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.     

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.     

The residual spatial abilities of hippocampally lesioned rats can be enhanced by peripheral sympathetic-adrenal interventions

In order to test the possible effectiveness of peripheral interventions with the adrenergic system for the alleviation of certain disorders that typically follow bilateral hippocampal lesions, rats with bilateral lesions of the hippocampus, the overlying neocortex, or sham operations were tested at two postoperative times in the Morris water maze, a frequently used "spatial task." Half of the animals in all groups were exposed to the adrenergic manipulations, i.e., a chronic, 7-day, systemic bretylium regime (5 mg/kg) and, in addition, a peripheral injection of norepinephrine (4 micrograms/kg) 30 min before the start of each training day. The other half received saline chronically and a single saline injection before each training day. Five days of training were given at each of the two training periods. The first began 7 days after surgery while the second began 33 days after surgery. As expected, the hippocampally lesioned animals were severely impaired in the task. The adrenergic treatment produced enhanced performances in the rats with hippocampal lesions at both training sessions, although the improvement was greatest at the later period. Although the animals receiving the pharmacologic treatment located the general area of the hidden platform better than the saline-treated animals with hippocampal lesions, the treated animals were still impaired, swimming directly to the hidden platform on fewer trials than did animals in the other groups.     

Effects of hepatic denervation on the anorexic response to epinephrine, amphetamine, and lithium chloride: a behavioral identification of glucostatic afferents

Intraperitoneal injections of epinephrine (20, 40, 80, and 160 microgram/kg) and amphetamine (.1, .2, and .4 mg/kg) were administered to rats with various forms of hepatic denervation. In Experiment 1, destruction of the esophageal trunks of the vagus attenuated epinephrine and amphetamine anorexia, but destruction of the hepatic vagus did not. In Experiment 2, rats with celiac ganglionectomy, subdiaphragmatic vagotomy, or the combined operation all exhibited decreased epinephrine anorexia to the same extent. However, ganglionectomized rats were less responsive to amphetamine anorexia than were vagotomized ones. Vagotomized rats were significantly more reactive to lithium chloride (10, 20, and 30 mg/kg) than were controls. These results suggest that the major component of hepatic metabolic afferent fibers travels from the liver, through the celiac ganglion, and into the esophageal vagal trunks where they ascend to the brain. The anorexic action of amphetamine appears to result from a centrally induced sympathetic action on the liver.     

The ventromedial hypothalamus and aggressive behaviour in rats

Male rats were given bilateral lesions in either the anterior or posterior ventromedial hypothalamus (VMH). The intermale aggressive behaviour of these animals within their own territory was observed before and after the surgical procedure and compared with the behaviour of sham-operated animals. The effects of anterior VMH lesions include an increased tendency to respond with frontal threatening upon approach of a conspecific male. This behaviour closely resembles the aggressive responses described in “shock-induced aggression” tests. Posterior VMH lesions facilitate territorial aggressive behaviour characterized by approaching the opponent followed by lateral threatening and fighting. It is suggested that 2 distinct neural substrates exist, which serve to inhibit defensive (anterior-VMH) and offensive (posterior-VMH) intermale aggression, respectively.     

Caudate-putamen lesions in the rat may impair or potentiate maze learning depending upon availability of stimulus cues and relevance of response cues

In Experiment 1 rats were required to learn a Y-maze in which reward was made available after a given response (e.g. a left turn) regardless of which arm was used as the start-box. Subjects with lesions of the caudate-putamen showed a deficit on this response-learning task compared with control subjects (unoperated animals and rats having lesions of the posterior cortex). In Experiment 2 rats with caudate-putamen lesions were unimpaired when the direction of the turn required to reach the correct goal-box (identified by means of a salient visual intra-maze cue) varied from trial to trial. In the absence of salient intramaze cues, but with enriched room (extra-maze) cues, the rats with caudate-putamen lesions were superior to controls on this task. It is argued that caudate-putamen lesions disrupt a mechanism responsible for processing information about responses, but that the other (spatial) mechanisms responsible for maze-learning remain intact and that caudate-putamen lesions may enhance performance on spatial tasks for which information about responses is irrelevant.     

