Factors influencing active avoidance behavior in rats with ventromedial hypothalamic lesions

Ventromedial hypothalamic lesioned rats maintained at preoperative body weight received an equal number of shocks while emitting significantly fewer responses than controls in a lever-pressing free-operant avoidance paradigm, and performed as well as unoperated animals in lever-pressing and shuttle box (both 1- and 2-way) discriminated avoidance tasks. The failure of VMH lesions to facilitate performance in the 2-way avoidance paradigm was probably the result of a ceiling effect. With the exception of the simple one-way avoidance task, obese lesioned rats were markedly impaired in the acquisition of all active avoidance behavior, but escape behavior was not affected. When tested in a free-operant paradigm, the avoidance performance of well trained lesioned animals varied inversely with body weight. As obese rats displayed lower flinch thresholds to shock than controls and similar levels of activity and responding as lean lesioned animals, it was concluded that their impaired avoidance behavior was not due to changes in sensitivity or mobility. The possible relation to other VMH lesion- and/or obesity-induced deficits is discussed.     

Passive avoidance behavior in lean and obese rats with ventromedial hypothalamic lesions

Lean and obese rats with ventromedial hypothalamic lesions performed reliably worse than control animals in the acquisition of a step-down passive avoidance task. However, obese rats performed significantly better than lean VMH animals, which consistently leaped off the platform on the second and succeeding trials. While there were no significant differences between groups in the acquisition of a step-through passive avoidance task, lean and obese rats with VMH lesions took reliably longer than control animals to reach criterion when an identical step-through response had previously been reinforced (punishment-extinction of a one-way conditioned avoidance response). Both lean and obese VMH-damaged rats made more punished approach responses to water than control animals following water-deprivation to 88% of body weight, but only lean VMH rats made a significantly greater number of punished approach responses to liquid food than unoperated animals following food-deprivation to 88% of body weight. The number of punished consummatory responses appeared to be influenced by baseline intake. Among the animals tested in more than one paradigm, there was a significant positive correlation between the number of punished consummatory responses and the number of shocks received during punishment-extinction of the one-way CAR, but no relationship was observed between the performances in either of these and the step-down avoidance paradigm. The impaired passive avoidance behavior by rats with VMH lesions is attributed to both an inability to inhibit a previously reinforced response and a change in response tendencies to aversive stimuli.     

Impaired and enhanced shuttle box avoidance behavior following ventromedial hypothalamic lesions in rats

VMH-lesioned female Long-Evans hooded rats held to preoperative body weight acquired a shuttle box avoidance response only as rapidly as control animals at both a moderate and high shock level when intertrial interval crossings were not punished, and at a moderate shock intensity with punished ITI crossings. Both groups displayed 90–95% asymptotic avoidance behavior under all three conditions. Obese rats with VMH lesions displayed impaired avoidance behavior under these conditions, displaying only 55–60% asymptotic avoidance behavior after 110 trials. The impaired avoidance behavior by obese rats was not due to immobility, for they emitted as many unpunished ITI crossings as control animals. Both lean and obese rats with VMH lesions avoided a significantly greater number of shocks than control animals at a high shock intensity when ITI crossings were punished, with control animals averaging only 20% avoidance responding after 110 trials. Lean VMH rats again performed better than obese rats, displaying 85% and 60% asymptotic avoidance behavior, respectively. Lean VMH rats made more punished ITI crossings than control animals at the high shock intensity, but there was no difference between the unoperated and obese VMH-lesioned animals. Previous discrepant results with shuttle box avoidance experiments are attributed to different testing conditions, although strain differences are also possible.     

Hyperphagia and obesity following ventromedial hypothalamic lesions in rats with subdiaphragmatic vagotomy

Bilateral subdiaphragmatic vagotomy chronically reduced body weight to 85–90% of sham vagotomy weight levels in female rats maintained on a standard pellet diet (observed for 114 days). Ventromedial hypothalamic lesions 70 days after vagotomy resulted in marked hyperphagia and obesity, although the increases were not as great as those following lesions in nonvagotomized animals. When the order of surgery was reversed, vagotomy reduced the body weight of obese VMH-lesioned rats to vagotomized control levels, with no evidence of recovery after 90 days. These results suggest that while enhanced vagal activity and/or vagally mediated hyperinsulinemia contribute to VMH lesion-induced overeating and weight gains, they are not necessary for the manifestation of either the hyperphagia or obesity. The importance of adaptation to the effects of vagal transections for the appearance of hypothalamic hyperphagia and obesity is discussed.     

