Effects of quinine adulterated diets on the food intake and body weight of obese and non-obese hypothalamic hyperphagic rats

Female rats given knife cuts between the medial and lateral hypothalamus overate and became obese on a high fat diet. When switched to a quinine diet the knife cut rats initially underate and lost weight, but their body weights did not fall significantly below that of controls maintained on the same diet. Knife cut rats also maintained weights at control levels when given a moderately bitter quinine diet immediately after surgery, but displayed subnormal weights when switched to a very bitter diet. Cuts lateral to the fornix produced a greater weight suppression on the quinine diet, but a smaller weight gain on a high fat diet than did cuts medial to the fornix. The results indicate that the hypothalamic knife cuts elevate the upper limit of body weight with little or no change in the lower body weight limit, and that obesity rather than hypothalamic damage per se is the major cause of the hyperphagic rat's finickiness to unpalatable quinine diets. A dual lipostatic model of the hypothalamic hyperphagia syndrome is discussed.     

Perifornical fiber system mediates VMH electrically-induced suppression of feeding

Fiber pathways mediating the cessation of food ingestion during continuous low-level electrical stimulation of the ventromedial region of the hypothalamus (VMH) were appraised in food-deprived male rats using knife cuts. Parasagittal knife cuts in the medial perifornical area of the hypothalamus produced much larger increases in threshold current intensities for the inhibition of feeding than did cuts in the lateral perifornical hypothalamus. These findings indicate that fiber pathways critical to the inhibitory feeding effect of continuous VMH electrical stimulation traverse the perifornical hypothalamus but not the lateral hypothalamus. A comparison of these and other results demonstrates an anatomical similarity between the fiber pathways mediating VMH electrically-induced inhibition of feeding and hypothalamic hyperphagia following lesions or knife cuts. The nature of the inhibitory feeding effect of VMH electrical stimulation is also addressed and behavioral observations strongly supportive of a specific anorectic effect produced by the stimulation are reported.     

PVN-hindbrain pathway involved in the hypothalamic hyperphagia-obesity syndrome

This study examined the involvement of caudal brainstem projections of the hypothalamic paraventricular nucleus (PVN) in the medial hypothalamic (MH) hyperphagia-obesity syndrome. Experiment 1 demonstrated that a unilateral parasagittal knife cut in the MH combined with a contralateral coronal knife cut in either the ventrolateral pons (vP) or ventrolateral medulla (vM) significantly increased food intake and body weight in adult female rats. Overeating and overweight were also produced by a unilateral MH knife cut combined with a contralateral oblique cut under the nucleus of the solitary tract and dorsal motor nucleus of the vagus complex (NST/DX). In contrast, an MH cut x dorsolateral medullary cut combination did not increase food intake or body weight compared to a MH cut alone or sham surgery. Experiment 2 demonstrated that the hyperphagia/obesity effect of MH x vP knife cuts was comparable to that obtained with bilateral PVN lesions, but less than that produced by bilateral MH knife cuts. Bilateral vP cuts also increased body weight but the effect was less than that obtained with the other experimental treatments. Feeding the rats a high-fat diet rather than chow potentiated the hyperphagia and obesity syndromes produced by the various lesion conditions. Taken together, these findings suggest that the medial hypothalamic hyperphagia and obesity syndrome is due, in part, to damage to PVN projections to the caudal brainstem, the NST/DX complex in particular. The functional significance of this PVN-hindbrain "feeding" pathway and the identity of extra-PVN components of the hyperphagia-obesity syndrome remain to be established.     

Hypothalamic obesity following knife cuts that minimize arterial damage

Parasagittal knife cuts that separate the medial hypothalamus from the lateral hypothalamus produce obesity. It has been assumed that the obesity results from the cutting of axons. However, these cuts also appear to sever arteries. The present study demonstrates that the severing of arteries is not necessary for the production of obesity. Knife cuts were placed at an angle so as to separate the medial hypothalamus from the lateral hypothalamus with minimal damage to arteries. These rats overate and became obese just as rapidly as rats with parasagittal cuts.     

