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.     

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.     

The effect of high fat diet on the behavioral patterns of male rats

Male albino rats were made obese by a high fat diet (40% by weight) initiated either after weaning or at adulthood. The behavioral characteristics of these obese male rats on those tasks which differentiate the VMH lesioned rats from control rats were compared to those of normal rats. It was found that dietary obese male rats were not finicky to quinine adulteration or sugar solution; they did not overreact to shock stimulation by performing better in the shuttle box, and did not drink more “shocked” water. The behavior of dietary obese male rats did not differ from normals in activity level and in food motivated operant behavior. No behavioral differences between early and late onset obese groups were found. The discrepancy in results between the present experiment and those previously reported and the possible physiological background are discussed.     

Effects of food restriction and adrenalectomy in rats with VMH or PVH lesions

The effects of adrenalectomy in rats with ventromedial or paraventricular hypothalamic lesions have been studied in two experiments. Rats with ventromedial hypothalamic lesions or lesions in the paraventricular nucleus were allowed to gain weight for fourteen days at which time they were adrenalectomized. Before adrenalectomy, animals with VMH lesions ate more, gained significantly more weight than animals with lesions in the paraventricular nucleus, and both were significantly heavier and consumed more food than sham-operated controls. Following adrenalectomy, food intake decreased and both groups of lesioned animals lost weight. The animals with VMH lesions stabilized at weights above the control animals. Implantation of corticosterone enhanced weight gain and food intake in animals with lesions in either the paraventricular nucleus or the ventromedial hypothalamus. In the second experiment, one subgroup of rats with VMH lesions was adrenalectomized, and allowed to eat ad lib. Two other groups of sham-operated rats with VMH lesions served as controls. One group ate ad lib and one group was pair fed to the food intake of the adrenalectomized VMH-lesioned rats. Weight gain in the adrenalectomized VMH-lesioned rats and the pair-fed VMH-lesioned controls was similar and less than the VMH-lesioned rats eating ad lib. GDP binding to interscapular brown adipose tissue was related to the degree of weight gain, not to the presence of the VMH lesion. These data show that corticosterone is essential for the expression of obesity in both PVH- and VMH-lesioned rats. They also argue that the reduction in the activity of the sympathetic nervous system of VMH-lesioned rats as estimated by the GDP binding to mitochondria from brown adipose tissue is associated with hyperphagia.     

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.     

Active avoidance learning during bilateral spreading depression

Rats were surgically prepared with chronic cannula inserts to study the effects of potassium chloride (KCL) induced bilateral spreading depression (BSD) and differing shock intensities on acquisition of an active avoidance response (AAR). A two-way shuttle box was utilized with either a visual or auditory conditioned stimulus (CS). Control animals in both CS conditions acquired the AAR whereas the BSD animals experiencing constant shock in both CS conditions failed. The BSD animals characteristically failed to escape the shock. Increasing the shock intensity induced escape learning and led to acquisition of the AAR. The sound CS was found to be more effective in AAR acquisition for both control animals and BSD animals experiencing increased shock intensities.     

Comparison of metabolic alterations in hypothalamic and high fat diet-induced obesity.

The heterogeneous nature of the experimental obesities induced by ventromedial hypothalamic (VMH) lesion and high fat diet (HFD) have been demonstrated by comparing VMH-lesioned and sham-operated rats fed a HFD or low fat diet (LFD). VMH rats had increased fat mass serum insulin and serum triglycerides but lower serum glucagon and smaller salivary glands than sham-operated animals. The body weight of HFD obese rats was intermediate between VMH and sham-operated animals on the LDF. Liver and fat pad weights showed effects of lesions and diet. Diet did not affect plasma glucagon or insulin. Pair-feeding VMH rats with sham-operated rats prevented weight gain but did not prevent the increase in insulin and fall in glucagon. Studies of insulin secretion from isolated perifused islets showed that basal and both phases of stimulated secretion were significantly increased in VMH groups. The changes in plasma insulin, plasma glucagon, and salivary gland weight in VMH groups are interpreted as showing decreased activity of the sympathetic nervous system following VMH lesions.     