Impaired free-operant avoidance behavior following ventromedial hypothalamic lesions in rats

Under each of 3 shock intensities, ventromedial hypothalamic lesioned rats emitted fewer responses and received more shocks than control animals in a lever-pressing free-operant avoidance paradigm. While the performance of the control animals improved across 10 days of testing and within each session, the between- and within-session performance of the lesioned rats, after improving moderately during the first few days of testing, deteriorated as training progressed. Although the response rates of the lesioned animals were relatively unrelated to the different current levels, their shock rates varied inversely with intensity. This resulted from an increase in the frequency of long interresponse times and a reduction in the number of consecutive shocks. Preoperative training substantially improved the avoidance behavior of lesioned animals, but their postoperative performance was nevertheless inferior to their preoperative levels.     

Reduced salivation in rats following ventromedial hypothalamic lesions

Salivation was assessed in normal rats and rats with bilateral lesions of the ventromedial hypothalamus (VMH). VMH lesioned rats demonstrated a reliable reduction of salivation. This hyposalivation occurred during a one month period that animals were maintained on dry rat chow and for a 16 day period that animals were maintained on a palatable liquid diet. VMH rats did not differ from control rats in the amount of saliva secreted in response to Prostigmin or wintergreen solution. Thus, while the VMH rat shows a reduced basal salivation level, such animals salivate normally in response to a strong taste substance.     

DRL performance following ventromedial hypothalamic lesions in rats

Obese ventromedial hypothalamic lesioned rats obtained more reinforcers than control or lean VMH animals when switched from a continuous reinforcement schedule to a differential-reinforcement-of-low-rate (DRL) operant schedule for food reinforcement. There was no significant difference among the three groups in the number of responses emitted on the DRL schedule. An examination of interresponse times revealed that both lean and obese VMH animals suppressed post-reinforcement short-latency responding earlier than control animals. The results do not support the hypothesis that VMH lesions cause a general deficit in response inhibition.     

Facilitation of liver regeneration after partial hepatectomy by ventromedial hypothalamic lesions in rats

Whether or not the hypothalamus is involved in initiating hepatic DNA synthesis after partial hepatectomy is unclear. To determine the role of the ventromedial hypothalamic nuclei in liver regeneration after partial hepatectomy, we studied hepatic DNA synthesis during liver regeneration in rats with bilateral lesions of these nuclei. Lesions of the ventromedial hypothalamus accelerated the increase in hepatic DNA synthesis and raised the peak level of thymidine incorporation after partial hepatectomy. These effects of hypothalamic lesions were completely inhibited by hepatic vagotomy. Thus, lesions of the ventromedial hypothalamus appear to promote hepatic regeneration by increasing vagal stimulation of the liver.     

Medial hypothalamic lesions and play fighting in juvenile rats

The effects of medial preoptic area (MPOA), anterior hypothalamic (AH) and ventromedial hypothalamic (VMH) lesions on play fighting were studied in juvenile rats that were housed and observed in heterosexual groups of 6-8 animals. Overall males engaged in play fighting more frequently than females and none of the lesions reliably affected this measure. Males also initiated more play fights. AH and VMH lesions reduced the frequency of play initiation in both sexes, but MPOA lesions had no reliable effect in either sex.     

Comparison of DNA synthesis in white and brown adipose tissue in rats with ventromedial hypothalamic lesions

Ventromedial hypothalamic (VMH) lesions cause excessive fat accumulation in white adipose tissue (WAT), and brown adipose tissue (BAT); however, little information is available on whether or not cell proliferation occurs in WAT and BAT after VMH lesioning. In this study, we determined the DNA content and thymidine incorporation in unilateral parametrial WAT and interscapular BAT 0, 1, 3, and 7 days after VMH lesioning, and examined the mechanism of increased DNA content in WAT. In rats with VMH lesions, the weight of WAT and BAT had increased significantly at 7 days, and the DNA content and thymidine incorporation of WAT had increased significantly at 3 days and continued to increase for up to 7 days, while those of BAT did not increase for as long as 7 days after VMH lesioning. Restricted food intake according to the pair-feeding method partially inhibited the increased DNA content in WAT. The increased DNA content in WAT was mostly restored but not completely by the administration of anti-insulin antibody, and by administration of propranolol, a -adrenergic blocker. The results demonstrated that VMH lesions induced DNA synthesis in WAT early after VMH lesioning, but did not induce DNA synthesis in BAT, and suggested that either hyperinsulinemia or a -adrenergic receptor mechanism or both may be responsible for the increased DNA content in WAT.     

