without compromising caloric balance. Similar changes in feeding pattern were obtained in both hooded and albino rats. Exposure to shock in a separate chamber did not produce these behavioral modifications. The magnitude of shock-induced alterations of meal patterns was greater with chained fixed-ratio 90 continuous reinforcement than with chained fixed-ratio 10 continuous reinforcement. Additionally, the rats seemed to be able to reduce food intake but increase caloric efficiency, such that the reduced food intake did not have deleterious effects on maintenance of body weight. These behavioral modifications reduced the number of shocks received from that which would have been expected if meal pattern changes had not occurred. We suggest that this technique may provide a useful laboratory simulation of the impact that the risk of predation has on foraging behavior.     

Midbrain-hypothalamic interrelationships in the control of aggressive behavior

Previous studies have suggested an involvement of the midbrain ventral tegmental area in the biting attack upon a rat elicited by electrical stimulation of the lateral hypothalamus in cats. In order assess further the relationship between these two regions, 12 cats were implanted with attack-eliciting electrodes in both the lateral hypothalamus and the midbrain ventral tegmental area. Following a lesion of the midbrain attack site, attack previously elicited from hypothalamic electrodes ipsilateral to the lesion was eliminated or significantly reduced in frequency. The attack elicited from electrodes in the hypothalamus contralateral to the lesion was unaffected. Midbrain lesions made at sites from which attack was never elicited had no effect on hypothalamically elicited attack. The midbrain lesion in some cases eliminated only certain components of the total attack pattern; for example, the approach of a cat to the rat frequently remained present while the bite was absent. Additionally, it was found that the attack elicited from rostral hypothalamic electrodes was disrupted to a greater degree by a single midbrain lesion than the attack elicited from more caudal hypothalamic electrodes. These finding are discussed in terms of the neural system mediating this form of aggressive behavior in cats.     

Medial septal lesions: disruptions of microregulatory patterns and circadian rhythmicity in rats

The microregulatory patterns of food and water intake were examined in male and female rats bearing medical septal lesions and in sham-operated controls. Medial septal ablation, although not affecting the total amount of food or water ingested, resulted in a profound disruption of the pattern of intake. Circadian rhythmicity was disrupted for a period, returning to normal by 25 days postlesion. Permanent disruptions occurred in feeding patterns in the rats with septal lesions ingested more frequent but smaller meals. There was also a marked increase in food-intake-associated drinking and a decrease in non-food-intake-associated drinking. The results are interpreted to reflect two separate independent effects, a general circadian disruption and an alteration in requlatory behavior produced by a chronic depletion of body fluid.     

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.     

Procurement time as a determinant of meal frequency and meal duration.

Foraging involves the expenditure of both time and effort in the acquisition of food; animals typically modify their meal patterns so as to reduce these expenditures or costs. The contribution of time, as compared with effort, to the overall cost perceived by an animal is not known. We investigated the effect of foraging time as a cost independent of effort by measuring the meal patterns of rats living in a laboratory foraging simulation in which they earned all their daily intake. They pressed a bar once to initiate an interval (procurement interval) leading to the presentation of a large cup of food from which they could eat a meal of any size. As the length of the interval increased from 1 s to 46 hr, meal frequency decreased regularly. Meal size increased in a compensatory fashion, and total daily intake was conserved through an interval of 23 hr. The changes in meal frequency occurred because of changes in the rat's latency to bar press after each meal. The functions relating meal frequency and size to the procurement interval were of the same shape as those seen when cost is the completion of a bar-press requirement, which entails the expenditure of both effort and time. When the bar-press requirement was increased to 10, meal frequency was reduced, but time and effort did not appear to simply add together in the rat's perception of cost. These data reveal that time is preceived to be a cost by rats foraging in this laboratory environment. These results suggest that the time parameters of foraging are different from those of consumption.     

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.     

Mouse killing in rats induced by lesions of the medial hypothalamus or medial accumbens: short-term preoperative exposure to a mouse does not suppress the killing

Rats were either exposed or not exposed to a mouse in their living cage for a 48-hr period. At the end of this time a bilateral lesion was made in the medial accumbens region or in the medial hypothalamus. When tested 2 days postoperatively, the killing frequency among rats that had been exposed to mice preoperatively was not significantly lower than that of rats that were not preoperatively exposed. The ineffectiveness of preoperative experience in suppressing the mouse killing induced by medial accumbens and medial hypothalamic lesions is similar to that found previously with dorsal-median raphe lesions and olfactory bulb lesions and is in contrast to the ease with which preoperative experience prevents mouse killing induced by septal lesions and serotonergic lesions induced by 5,7-dihydroxytryptamine.     