Pituitary-adrenocortical response to shock-induced stress in normal and hypothalamic hyperphagic rats.

Several previous experiments have reported that mediobasal hypothalamic lesions that include the ventromedial nuclei result in decreased adrenal weights and impaired pituitary-adrenocortical responses to stress. In the present experiment, lean and obese rats with lesions of the ventromedial hypothalamus that spared the median eminence were found to have normal adrenal weights and normal elevations in plasma corticosterone to shock-induced stress. The previous results were attributed to incidental damage to adjacent structures, particularly the median eminence. Lean but not obese VMH-lesioned rats were found to have higher baseline corticosterone levels.     

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.     

Enhanced responses of the chorda tympani nerve to sugars in the ventromedial hypothalamic obese rat

Sweet taste sensitivity in obese rats with lesions of the ventromedial hypothalamus (VMH) was studied by examining chorda tympani nerve responses to various taste stimuli including sugars. In the early progressive phase of obesity (2 wk after creating VMH lesions), there was no significant difference in the nerve responses to any taste stimulus between sham-operated and VMH-lesioned rats. In contrast, in the late phase of obesity (15-18 wk after VMH lesions), the magnitude of responses to sugars (except for fructose) was prominently greater than that in age-matched controls. High-fat diet-induced obese rats and streptozotocin-diabetic rats also showed greater chorda tympani nerve responses to sugars as was observed in VMH-lesioned obese rats, indicating that VMH lesions might not be specifically related to the enhanced gustatory neural responses to sugars. Although it has been demonstrated that the enhanced responses of the chorda tympani nerve to sugars in genetically diabetic db/db mice is largely attributable to the lack of the direct suppressive effect of leptin on the taste receptor cells, plasma leptin levels were not correlated with the changes in chorda tympani responsiveness to sugars in these models of obesity and diabetes. Accordingly, our results suggest that some chronic factors, including high blood glucose, inefficiency of insulin action, or leptin resistance may be related to the enhancement of chorda tympani nerve responses to sugars.     

Inbred Roman high- and low-avoidance rats: differences in anxiety, novelty-seeking, and shuttlebox behaviors.

In the present study, male inbred animals (from the 10th generation of an inbreeding program that has been carried out in parallel to that of the outbred Roman high- and low-avoidance rat lines), were compared for emotionality in different testing situations, exploratory behavior in the holeboard and two-way, active-avoidance acquisition. Compared to the inbred Roman high-avoidance (RHA-I/Verh) rats, inbred Roman low-avoidance (RLA-I-Verh) rats showed higher emotionality in the open field (reduced distance travelled and number of rearings, and increased self-grooming behavior), in the elevated plus-maze test (increased number of total and open-arm entries, reduced distance travelled in the open arms, and increased self-grooming behavior), and during the habituation period in the shuttle box (decreased number of crossings, increased self-grooming behavior and defecations). Results from the hyponeophagia test were not conclusive, probably due to the test-dependent hyperactivity shown by RHA-I/Verh rats. In the holeboard apparatus, RHA-I/Verh rats explored more than RLA-I/Verh rats, especially when novel objects were located beneath the holes. Finally, RHA-I/Verh animals rapidly acquired active, two-way (shuttlebox) avoidance, whereas RLA-I/Verh animals required four 50-trial sessions to achieve an assymptotic level of 30-40% avoidance. Thus, the behavioral patterns of the Roman inbred strains were very similar to those previously reported for the RHA/Verh outbred lines. Differences in locomotor activity, exploratory, and self-grooming behavior were actually greater between the inbred strains than between the outbred lines. Differences in defecation, however, although still significant, were not so pronounced as those noted previously at this laboratory with the outbred lines.     

