Food intake and utilization in lateral hypothalamically lesioned rats

The daily food intake of rats with lateral hypothalamic (LH) lesions was monitored in two experiments. Confirming earlier reports, LH-lesioned animals were found to ingest nearly the same amount of food per day as nonlesioned controls even though their body weights remained substantially below those of the controls. In view of this result, an experiment was conducted to compare the efficiency of food utilization of LH-lesioned and control animals at different body weights. First, the daily food intakes of seven LH-lesioned rats and seven nonlesioned controls were determined. The body weights of these animals were then lowered by restricting food intake in four successive weekly periods to 85%, 70%, 55% and 40% of their ad lib level. Finally, all animals were refed for one week at their prerestriction levels of food intake reduced in proportion to the intervening loss in metabolic mass (body weight_kg^0.75). At each level of caloric restriction, the weight losses observed in the LH-lesioned and control animals were equivalent. Likewise, though given only prerestriction amounts (indexed to their reduced metabolic mass), LH-lesioned and nonlesioned animals both gained weight rapidly and at equivalent rates during refeeding. Thus, LH-lesioned animals appear to utilize food in a normal fashion and, as do controls, adapt to weight loss by increasing their efficiency of food utilizazion. In the case of LH-lesioned animals, however, such adjustments occur around a reduced level of maintained body weight, or set-point.     

Resting oxygen consumption in over- and underfed rats with lateral hypothalamic lesions

Rats maintaining stable, reduced body weights following lateral hypothalamic (LH) lesions were given either ad lib amounts of a palatable liquid diet or restricted amounts of a hydrated chow diet. The palatable diet produced weight gains while the diet restriction led to weight reductions in both LH- and sham-lesioned rats. Body composition analysis indicated that these changes in body mass were accounted for largely by changes in carcass fat. Resting oxygen consumption (expressed relative to body weight raised to the 3/4 power) was altered by both dietary regimens. Resting oxygen consumption in sham-lesioned rats increased by 5% following overfeeding and decreased by 13% following food restriction. LH-lesioned rats made similar responses to these dietary challenges. Overfed LH-lesioned rats increased their rate of resting oxygen consumption by 11%. Underfed LH-lesioned rats decreased oxygen consumption by 11%. These findings provide further evidence that rats with LH lesions defend a reduced level of body weight. The changes in energy expenditure that mitigate weight change in sham-lesioned animals are also present in LH-lesioned rats. In the latter, however, these adjustments serve to stabilize body weight at a lower level.     

Defense of a lowered weight maintenance level by lateral hypothamically lesioned rats: Evidence from a restriction-refeeding regimen

Male rats maintained their body weight at approximately 85% that of sham-lesioned controls following lesions of the lateral hypothalamus (LH). One month following surgery, the food intake of half the LH-lesioned animals was restricted until their body weight had declined to 80% that of nonrestricted LH animals. Half the sham-lesioned animals were similarly restricted until their body weight fell to 80% that of nonrestricted control animals. When returned to an ad lib feeding schedule, both restricted groups were initially hyperphagic and quickly restored their body weights to the level of the nonrestricted group from which they were originally selected. In doing so, the LH animals increased their food intake by the same amount and took the same number of days to restore their weight to control levels as the sham-lesioned animals. These observations provide further evidence of the vigor and effectiveness with which LH animals defend their reduced level of maintained body weight.     

Response to chronic insulin administration: effect of area postrema ablation

The effects of daily administration of protamine zinc insulin (PZI) on plasma insulin and glucose levels and on food intake and body weight of rats with lesions of the area postrema and adjacent caudal-medial portions of the nucleus of the solitary tract (APX rats) were examined. Prior to insulin treatment, APX rats weighted less and had lower plasma immunoreactive insulin (IRI) levels than nonlesioned controls but did not differ from controls in plasma glucose levels. Five daily injections of 5 U/kg PZI raised plasma IRI and lowered plasma glucose levels similarly for both lesioned and nonlesioned rats. When injected with increasing doses of PZI over a 30-day period, both lesioned and nonlesioned rats showed increases of food intake and rate of weight gain in response to 8 U/kg PZI. These data indicate that APX does not affect either physiological or behavioral responses to chronic peripheral insulin administration.     