The connections of the medial preoptic region and maternal behavior in the rat

Female rats which are hysterectomized and ovariectomized on Day 16 of pregnancy and injected with estrogen show a short latency to onset of maternal behavior when presented with test pups 48 hrs later. In the present experiment, female rats were treated similarly except that on Day 16 of pregnancy they received knife cuts which severed either the lateral, anterior, dorsal, or posterior connections of the medial preoptic area (MPOA), or sham knife cuts. Severing the lateral connections of the MPOA severely disrupted materal behavior, while severing the dorsal or posterior connections of the MPOA produced either minor deficits or no deficits. Severing the anterior connections of the MPOA did produce large deficits in maternal behavior, but this was associated with hypoactivity and loss of body weight. Therefore, the maternal behavior deficits observed in the anterior cut group may have been a secondary effect of the knife cut. The results emphasize the importance of the lateral connections of the MPOA for maternal behavior.     

Dorsolateral connections of the medial preoptic area and maternal behavior in rats

The lateral connections of the medial preoptic area (MPOA) are essential for maternal behavior in rats. The purpose of this study was to more exactly specify the nature of this pathway. Experiment 1 found that knife cuts that severed the dorsolateral connections of the MPOA were as effective as complete cuts in disrupting maternal behavior, whereas knife cuts that severed the ventrolateral MPOA connections were ineffective. These results suggest that MPOA efferents and afferents critical for maternal behavior leave or enter the MPOA dorsolaterally. Experiment 2 located possible sources of critical afferent input. Lactating rats received MPOA lateral cuts with a horseradish peroxidase (HRP)-coated wire knife. Full lateral cuts and dorsolateral cuts disrupted maternal behavior and labeled more cells with HRP in the nucleus of the solitary tract and the locus coeruleus than did ventrolateral cuts, which did not disrupt maternal behavior.     

Histochemical identification of a PVN-hindbrain feeding pathway

Unilateral coronal knife cuts through the ventrolateral pontine reticular formation produce overeating and overweight when combined with contralateral parasagittal knife cuts in the medial hypothalamus (MH). The knife cuts were in a position to sever fiber projections from the paraventricular nucleus to the hindbrain. The present study used histochemical techniques to confirm that hyperphagia-producing knife cuts transect PVN-hindbrain fiber connections. In Experiment 1, adult female rats received a unilateral coronal knife cut in the ventrolateral pontine reticular formation. Horseradish peroxidase (HRP) was applied to the knife cut region and two to three days later brains were processed for the localization of neurons labeled with HRP. HRP-labeled neurons were found in the PVN, particularly in the caudal parvocellular region. Additional HRP-labeled neurons were observed in other medial hypothalamic areas but none were found in the ventromedial nucleus. HRP-filled cells were also found in the lateral hypothalamus, central nucleus of the amygdala, and in the nucleus of the solitary tract (NST). Many of the PVN projections to the hindbrain contain oxytocin and Experiment 2 determined if hyperphagia-inducing knife cuts sever PVN oxytocinergic fibers. Adult female rats received unilateral MH cuts, unilateral pontine cuts, or a contralateral combination of both cuts. One to eight days later the brains were processed for immunocytochemistry. The MH cuts and pontine cuts were found to interrupt descending oxytocinergic fibers. Taken together, these results support the hypothesis that interruption of a direct PVN-hindbrain oxytocinergic projection is responsible for the hypothalamic hyperphagia-obesity syndrome. However, the results do not rule out the involvement of a multisynaptic pathway or additional neurochemical systems.     

Preoptic-brainstem connections and maternal behavior in rats.

This study presents evidence supporting the view that preoptic area (POA) projections through the ventral tegmental area (VTA) to lower brainstem regions are important for maternal behavior in postpartum rats. Experiment 1 demonstrated that bilateral coronal knife cuts posterior to the VTA disrupted maternal behavior, and Experiment 2 demonstrated a similar disruption when a unilateral knife cut that severed the lateral connections of the medial POA was paired with a contralateral knife cut posterior to the VTA. In a final anatomical experiment using horseradish peroxidase histochemistry, it was shown that knife cuts posterior to the VTA do sever POA efferents. However, such cuts severed other ascending and descending pathways as well, and these may also be involved in maternal behavior control.     