Brown adipose tissue of rats with obesity-inducing ventromedial hypothalamic lesions

Male and female Holtzman rats were made hyperphagic and obese with bilateral radiofrequency heat lesions of the ventromedial hypothalamic (VMH) area. When VMH rats were maintained at 28 degrees C, their brown adipose tissue (BAT) DNA, protein, and cytochrome oxidase contents were normal although more stored lipid was present, as judged from a threefold increase in wet weight. Thermogenic activity of BAT mitochondria was normal in male VMH rats, as judged from the unchanged level of guanosine diphosphate (GDP) binding (known to be a sensitive index of the functional activity of the thermogenic proton conductance pathway), and reduced in female VMH rats. When rats with VMH lesions were exposed to cold (4 degrees C for 24 h), the visible hyperemia of their BAT and normal large increase in mitochondrial GDP binding indicated normal thermogenic responsiveness. We conclude that the medial nuclei of the hypothalamus and associated afferent or efferent nerve tracts do not represent an essential central nervous system link for cold-induced, sympathetic-mediated activation of BAT thermogenesis. It is possible, however, that diet-induced, sympathetic-mediated activation of BAT function and growth might require an intact VMH region because no enhancement of BAT mitochondrial function normally associated with hyperphagia was detected in these hyperphagic VMH-lesioned animals.     

Effects of undernutrition and handling during suckling on shuttle avoidance and footshock escape behavior and on plasma glucose levels of young rats

The present report examined the effects of undernutrition and handling on shuttle and footshock escape avoidance behavior of female rats. Rats were undernourished by feeding their dams a 7% casein diet from birth until 23 days of life. During this period rats were separated from their dams for 4 to 10 min. On days 23 and 24 after delivery, young rats were subjected to sessions in a two-way shuttle avoidance task. The results demonstrated that nonstimulated and stimulated undernourished and stimulated well-nourished rats escape faster than nonstimulated well-nourished animals from footshock during the first session of shuttle avoidance. Further, undernutrition interacted with early stimulation, disrupting the shuttle avoidance behavior of female rats. These results suggest that both undernutrition and early handling can change the footshock behavior of young rats. Undernourished rats presented lower basal glucose levels than well-nourished animals, but responded to shuttle avoidance testing in the same way as do normal rats, increasing the glucose levels.     

Acquisition of an Active Avoidance Reaction in Rats and Morphological Changes in the Hippocampus in Pentylenetetrazol Kindling

The relationship between measures of active avoidance behavior and morphological changes in the hippocampus was studied in rats after kindling induced by administration of pentylenetetrazol. Pentylenetetrazol kindling impaired the acquisition of the avoidance reaction and increased the number of intersignal reactions without altering the acquisition of the avoidance reaction in the shuttle box in rats. The numbers of neurons in the hippocampus (fields CA1 and CA3) and dentate fascia decreased, while the numbers of damaged neurons increased. Inverse correlations between seizure severity and the numbers of neurons in hippocampal fields CA1 and CA3 and the dentate fascia were seen in rats subjected to kindling. Rats of this group also showed positive correlations between seizure severity and the numbers of damaged neurons in field CA1 and the dentate fascia. There were no correlations between measures of convulsive activity or the number of cells in hippocampal zones and measures of the acquired avoidance behavior. Control animals showed negative correlations between the numbers of damaged cells in field CA1 and the dentate fascia and the characteristics of avoidance behavior in the first and third training sessions.     

Unimpaired maintenance of a conditioned avoidance response in the rat with diabetes insipidus.

The ability to maintain a conditioned avoidance response (CAR) was studied in normal Long-Evans rats and rats of the Brattleboro strain which were either homozygous or heterozygous for hereditary hypothalamic diabetes insipidus (DI). Homozygous DI rats had a lower CAR acquisition rate than did normal or heterozygous DI rats. However, the homozygous DI rats exhibited significantly greater CAR retention than did the other animals over the total period of extinction testing. The greater CAR retention could not be accounted for by either increased sensitivity to the electric foot shock used as the unconditioned stimulus or by perching on the metal center barrier of the training shuttle box, a form of behavior unique to the homozygous DI rats. Since the homozygous DI rat is totally lacking in hypothalamic antidiuretic hormone (ADH), the greater CAR retention of these animals indicates that ADH is not a requirement for CAR retention.     