Area postrema/nucleus of the solitary tract ablations: Analysis of the effects of hypophagia

The effect of hypophagia following lesions of the area postrema and caudal-medial aspect of the nucleus of the solitary tract (AP/cmNTS) on body-weight, water intake and preference for palatable diets was examined. Following AP/cmNTS ablation, rats reduced pelleted-food intake to a degree which was sufficient to account for the weight loss and increased water:food ratios observed. Restricting food intakes of intact rats to levels taken by lesioned animals resulted in similar weight losses and increased water:food ratios. When offered both pelleted food and milk, lesioned rats took more calories as milk than did previously food-restricted intact rats. Thus, the hypophagia of AP/cmNTS lesioned rats does not account for their increased preference for milk diets. Lesioned rats ate less high-fat diet than did intact or sham-lesioned controls and did not increase their intakes when this diet was sweetened. At autopsy, retroperitoneal and epididymal fat-pad weights accounted for less of the total body weight of lesioned animals than controls suggesting that body-fat levels are reduced following AP/cmNTS ablation.     

Area postrema lesions produce feeding deficits in the rat: Effects of preoperative dieting and 2-deoxy-D-glucose

To investigate the possible role of the area postrema (AP) in the control of food intake and body weight, male albino rats were divided into four groups: (a) animals dieted to 80% of their original body weights prior to receiving AP lesions, (b) nondieted animals with AP lesions, (c) animals dieted to 80% prior to receiving sham lesions, and (d) nondieted animals with sham lesions. Lesions of the AP in nondieted rats resulted in hypophagia, hypodipsia and body weight loss followed by recovery of normal intake and maintenance of body weight at a fixed percentage of the sham operated animals' weight. Reducing body weight prior to surgery led to body weight maintenance levels equivalent to those of the nondieted groups. We also tested the animals for sensitivity to glucoprivation caused by intraperitoneal injections of 2-deoxy-D-glucose (2-DG). Injections of 2-DG produced hyperphagia in sham lesioned rats, but not in rats with AP lesions. Our data suggest that the effects of AP lesions on intake and body weight are similar, in several important respects, to the lateral hypothalamic feeding syndrome and to the effects of subdiaphragmatic vagotomy. We discuss the results with respect to hierarchical levels of neural circuitry involved in controlling feeding behavior.     

Diet selection following area postrema/nucleus of the solitary tract lesions

Ten adult Long-Evans male rats were offered access to fat, protein and carbohydrate from separate sources. After adaptation to this diet, 5 animals received thermal lesions of the area postrema and adjacent caudal-medial portion of the nucleus of the solitary tract (AP/cmNTS). The remainder were sham-operated. AP/cmNTS lesioned rats ate significantly less and lost more weight than controls during the first postsurgery measurement period (Days 4–13 after lesioning). The decrease of food intake of AP/cmNTS lesioned rats was due to reduced fat consumption. Carbohydrate and protein intakes of lesioned animals did not differ from those of controls. Food intakes and weight changes of lesioned rats did not differ from those of controls during days 14–23 after lesioning. Intake of fat by lesioned animals remained low but was no longer significantly different from that of controls. Carbohydrate and protein intakes of lesioned rats increased slightly but did not differ significantly from those of nonlesioned controls.     

Anteroventral third ventricle lesions reduce antidiuretic responses to angiotensin II.

Ablation of anteroventral third ventricle (AV3V) periventricular tissue renders animals temporarily adipsic with no compensatory change in urine volume or concentration. The present experiment was designed to determine whether lesions of the AV3V region attenuate vasopressin (AVP) release in response to intraventricular (ivt) injections of angiotensin II (AII), hypertonic NaCl, and phenylephrine during the adipsic period. Blood pressure, urine conductance, and urine flow rate were monitored in awake, unrestrained animals during a continuous intravenous hydrating infusion. Changes in blood pressure and urine parameters were recorded following ivt injections of 100 ng AII, 500 ng AII, 1 microliter 3% NaCl, and 50 microgram phenylephrine. In addition, a radioimmunoassay (RIA) measured AVP following 500 ng AII ivt in lesioned and nonlesioned animals. Antidiuretic and pressor responses to ivt AII were attenuated after AV3V lesions. In addition, RIA analysis showed a significantly smaller concentration of AVP in lesioned animals following AII injections. These data suggest that the AV3V region is important for AVP release in response to central AII and osmotic stimuli.     