Recovery of anticipatory activity to restricted feeding in rats with ventromedial hypothalamic lesions

Entrainment of circadian activity rhythms to a fixed daily mealtime was measured in intact and ventromedial hypothalamic (VMH) lesioned rats housed in tilt-cages. Intact rats showed a clear increase in activity for 2–3 hr prior to the 2 hr daytime feeding period. Anticipatory activity in lesioned rats was attenuated or absent during restricted feeding 5–9 weeks after surgery, but was evident in all rats, even those bearing apparently total VMH damage, during a second restricted feeding schedule 14–21 weeks after surgery. These results show recovery of function and argue against a necessary role for the VMH in food entrained rhythms.     

VMH lesions in vagotomized rats: a note of caution

Transections of the vagus nerve immediately below the diaphragm in female rats resulted in a high percentage of deaths by starvation and/or dehydration. Those that did survive had to be chronically maintained on a high fat diet. Transections midway between the stomach and diaphragm usually allowed recovery of normal food intake with a pellet diet, although body weight remained below that of sham-vagotomized animals. VMH lesions in these recovered (90 days) midlevel vagotomized rats caused either marked weight gains, marked weight losses, or wide fluctuations in body weight, results which would not be predicted by hypotheses which attribute VMH obesity to increased vagally mediated insulin secretion. We previously found that VMH lesions in rats with vagal transections just above the stomach resulted in a high percentage of rats that displayed hyperphagia and obesity, and conclude that the level of transection is of critical importance to the manifestation of VMH obesity. Autopsies revealed that midlevel vagally transected rats which failed to gain weight after VMH lesions suffered a loss of esophageal tonus or obstruction at the pyloric sphincter. We believe that the failure to observe hyperphagia in vagotomized rats following VMH lesions is at least partially due to overloading the capacity of the stomach and/or the accumulation of food in the esophagus (resulting in choking) with attempts at overeating.     

Effects of chronic quinine-adulteration of the water supply on food and fluid intake and body weight in lean and obese hypothalamic hyperphagic rats.

Obese rats with lesions of the ventromedial hypothamamus (VMH) consumed little or no food or fluid for 8–20 days when their water supply was chronically adulterated with 0.03% quinine hydrochloride. Three of the obese animals consumed significant amounts of food and fluid after the first week, five others continued to lose weight (at the rate of approx. 10 g./day) throughout the experiment. The experiment was terminated after 20 days when two animals died, and three others were so emaciated that death appeared imminent. Lean VMH rats that had been maintained at pre-operative body weights by restricted feeding prior to the quinine adulteration reduced their liquid and food intake only briefly after the quinine was introduced. After 4 or 5 days these animals were hyperphagic and hyperdipsic and displayed a substantial and sustained increase in body weight during the remaining 15 days of the experiment. The control animals curtailed both food and fluid intake sharply during the first 24–48 hours after the introduction of the quinine adulteration. Fluid intake subsequently recovered to approx. 60% of baseline and food intake returned to essentially normal levels. Body weight remained stable although slightly below baseline throughout the 20-day test period. The different response to quinine-adulterated water by lean and obese VMH-lesioned rats is similar to previously reported reactions to adulterated food. It is therefore concluded that explanations of VMH finickiness in terms of dysfunctions in appetite or hunger (terms appropriate only for food intake) are too limited. A more general deficit is proposed.     

Effects of dopamine-depleting brain lesions on experimental hyperphagia in rats

Dopamine (DA)-depleting brain lesions of various sizes were produced in rats either by intracerebroventricular injections of 6-hydroxydopamine (6-HDA) or by electrolytic lesions of the lateral hypothalamic (LH) area. Among 30 animals that became aphagic and adipsic for at least four days after large LH or 6-HDA-induced brain lesions, only three developed hyperphagia after electrolytic lesions of the ventromedial hypothalamus (VMH) or daily injections of long-acting protamine-zinc insulin (PZI). In 20 rats with smaller LH or 6-HDA-induced lesions, which had not shown marked initial behavioral dysfunctions, only three gained as much weight after VMH lesions as the control animals. Similarly, 6 of 10 rats with smaller LH lesions could not tolerate a 15-day series of PZI treatments, although 14 of 17 rats with smaller 6-HDA-induced lesions increased their food intake and gained weight during the PZI treatments as did control animals. These results indicate that hypothalamic hyperphagia can be blocked by DA-depleting brain lesions that neither produce an initial period of aphagia and adipsia nor involve hypothalamic tissue. They further indicate that even small LH lesions may prevent the development of hyperphagia elicited by PZI, whereas only very large 6-HDA-induced lesions consistently have this effect.     