Sparing of function after infant lesions of selected limbic structures in the rat.

The effects, in adult animals, of limbic lesions produced in infancy were studied in 273 male Wistar rats using weight gain and conditioned emotional response (CER) and conditioned avoidance response (CAR) acquisition as the critical measures. Subjects received bilateral lesions of the amygdala, septum, posteroventral hippocampus (PH), anterodorsal hippocampus (AH), or frontal cortex either as infants (at 10 days of age) or as adults (at 60 days). Normal and anesthetized control groups were also used. Frontal cortical lesions, AH lesions, and anesthetization had no effect on weights or on CER and CAR acquisition. Both infant and adult amygdala and septal lesions significantly disrupted normal weight gain. Adult-accrued amydala and PH lesions significantly retarded CER acquisition, and adult septal and PH lesions significantly facilitated CAR acquisition. Infant-accrued amygdala lesions significantly retarded CER acquisition but had no effect on CAR acquisition. Infant septal lesions significantly facilitated CAR acquisition, and infant PH lesions had no effect on either task. The results were interpreted to mean that the observed task-specific recovery in early-operated animals may have been due to some form of functional reorganization.     

Knockdown of Nurr1 in the rat hippocampus: implications to spatial discrimination learning and memory

Nurr1 expression is up-regulated in the brain following associative learning experiences, but its relevance to cognitive processes remains unclear. In these studies, rats initially received bilateral hippocampal infusions of control or antisense oligodeoxynucleotides (ODNs) 1 h prior to training in a holeboard spatial discrimination task. Such pre-training infusions of nurr1 antisense ODNs caused a moderate effect in learning the task and also impaired LTM tested 7 d later. In a second experiment, ODN infusions were given immediately after the animals had received two sessions of training, during which all animals showed normal learning. Although antisense treated rats were significantly impaired during the post-infusion stages of acquisition of the task, no group differences were observed during the LTM test given 7 d later. These animals were subjected 3 d later to reversal training in the same maze in the absence of any additional treatments. Remarkably, rats previously treated with antisense ODNs displayed perseveration: The animals were fixated with the previously learned pattern of baited holes, causing them to be significantly impaired in the extinction of acquired spatial preferences and future learning. We postulate that Nurr1 function in the hippocampus is important for normal cognitive processes.     

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.     

Weight Loss in Rats Produced by Running: Effects of Prior Experience and Individual Housing

To investigate factors affecting activity-based anorexia (ABA) or activity-stress (AS), rats were given 2-hr access to a running wheel immediately prior to their daily 1.5-hr food access during the light cycle. This produced a reduction in food intake, a steady increase in running, and a large drop in body weight with a prolonged delay before weight recovery began. Experiment 1 found that these effects were reduced in rats with prior experience of eating at this time of day. In contrast, prior experience of running in the wheel when on ad lib food enhanced these effects in Experiment 2, where a subsequent change for half the subjects to individual housing produced a further decrease in body weight. The latter factor was investigated from the outset of Experiment 3 and again individually housed rats showed greater weight loss than did group-housed rats. This experiment also found that in rats of the same age a low initial body weight predicts greater vulnerability to ABA. It was concluded that ABA results from activity-induced reduction of feeding, which prolongs adaptation to a new feeding schedule and is accentuated by social isolation.     

Medial dorsal thalamic lesions and working memory in the rat

Pigmented rats of the DA strain with either radiofrequency or ibotenic acid lesions of the thalamic nucleus medialis dorsalis were postoperatively given nonspatial and spatial tests of working memory. In the nonspatial task, delayed nonmatching-to-sample, rats with both types of thalamic lesions showed acquisition impairments. The subgroup of rats with nucleus medialis dorsalis lesions that were able to reach the acquisition criterion did, however, perform normally when the retention interval was extended to 60 s. In the spatial task, delayed forced-alternation, rats were tested with differing retention intervals and with both spaced and massed trials. Damage to nucleus medialis dorsalis had no effect on acquisition or on spaced trials, but a slight deficit was found in the animals with radiofrequency lesions under the massed trial condition. Much clearer deficits were, however, present in those animals in which the lesion extended appreciably into the anterior thalamic nuclei. The findings indicate that while cellular damage to nucleus medialis dorsalis may disrupt learning, some impairments in tests of spatial working memory attributed to this nucleus may reflect damage to the adjacent anterior thalamic nuclei.     