Rats drinking quinine- or caffeine-adulterated water defend lean body weights against caloric and osmotic stress

Adult male and female rats drank ad lib water containing as much as 0.2% quinine hydrochloride or caffeine, and ate dry food. Maintained body weights were lower in direct proportion to the concentration of adulterant. Cumulative caloric intakes and the water and fat contents of carcasses showed that the weight lost on adulterated water and regained on tap water was fat rather than fluid. Furthermore, lean rats on adulterated water ate and drank more when ambient temperature was reduced; drank more and approximately maintained caloric intake when their food contained up to 5% sodium chloride; and ate less to compensate for the caloric value of a nonhydrating liquid diet force fed by gavage. The rats also adapted to activity wheels and behaved like rats drinking tap water during and after two days of food deprivation. Thus, the percentage adulteration of obligate drinking water determines the body weights at which rats eat and drink to defend energy balance. The rats remain in water balance even though ratios of water to food intakes were depressed by one-third in males and one-half in females for concentrations of adulterant between 0.05 and 0.2%, inclusive. These results can be used to argue that standard concepts and procedures for describing motivational and physiological states are inadequate.     

Preoperative experience with insulin enhances glucoprivic feeding in rats with lateral hypothalamic lesions

Adult male Sprague-Dawley rats received either one injection per week of regular insulin (IP, 5 Units) or saline for 4 weeks prior to destruction of the LH or sham-operations. During this preoperative period, animals given insulin consumed significantly more food in a 6-hr test period than animals given saline. Following surgery, animals were given 3 weeks to recover from the acute effects of LH lesions and then tested for responsiveness to glucoprivic challenges. Sham-operated animals from both pre-operative injection groups consumed significantly more food during a 6-hour period when injected with either insulin (5 and 7.5 Units) or 2-DG (400 mg/kg) than when given saline injections. Similarly, LH-lesioned rats with preoperative experience with insulin significantly increased food intake when given insulin or 2-DG. In contrast, LH-lesioned rats without preoperative experience with insulin failed to increase feeding in response to the administration of either insulin or 2-DG. Differences in feeding responses following glucoprivation between LH-lesioned rats with and without preoperative exposure to insulin were not a function of differences in the extent of central nervous system damage. The present data indicate that experimental conditions play an important role in determining the presence or absence of regulatory deficits following brain damage.     

Effects of amygdalar lesions on eating and drinking and saline preference in the rat

Extensive electrolytic lesions were placed bilaterally in the amygdala in albino rats. Both food and water intake relative to preoperative body weight were significantly higher in lesioned animals than in operated controls. Saline preference behavior was also investigated in a two-bottle choice situation. No difference in preference for tap water or a 1.5% NaCl solution was observed between lesioned and control animals.     

Ventral noradrenergic bundle “area” lesions producing reduced body weight and activity

Bilateral lesions in the area of the ventral noradrenergic bundle (VNAB) were performed on male rats. Except on a few days, food intake (FI) of the lesioned rats was not significantly different from the controls. However, body weight (BW) of the lesioned rats was significantly less than the controls 15 days after lesioning. Neither FI data nor state of hydration can explain the lesioned rats' lower BW. The lesioned animals were hypoactive but increased their running the same percentage as shams when both groups were fasted. In the lesioned rats body composition and insulin concentrations were normal while mean growth hormone concentrations and body length tended to be less than normal, but significance was not reached. Hypothalamic norepinephrine was reduced following lesioning. It is suggested that damage to a tract near the VNAB may explain the hyperphagia and obesity seen by others after lesioning in this area. Lastly, it is proposed that damage to yet another fiber tract near the VNAB may explain part of the results of present investigation.     

The effect of dorsomedial hypothalamic nuclei lesions on body weight regulation.