Glucose oxidation in the ventromedial hypothalamus is not affected by insulin or ouabain but depressed by alloxan treatment

Summary Insulin is apparently not required for VMH glucose oxidation in vitro. Ouabain, an inhibitor of the Na-K pump ATPase, does not prevent VMH glucose oxidation in vitro. These data suggest (a) the VMH does not exhibit a cotransport phenomenon of glucose with the Na-K pump mechanism, and (b) glucose oxidation in the VMH is not insulin dependent. Alloxan-diabetes was induced to increase tissue insulin sensitivity. A comparison of glucose oxidation rates in alloxan-diabetic VMH tissue and normal VMH tissue, supplemented only with saline, indicated a highly significant (p < 0.001) depression of glucose oxidation in the alloxan-treated tissue. Cell membranes in the VMH are perhaps altered by alloxan.This work was supported by PHS/NIH Grant No. 5 SO5 RR07034, NIMH Grant No. R03 MH32916, in part by a grant from the Graduate College, Iowa State University, and in part by a gift from Houston Endowment Inc     

Reinforcement frequency and body weight as determinants of motivated performance in hypothalamic hyperphagic rats

Non-Obese and Obese VMH lesioned rats were tested on a series of increasing VI schedules (from 0.25 to 4.0 min). Response rates decreased as a function of increases in interreinforcement interval for all groups, and the functions did not differ in form or in slope between the groups. Respone rates for the Non-Obese VMH, Lesion Control, and Normal Control groups were similar, while response rates for the Obese VMH group were significantly less than those of the other groups. This reduction in work output by the Obese VMH rats was attributed solely to their increased weight at the time of testing.     

Ingestive behavior in adult rats with dorsomedial hypothalamic lesions

Large lesions in the dorsomedial hypothalamus (DMH) resulted in transient hypophagia that produced a significant weight loss. Energy intake per g of body weight returned to normal levels within 2 weeks after surgery but the body weight loss incurred during the immediate postoperative period was not compensated in 3 months of observation. The experimental animals responded poorly, if at all, to 2-deoxy-D-glucose induced cellular glucoprivation but ate normally after 2 doses of insulin and compensated appropriately for 24 hours of food deprivation. Rats with DMH lesions also displayed persisting hypodipsia (even when the animals' reduced body weights were taken into account) but responded normally, or nearly so, to water deprivation (with and without food), cellular dehydration, or extracellular hypovolemia. (Rats with DMH lesions drank slightly less than controls on most of these tests even when their chronically lowered body weights were taken into account but the impairment was small and, in most instances, not statistically reliable.)     

Effect of ventromedial hypothalamic stimulation on blood flow of brown adipose tissue in rats

The changes in regional blood flows to the rat's interscapular brown adipose tissue and several other tissues during electrical stimulation of the ventromedial hypothalamus (VMH) were studied using radioactively labelled microspheres. Measurement of blood flow was carried out, along with monitoring heart rate, under anesthesia and at thermoneutrality. During VMH stimulation the heart rate was clearly augmented and cardiac output increased about 45%. Regional blood flows were significantly increased in response to VMH stimulation in interscapular brown adipose tissue, adrenal glands, diaphragm and gastrocnemius muscles. The response of interscapular brown adipose tissue was the most prominent (approx. fiftyfold increase). Blood flows tended to decrease in spleen, lungs and kidneys during VMH stimulation, but did not change in liver or in other visceral organs. These observations suggest that the VMH is concerned with the regulation of regional blood flow to brown adipose tissue and contributes to thermogenesis in this tissue.     

Hyperinsulinemia and its role in maintaining the hypothalamic hyperphagia in chickens

Body weights and skeletal growth of female rats treated neonatally with low doses of testosterone propionate (TP) or estradiol benzoate (FB) were greater than oil-treated controls. After ovariectomy at 75 days of age EB-treated animals gained less weight than did the oil-treated controls and TP-treated rats which were comparable in weight gain. Neonatal treatment with TP or EB produced decreased sensitivity to the anorexic and weight-limiting effects of estrogen treatment after ovariectomy. However, all groups were equally sensitive to the anorexic effects of a single dose of CI-628. The possible mechanisms by which neonatal treatments with gonadal hormones influence food intake and body weight regulation are discussed.     

Effects of lateral hypothalamic lesions on consummatory behavior in developing rats.

Bilateral lesions aimed at the lateral hypothalami of preweanling rats result in decreased weight gain and eventual death within 5 days after the operation. Ten-day-old rats with unilateral damage to the lateral hypothalamus show retarded growth, food and water intake regulatory deficits, and altered sensitivity to quinine adulteration of the water for up to 60 days of age. These results suggest that at least one neural mechanism that regulates food and water intake matures early in the postnatal life of the rat.