Visual sampling after lesions of the superior colliculus in rats

In two separate experiments, rats with bilateral lesions of the superior colliculus showed significantly poorer relearning of a horizontal/vertical stripe discrimination than control animals. In Experiment 1, all animals showed disruption of performance when a stimulus--response (S--R) separation was introduced by raising the stimuli above the site of responding. However, the colliculectomized rats were much more disturbed by the S--R separation than were animals in the control group. In Experiment 2, all animals showed lower performance levels when conflicting patterns were introduced into the upper portion of the stimulus doors, but this time the rats with collicular lesions were less disturbed than the control animals. It is suggested (a) that when the stimulus and response sites are discontiguous, animals must make an appropriate orienting response in order to effectively sample the visual stimuli and (b) that lesions of the superior colliculus alter performance by interfering with this orienting behavior. The impairment in relearning is tentatively attributed to the absence of preoperative overtraining on the discrimination task.     

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.     

Effects of BIM-22015, an analog of ACTH4-10, on functional recovery after frontal cortex injury.

Male rats, 90-100 days old, with frontal cortex lesions were given either subcutaneous sterile water (SW) as a vehicle control or 1, 10, or 100 micrograms of BIM-22015 every other day for 20 days. Brain-injured subjects tested in the Morris water maze with either 10 micrograms BIM-22015 or SW took significantly more trials than sham-operated rats to locate a submerged platform eight consecutive times within 60 s. The animals given 1 or 100 micrograms BIM-22015 took significantly fewer trials to reach criterion than brain-injured animals in the other drug treatment groups. On a percentage of savings, measured 8 days after reaching criterion, the brain-injured subjects given 1, 10, or 100 micrograms BIM-22015 did not differ from sham-operated rats. In contrast, the brain-injured animals given SW took longer to find the submerged platform than they did during the initial training. To assess long-term effects of the ACTH analog treatment, rats were trained on a delayed spatial alternation task 30 days after receiving the last injection. On this task, brain-injured rats treated with the 10-micrograms dose performed significantly better than those given sterile water. Acetylcholinesterase (AChE)-labeled neurons counted in the nucleus basalis magnocellularis indicated that rats with frontal cortex damage given the 10-micrograms treatment did not differ from the sham controls and had significantly more AChE-positive neurons than injured counterparts treated with SW or 100 micrograms.     

Kainic acid lesions disrupt fear-mediated memory processing

Previous research has shown that hippocampal lesions impair the expression of fear conditioning. This fear conditioning deficit may be due to memory impairment or a reduction in fear in lesioned animals. To address these possibilities, the authors examined unconditioned and conditioned fear in male Sprague-Dawley rats that had received intracerebroventricular (ICV) infusions of kainic acid (KA) 30 days prior to testing. Animals that had received bilateral ICV infusions of KA (1.0 microl of 0.8 mg/ml solution per side) exhibited cell loss that was primarily confined to the CA3 region of the dorsal hippocampus. Kainic acid lesions impaired contextual and cued fear conditioning but did not affect unconditioned fear in a light:dark test of anxiety. Moreover, animals with KA lesions did not habituate to the light:dark apparatus when tested over a 3-day period. These data suggest that decreases in fear conditioning produced by hippocampal lesions reflect a memory deficit and not a lack of fear.     

Caudate nucleus and memory for egocentric localization

A large body of evidence suggests that the caudate nucleus (CN) plays a critical role in the processing of spatial localization information. Furthermore, evidence has begun to accumulate that the CN is involved in the processing of a very specific class of spatial cues, namely, egocentric cues (localization with reference to the organism). This is in contrast to allocentric localization, where an organism localizes on the basis of cues external to the organism. One would then predict that lesions to the CN should disrupt performance on any tasks that depend chiefly on egocentric spatial cues, while leaving performance on allocentric tasks intact. To test this prediction, two groups of rats were trained on two different egocentric memory tasks and two different allocentric memory tasks. Specifically, one group of rats was trained on an adjacent-arm (egocentric) and an 8-arm radial maze task (allocentric). A second group of rats was trained on a right-left discrimination (egocentric) and a place-learning task (allocentric). After training, both groups received bilateral lesions of the CN. Results showed that CN-lesioned animals were profoundly impaired on retention of the egocentric tasks. In sharp contrast to this, the same animals were not or were only transiently impaired or transiently affected on allocentric tasks. Sham-operated controls were either unimpaired or transiently affected on all tasks. These findings further support the idea that the CN plays a critical modulatory role in the processing of egocentric spatial and not allocentric spatial cues.     