Prior to hypothalamic surgery 1 group of male rats was placed on a partial starvation regimen to lower their body weight. A second group was fed ad libitum. Just before surgery the 2 groups were divided into 2 sub groups. Bilateral electrolytic lesions were then placed in the dorsomedial hypothalamic nucleus in some of the partially starved and some of the ad libitum fed rats. The remaining animals were sham operated. After surgery all groups were fed ad libitum. Following hypothalamic operation the group that before surgery had been fed ad libitum showed the previously reported postoperative hypophagia and reduced body weight. On the other hand, the rats that were partially starved prior to placement of the lesion, ate significantly more than ad libitum fed lesioned animals during the first 9 days after surgery. The body weights of the partially starved, lesioned rats increased steadily from the day of the operation while lesioned rats fed ad libitum showed an initial delay of ponderal growth. The data suggest that the transient postoperative increase in food intake of the partially starved, lesioned rats is an active process to bring the body weight of these animals up to a new but lowered ‘body weight set point’ initiated by the hypothalamic destruction. Since previous studies had shown that rats with a lesion in the dorsomedial nucleus have a normal body composition, it is suggested that the lesions change the animals' ‘body weight set point’ and not the ‘body fat set point’, as has been suggested after ventromedial and lateral hypothalamic lesions.     

Alterations in NMDA receptors in a rat model of cortical dysplasia

Recent studies have demonstrated an important role for the N-methyl-D-aspartate receptor (NMDAR) in epilepsy. NMDARs have also been shown to play a critical role in hyperexcitability associated with several animal models of human epilepsy. Using whole-cell voltage clamp recordings in brain slices, we studied evoked paroxysmal discharges in the freeze-lesion model of neocortical microgyria. The voltage dependence of epileptiform discharges indicated that these paroxysmal events were produced by a complex pattern of excitatory and inhibitory inputs. We examined the effect of the NMDAR antagonist D-2-amino-5-phosphopentanoic acid (APV) and the NMDA receptor subunit type 2B (NR2B)-selective antagonist ifenprodil on the threshold, peak amplitude, and area of evoked epileptiform discharges in brain slices from lesioned animals. Both compounds consistently raised the threshold for evoking the discharge but had modest effects on the discharge peak and amplitude. For comparison with nonlesioned cortex, we examined the effects of ifenprodil on the epileptiform discharge evoked in the presence of 2 microM bicuculline (partial disinhibition). In slices from nonlesioned cortex, 10 microM ifenprodil had little effect on the threshold whereas 71% of the recordings in bicuculline-treated lesioned cortex showed a >25% increase in threshold. These results suggest that NR2B-containing receptors are functionally enhanced in freeze-lesioned cortex and may contribute to the abnormal hyperexcitability observed in this model of neocortical microgyria.     

Refeeding after the late increase in nitrogen excretion during prolonged fasting in the rat.

Recovery of body mass, food intake and body composition was studied in the laboratory rat after the late increase in nitrogen excretion that characterizes prolonged fasting in mammals and birds. The rats lost 43% of their body mass during 13 days of food deprivation. They all regained their prefasting body mass within a shorter period of 11 days of refeeding. These results confirm that the late increase in nitrogen excretion in rats, as in spontaneously fasting birds, is reversible and is a part of the physiological adaptations to long-term food deprivation. Water intake of the rats continuously decreased during fasting, and the animals virtually stopped drinking as protein utilization increased. On refeeding, changes in water intake paralleled those in food intake. The refed rats progressively increased their daily food intake, that was always higher than the prefasting value (8.0-10.4 vs. 6.7% of body mass). The comparison of organ weights between fed and ad lib refed rats of similar body weight indicates that muscle mass was regained earlier than body fat during refeeding. The laboratory rat therefore appears to be a good experimental model to investigate the metabolic and behavioural changes that occur during spontaneous anorexia and refeeding in wild animals.     

Factors influencing the hunger and thirst motivated behavior of hypothalamic hyperphagic rats.