The effects of paraventricular hypothalamic lesions on maternal behavior in rats

The present study was undertaken to determine whether the disruptive effects of knife cuts which sever the lateral connections of the medial preoptic area (MPOA) on maternal behavior are mediated by interfering with the output of the paraventricular hypothalamic nucleus (PVN). Postpartum rats received one of the following: Knife cuts severing the lateral connections of the MPOA; knife cuts severing the lateral connections of the PVN; radiofrequency lesions of the PVN; sham lesions or knife cuts. Only females that received knife cuts severing the lateral connections of the MPOA showed severe deficits in maternal behavior. These results indicate that the influence of the MPOA on maternal behavior is not mediated by the output of the PVN. Since the PVN is the major source of oxytocin input to other brain regions, these results also suggest that oxytocinergic neural pathways are not critical for postpartum maternal behavior. Another important finding was that females with MPOA knife cuts that did not retrieve their young were capable of hoarding candy, suggesting that the retrieval deficit was not the result of a general oral motor deficit.     

Deficits in glucose appetite and satiety produced by ventromedial hypothalamic lesions in the rat

Rats with ventromedial hypothalamic lesions displayed a reduced sensitivity to dilute (5 or 7%) glucose solutions. The lesioned animals were less responsive to the food suppressive effects of glucose ingestion, and they drank less dilute glucose when food deprived compared to controls. The VMH lesioned rats, on the other hand, appeared normally sensitive to concentrated (20 or 33%) glucose solutions. They suppressed their feeding in response to glucose intubation, and they consumed more concentrated glucose solution than did controls, which is consistent with the hyperphagia effects of the lesions. The nature of the neural impairment responsible for these lesion effects is discussed.     

Does the ventromedial hypothalamus inhibit the lateral hypothalamus?

Electrical stimulation of the ventromedial hypothalamus inhibited feeding in hungry rats. Neither knife cuts of the VMH-LH connections nor LH electrolytic lesions significantly altered the feeding inhibitory effects of medial stimulation. This suggests that the common assumption that the VMH inhibits the LH feeding system is incorrect. However, electrical stimulation may not be an appropriate method to study VMH feeding pathways, and this problem is discussed.     

Glucoprivic feeding is impaired by lateral or fourth ventricular alloxan injection

Feeding and blood glucose responses to insulin and 2-deoxy-D-glucose (2-DG) were examined in rats previously given lateral or fourth ventricular injections of the diabetogenic agents, alloxan and streptozotocin. Although streptozotocin (120, 200, and 400 micrograms) was ineffective, lateral ventricular alloxan injections (40 micrograms in 5 microliters) reduced feeding to 45% of control after 350 mg/kg 2-DG (sc), 33% of control after 150 mg/kg 2-DG, and 65% of control after insulin (2 U/kg). Fourth ventricular alloxan injections produced greater deficits, reducing feeding to 19, 7, and 46% of control, respectively. The sympathoadrenal response to glucoprivic agents was normal after alloxan treatment; however, blood glucose levels fell more rapidly during fasting than in controls. Alloxan-induced deficits did not appear to result from damage to catecholamine neurons, since neither regional concentrations nor glucoprivation-induced elevation of catecholamine turnover was altered by alloxan pretreatment. We conclude that cells involved in the glucoprivic control of feeding can be selectively and permanently damaged by intracerebroventricular alloxan administration. Such cells appear to reside in the hindbrain, to be noncatecholaminergic, and to function independently of glucoreceptors mediating sympathodrenal discharge.     

Opiates and medial hypothalamic knife cuts cause hyperphagia through different mechanisms

Several experiments were performed to determine whether the hyperphagia caused by medial hypothalamic knife cuts and that induced by opiate agonists are mediated by a common mechanism. In the first set of experiments, male Sprague-Dawley rats were given bilateral parasagittal medial hypothalamic knife cuts or a sham procedure and fed a high-fat Crisco-chow diet. Knife-cut and sham-operated rats were approximately equally sensitive to the suppressive effects of naloxone on food intake. The kappa opiate receptor agonist ketocyclazocine generally increased daytime food intake in sham-operated rats; in contrast, the normal hyperphagia of knife-cut rats was in most cases either unchanged or decreased by ketocyclazocine. In a second set of experiments, neither diet composition nor hypothalamic knife cuts significantly affected the feeding responses to naloxone or the stimulatory effects of the kappa agonist butorphanol tartrate. It was hypothesized that the differential effects of ketocyclazocine in knife-cut and sham-operated rats are a consequence of the sedative effects of the drug combined with the elevated baseline of the knife-cut subjects. This hypothesis was supported by a third experiment, in which ketocyclazocine also reduced nocturnal intake in unoperated rats and butorphanol increased intake. That feeding responses to naloxone and butorphanol were essentially unchanged by hypothalamic knife cuts suggests that the opioid feeding system is independent of the longitudinal feeding inhibitory pathway believed to be involved in knife-cut-induced hyperphagia.     