Conditioned taste aversion in lean and obese rats with ventromedial hypothalamic knife cuts

The development of a conditioned taste aversion (CTA) was assessed in rats made hyperphagic with parasagittal knife cuts in the ventromedial hypothalamus (VMH). The animals were water deprived and presented with a .1% saccharin solution paired with injections of either lithium chloride or sodium chloride. In Experiment 1, VMH rats tested at a nonobese weight level did not differ from sham-operated control rats in the acquisition and extinction of the CTA. In Experiment 2, moderately obese VMH rats displayed a stronger CTA than did sham-operated control rats as evidenced by a slower rate of extinction. This effect was not due to the higher absolute dose of LiCl given to the obese VMH rats. A second group of obese VMH rats given an amount of LiCl equivalent to that given to the control rats also displayed retarded extinction of the CTA. The results of these experiments demonstrate that hyperphagia-inducing knife cuts do not alter aversive taste conditioning in rats but that hypothalamic obesity does enhance conditioned taste aversions. This may reflect an obesity-induced suppression in appetitive motivation.     

Transfer of control of avoidance behavior in normal and telencephalon ablated goldfish (Carassius auratus)

Three groups of goldfish (2 normal and 1 telencephalon ablated) were trained to avoid electric shock by crossing a barrier in a twoway shuttle box whenever a tone sounded. Then, while isolated in a distinct compartment, one normal and the ablated group received discriminative classical defense conditioning with two visual cues (CS+, CS?), while the other normal group received pseudoconditioning. Lastly, in the shuttle box, all fish had unreinforced test presentations of the visual CSs intermixed with avoidance retraining trials to the tone. The classical conditioned normal and ablated groups did not differ and both showed immediate, discriminative transfer of control of avoidance responding to the CS+ as they did to the tone, while for the pseudoconditioned normal fish the CSs did not control avoidance behavior. These results suggest that the telencephalon does not play a significant role in the integration and utilization of conditioned fear reactions with previously learned avoidance responses to generate appropriate behavior.     

Immunomodulation of inherent behavior in C57Bl/6 and BALB/c mice with antibodies to glutamate

Immunization of BALB/c mice with glutamate-BSA conjugate reduced anxiety and improved passive avoidance retention, while in C57Bl/6 mice immunization disturbed passive avoidance retention, but had no effect on anxiety. Interstrain differences in the shuttle box behavior were found between control animals.     

Effects of additional cues on passive avoidance learning and extinction in rats with hippocampal lesions

Following the acquisition of a water-rewarded approach response in a straight runway, the effects of introducing shock in the goal box (passive avoidance - PA) or withdrawing reinforcement (extinction) were compared in hippocampal, cortical, and operated control groups of rats. Under standard test conditions, hippocampal groups were impaired in PA learning and showed strong resistance to extinction, relative to the control groups. When additional cues were provided such that external stimuli associated with goal box events could be easily detected early in the runway, performance differences between the hippocampal and control groups were eliminated in the PA test and significantly reduced in extinction. The results emphasize the inefficient processing by hippocampally-damaged animals of stimulus cues following a shift in experimental contingencies.     

LHRH and rat avoidance behavior: influence of castration and testosterone

Pretraining subcutaneous administration of a high dose of LHRH (100 micrograms/kg) to intact rats impaired acquisition of a conditioned avoidance response (CAR) in a two way shuttle box. Acquisition of a CAR was also decreased when LHRH was administered to castrated rats. LHRH antagonized the dose related impairment in acquisition and retention performance induced by testosterone in castrated animals. The results are discussed based on the interrelationships between castration, testosterone, LHRH and brain monoamines.