Female rats with lesions in the area of the ventromedial hypothalamus were hyperphagic but performed significantly worse than controls on high fixed ratio schedules for both food and water reinforcements. Preoperative training of the experimental task eliminated these performance deficits but identical deprivation in terms of preoperative body weight did not. Identical deprivation had no effect on either the pretrained or nonpretrained lesioned groups using water reinforcement, and only a moderate effect with nonpretrained animals for food reinforcement. Preoperative training, on the other hand, greatly facilitated the hunger and thirst motivated behavior of obese as well as deprived lesioned rats. Pretraining was most effective when postoperative testing at the highest ratio of reinforcement was not preceded by a period of ad lib feeding or the reintroduction of lower ratios. Rather than hypothesizing a reduction in motivation, the performance deficits of nonpretrained lesioned animals are attributed primarily to a lesion induced hyperreactivity to long periods of nonreinforcement.     

A behavioral model for quantifying physiologic adjustments during increased exercise

A complete system to facilitate quantitative measurements of behavioral feeding patterns, body compositional changes, metabolic utilization of food sources, and energetic work efficiencies in the exercising rat is described. The system includes a behavioral contingency of wheel running to gain access to food, a torqueing method to quantify work performed and increase energy expenditure, an enclosed chamber to provide for gas collection and analyses, and metabolic caging to facilitate collection of urine and feces for use in carbonnitrogen balance procedures. The system allows the animal to establish and modify its own feeding pattern. Construction of the apparatus, methodology, operative outline and advantages of the system are included.     

Sex differences in the effects of high-fat feeding on behavior and carcass composition

Male and female Sprague-Dawley rats were fed a high-fat diet (40% by weight) for 11 weeks beginning at 70–80 days of age. At the end of the 11th week, high-fat fed rats of both sexes were significantly heavier than chow-fed controls. All rats were then food deprived and were trained to bar-press in an operant chamber for Noyes pellets. Testing on fixed ratio (FR) schedules started when their body weights reached 85% of pre-deprivation levels and they pressed bar steadily. At the end of operant testing, all rats were refed their previous diet until body weights returned to pre-deprivation levels. The animals were then sacrificed. Fat pads from retroperitoneal, inguinal and gonadal regions were dissected out and cellularity determined. Carcass composition was analyzed by chemical methods. On the operant apparatus, the high-fat fed female rats (F-HF) behaved more like VMH lesioned obese rats, i.e. decreased bar pressing responses when compared with controls. No difference in operant responding was found between males fed high-fat diet and chow. Fat cell number and size were increased in retroperitoneal and inguinal fat pad for rats fed high-fat diet. In gonadal pads, only cell size was increased. Females on the high-fat diet had higher percentages of body fat than males on the high-fat diet. The behavioral difference in F-HF rats could be attributed to their higher adiposity. The results support previously reported findings on the behavior and adipose tissue cellularity of dietary obese rats.     

Body weight regulation in ground squirrels and hypothalamically lesioned rats: slow and sudden set point changes

Golden-mantled ground squirrels. Citellus lateralis, have a near annual cycle in body weight. In the present experiments their weights were temporarily forced off the usual levels either by food deprivation during a phase of weight gain or by offering extra palatable food during a phase of weight loss. When these treatments ceased the weights returned to levels appropriate for that time of year rather than to pretreatment values. Therefore the cycle of body weight in uniform and ad lib conditions reflects an underlying cycle in slowly climbing or sliding set points for body weight. In contrast to fattening ground squirrels, lesioned rats in the dynamic phase of hypothalamic hyperphagia did not compensate well for weight losses incurred during food deprivation. Weight gain during the dynamic phase appears to be roughly proportional to the discrepancy between actual and set weights, the latter being suddenly much elevated by the lesion.     

Effects of septal and amygdaloid lesions on discrimination, eating and drinking

Rats were given preoperative training on a visual discrimination task for which lever pressing in the presence of a cue light was continuously reinforced with food. Bilateral septal lesions increased nonreinforced responding, while bilateral amygdaloid lesions reduced responding under conditions of both reinforcement and nonreinforcement. Food intake relative to preoperative body weight increased for the septal lesioned animals. Decreased water intake relative to preoperative body weight and weight reduction were displayed by the amygdaloid lesioned rats. Possible interpretations of the results are discussed.