Transection of fibers crossing the lateral border of the lateral hypothalamus: fragmented spontaneous ingestive patterns and reanalysis of "regulatory deficits" in rats with sagittal knife cuts.

Rats bearing sagittal knife cuts lateral to the LH showed fragmented meal patterns. Both drinking and locomotor activity occurred during the interruptions in dry chow meals. This fragmented pattern resembles that found in rats with LH lesions, yet it is anatomically unlikely these knife cut animals sustain damage to any known salivary pathway. The cut animals were also found to show delayed drinking responses after intracellular or extracellular dehydration, yet they increased their water intake normally when offered a salty chow. They showed impaired glucoprivic feeding. The similarities of these findings to those in LH and other preparations are discussed.     

Effects of knife-cut lesions of the medial forebrain bundle in self-stimulating rats

Unilateral frontal-plane knife-cut lesions were made in the anterior medial forebrain bundle ipsilateral to a lateral hypothalamic self-stimulation electrode. Behavioral effects of the knife cut on self-stimulation reward and operant performance capacity were measured via the reward summation function method. Knife cuts placed at the level of the anterior commissure were ineffective in altering reward or motor/performance capacity, whereas knife cuts just posterior in the caudal lateral preoptic area degraded reward and sometimes impaired motor/performance capacity. In a second experiment, knife cuts placed posterior to the ventral tegmental area were ineffective unless they intruded on the ventral tegmental area itself. Several small knife cuts placed just anterior to the ventral tegmental were effective in reducing self-stimulation reward. The results are discussed in terms of the anatomical substrate of lateral hypothalamic self-stimulation reward and as a first step in a larger mapping study.     

Effects of hypothalamic knife cuts and experience on maternal behavior in the rat

Recent investigations suggest that the disruption of placentophagia, pup-directed maternal behavior, and nestbuilding seen after lesions of the medial preoptic area (MPO) or the lateral hypothalamus may be due to the interruption at different points of a single longitudinal neural system mediating these behaviors. To test this, we compared the effects of knife cuts on the lateral border of the MPO, and of the posterior medial forebrain bundle (MFB), with asymmetrical cuts combining a unilateral MPO cut with a contralateral MFB cut. We observed placentophagia, nestbuilding, and pup-directed maternal behaviors at, and after, parturition in both primiparous and biparous rats. In primiparae, MPO cuts (a) disrupted placentophagia, (b) delayed the onset of crouching and pup-licking, and (c) eliminated retrieval and nestbuilding. MFB cuts (a) disrupted placentophagia, (b) delayed the onset of maternal behavior, and (c) eliminated nestbuilding. Asymmetrical cuts (a) disrupted placentophagia, and (b) delayed the onset of maternal behavior. In biparous rats, MPO cuts eliminated nestbuilding and retrieval. MFB cuts (a) disrupted placentophagia, and (b) eliminated nestbuilding. Asymmetrical cuts (a) delayed nestbuilding. These results suggest the involvement of a longitudinal neural system in the production of immediate pup-directed maternal behavior, placentophagia, and nestbuilding in parturient primiparae, but which is not critical for the eventual display of maternal behavior and nestbuilding in maternally naive rats, nor for the immediate onset of placentophagia and maternal behavior in maternally experienced rats.     

Medial hypothalamic involvement in maternal aggression of rats

Extensive electrolytic lesions of the medial hypothalamus, or more restricted ones in its ventral division, decreased maternal aggression in rats operated upon on postpartum Days 2 and 3 and tested with female intruders 4 days later. Maternal aggression was attenuated also in mothers receiving intrahypothalamic infusions with ibotenic acid or parasagittal knife cuts along the lateral border of the ventromedial hypothalamic nucleus; in addition, the females with ibotenate lesions or knife cuts showed impaired lordosis behavior. None of the hypothalamic interventions were associated with deficits in pup retrieval. Lactation was impaired in groups with hypothalamic electrocoagulations but not in mothers with ibotenate lesions or knife cuts. The results suggest that the ventromedial hypothalamus and its lateral connections participate in control of maternal aggression.     