Long-term memory loss in senescent rats: neuropsychological analysis of interference and context effects

Four experiments are reported in which normal, senescent (25-27 months) and young adult (6 months) rats were tested for recall of a passive avoidance response 1 hr or several weeks after conditioning. There were no age differences at the 1-hr test, but a decrement was observed in old rats tested under standard conditions after long delays. The age-related impairment was exaggerated when additional approach training was administered in an identical apparatus between avoidance conditioning and testing. When the approach training was administered in an apparatus that contrasted markedly from the original, no age differences were observed. It was concluded that increased susceptibility to interference and contextual factors contributed to rapid forgetting in old rats, a pattern very similar to that observed previously in young adult rats with selective lesions to the hippocampus.     

Performance of rats on the Maier three-table task following septal lesions occurring 24 hours after birth

The purpose of this study was to determine whether behavioral sparing would be demonstrated when septal lesions occurred prior to the age at which the tested behavior first appears in normal rats. Rats given septal lesions at 1 day or 7 days after birth performed at approximately chance on the Maier three-table task when tested at 90 days of age. Rats that had control electrode insertions at the same ages performed at a level similar to normal animals. Animals given septal lesions at either age explored significantly more than did control animals. Results are discussed in terms of the constancy over time of the septal contribution to performance on the three-table task and the involvement of the septum and hippocampus in the processing of spatial information.     

Differential ethanol olfactory experiences affect ethanol ingestion in preweanlings but not in older rats

Preweanling (21 days old) and adult (60-80 days old) rats were exposed to ethanol odor either paired with the early stages of apomorphine-induced toxicosis, paired with the recovery from toxicosis, or unpaired with the induction of distress. Twenty four hours later, ethanol preferences were measured in a spatial olfactory test (ethanol vs lemon odor) or a drinking test (5.6% v/v ethanol vs 0.25% w/v citric acid solutions). During the olfactory test both young and adult rats expressed substantial ethanol odor aversions when previously exposed to this odor paired with toxicosis. However, changes in ethanol intake became apparent only in preweanling subjects. Preweanlings which received the ethanol odor paired with illness drank significantly less of the ethanol solution relative to controls, while subjects experiencing the odor paired with recovery from distress significantly increased their consumption of the ethanol solution. These prior aversive and appetitive olfactory experiences had no effect upon ethanol intake in adult rats. These results implicate both an ontogenetic and a sensorial factor in the regulation of ethanol intake.     

Abdominal vagotomy disrupts food-related drinking in the rat

Rats with complete subdiaphragmatic bilateral transection of the abdominal vagus (Vgx-C) showed disordered food-related drinking when drinking water in temporal association with a meal of dry food after 5-hr food deprivation and when drinking water in association with a liquid meal after 24-hr food deprivation. The Vgx-C rats drank after significantly longer latencies and drank significantly less water in 1 hr than did sham-vagotomized (Sham) rats after eating the same size meal (solid or liquid) as Shams. Rats with incomplete vagal transection (Vgx-I) ate and drank like Shams. Water intake of Sham and Vgx-I rats correlated positively with the meal size of solid food, but the water intake of Vgx-C rats did not. The failure of Vgx-C rats to drink water normally when food was ingested was not due to failure of a food stimulus to reach the intestine, because Vgx-C and Sham rats emptied equivalent volumes of liquid food from the stomach into the intestine within 10 min of food entering the stomach. These results indicate that the abdominal vagus is an important neurological substrate for food-related drinking in the rat.     

Handling from weaning to adulthood does not prevent hyperdefensiveness induced by septal, medial accumbens, or medial hypothalamic lesions

Weanling male hooded rats were handled or not handled for 10 min each day, 5 days/week, for 6 weeks. At the end of this time all animals received one of the following: a septal lesion, a medial accumbens lesion, a medial hypothalamic lesion, or a sham lesion. The animals were tested for defensiveness toward the experimenter on Days 3, 7, and 14 postoperatively. All behavioral testing was done blind. Each of the three lesions increased defensiveness toward the experimenter. However, with each lesion, there was no difference in the defensiveness scores of preoperatively handled and nonhandled animals at any of the postoperative test sessions while those of animals with medial hypothalamic lesions did not. These results are consistent with observations that hyperdefensiveness occurs in human subjects following tumors in each of these brain areas in spite of their familiarity with the situation in which they are observed. They contrast with observations that mouse killing induced by septal lesions is readily prevented by preoperative exposure to a mouse.     

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.