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.     

Septal damage in infant and adult rats: Effects on activity,emotionality, and muricide

Septal lesions produced signs of increased emotionality in the adult rat, the septal syndrome (hyperresponsiveness to handling; in the open field: decreased rearing and ambulation activity, increased defecation, deficient habituation) being more or less complete and more or less marked depending on the age at which the lesion was performed (7 days or 3 months), the extent of the lesion (restricted to the septum or extending to more ventrally located structures) and the environmental conditions in which the animals were reared (in groups or in isolation). All septal lesions provoked a similar and significant increase in the probability of occurrence of mouse-killing behavior, irrespective of age of operation, extent of lesion and kind of rearing environment. In a 24-hour actography starting at 11:30 a.m., the rats septalectomized at adult age were less active than controls during the initial period, while all septals were markedly more active than controls during the night period. Early septal lesions only transiently disrupted weight gain. The results obtained point to complex interactions between the effects of early brain damage and environmental conditions.     

The effects of unilateral destruction of fimbria-fornix and supracallosal pathways in the rat

Rats with unilateral lesions of either the supracallosal regions (including the dorsal cingulate cortex) and the fimbria-fornix either on the same (S) or the opposite (O) sides of the brain were studied in a 16-hole open field without pharmacologic intervention and, subsequently, after 0.1 and after 1.0 mg/kg scopolamine HBr. Their performances were compared with those of unoperated control animals subjected to the same testing regime. Certain of their behaviors were compared with those of a larger number of animals with bilateral hippocampal destruction (and their control groups) from prior studies. Unilateral lesions of fimbria-fornix and supracallosal afferents to the hippocampal formation produced a decrease in hole poking activity relative to control animals. A further decrease in hole-poking behavior, coupled with increased locomotion, was observed in rats with fimbria-fornix and cingulate cortex lesions on opposite sides of the brain (group O). The smaller dose of scopolamine accentuated these effects. Indeed, the behavior of group O after scopolamine treatment was similar to animals with large bilateral hippocampal lesions. The large dose of scopolamine induced stereotyped rearing or hole poking in the brain-damaged animals but not in the control group. These findings suggest that both the fimbria-fornix and the supracallosal pathway is necessary for normal hippocampal function and that the behavioral deficit is greater when these structures are damaged on the opposite sides of the brain.     

Place and response learning of rats in a Morris water maze: differential effects of fimbria fornix and medial prefrontal cortex lesions

The question examined in this study is concerned with a possible functional dissociation between the hippocampal formation and the prefrontal cortex in spatial navigation. Wistar rats with hippocampal damage (inflicted by a bilateral lesion of the fimbria fornix), rats with damage to the medial prefrontal cortex, and control-operated rats were examined for their performance in either one of two different spatial tasks in a Morris water maze, a place learning task (requiring a locale system), or a response learning task (requiring a taxon system). Performance of the classical place learning (allocentric) task was found to be impaired in rats with lesions of the fimbria fornix, but not in rats with damage of the medial prefrontal cortex, while the opposite effect was found in the response learning (egocentric) task. These findings are indicative of a double functional dissociation of these two brain regions with respect to the two different forms of spatial navigation. When the place learning task was modified by relocating the platform, the impairment in animals with fimbria fornix lesions was even more pronounced than before, while the performance of animals with medial prefrontal cortex lesions was similar to that of their controls. When the task was again modified by changing the hidden platform for a clearly visible one (visual cue task), the animals with fimbria fornix lesions had, at least initially, shorter latencies than their controls. By contrast, in the animals with medial prefrontal cortex damage this change led to a slight increase in escape latency.