Sagittal knife cuts in the near and far lateral preoptic area-hypothalamus disrupt maternal behaviour in female hamsters

Parasagittal knife cuts with a varied mediolateral position were placed along the medial preoptic-medial anterior hypothalamic continuum (MPOA-MAH) in female hamsters. Near lateral (NL) knife cuts severed mediolateral connections between the MPOA-MAH and the medial forebrain bundle (MFB) while far lateral cuts (FL) were placed more laterally, sparing MPOA-MAH connections with the MFB. Across the knife cut condition, hamsters were either allowed to construct and maintain a food hoard or allowed to feed ad lib but not permitted to hoard. Animals were then tested for maternal behaviours. Both NL and FL cuts disrupted pup-directed behaviours in virgin maternal tests. NL, but not FL cuts severely disrupted nest building. These same animals were then mated and tested for maternal behaviour with their own young. There were no differences among the experimental groups in various maternal behaviours during these tests. Throughout lactation, however, the majority of NL and FL hamsters not permitted to hoard progressively cannibalized their entire litters. NL and FL counterparts with the hoarding opportunity, on the other hand, cannibalized fewer pups and reared healthy, moderate-sized litters that were smaller than those of surgical controls. That FL cuts were just as effective as NL cuts in disrupting pup-directed behaviour suggests that the mediolateral connections of the MPOA-MAH, other than with the MFB, are important for these behaviours.     

Food and water intake in rats after transections of fibers en passage in the tegmentum

A 145 micron diameter wire knife was used to transect fibers en passage in ventral, medial, and dorsal aspects of the tegmentum. Data from 74 rats with bilaterally symmetric cuts indicate that the interruption of fibers which course through the central region of the tegmentum result in hyperdipsia. Three distinct syndromes were observed: (a) extreme hyperdipsia beginning on the first or second day after surgery and persisting for 4–6 days; (b) a smaller increase in water intake beginning on the first or second day after surgery and persisting for the duration of the experiment; and (c) normal or subnormal water intake for several days after surgery followed by a sharp increase which persisted for 4–6 days. Cuts through the dorsolateral tegmentum consistently produced hyperphagia in male rats maintained on a dry pellet diet. The magnitude of the effects was comparable to that seen in male rats after ventromedial hypothalamic (VMH) lesions. These cuts, as well as others which did not result in hyperphagia, abolished the normal feeding responses to 2-deoxy-D-glucose (2-DG) without affecting the feeding response to insulin. Some of our cuts produced significant overeating but no commensurate weight gain, suggesting that metabolic disturbances may have occurred. Knife cuts of comparable size through the ventral third of the tegmentum, the pons, or the ventral aspects of the central grey, failed to affect either food or water intake reliably. Histological evidence of minimal direct damage to cellular components of the region of the behaviorally effective cuts and their extensive rostro-caudal distribution indicate that direct damage to perikarya of tegmental neurons probably is not responsible for the effects of the cuts.     

The dorsomedial hypothalamic nucleus and its role in ingestive behavior and body weight regulation: lessons learned from lesioning studies

This review article discusses the well-established role of the dorsomedial hypothalamic nucleus (DMN) in feeding, drinking and body weight (BW) regulation. DMN lesions (L) in both weanling and mature rats of both sexes produce hypophagia, hypodipsia and reduced ponderal and linear growth in the presence of normal body composition. The growth reduction is not due to a deficient secretion of growth hormone, insulin-like growth factor-1, thyroxine, triiodothyronine or insulin. DMNL rats actively defend their lower BW (BW settling point) by becoming either hyper- or hypophagic, depending on the experimental manipulation, thereby defending both lean and fat mass. They also regulate their 24-h caloric intake, but they may overeat during the first hour of refeeding following a fast, possibly due to a reduced ability to monitor blood glucose or to respond to cholecystokinin (CCK). 2-Deoxy-D-glucose (2DG) increases c-fos expression in orexin-A neurons in the DMN, and DMNL eliminated the orexigenic effect of 2DG. DMNL rats on high-fat diets do not get as obese as controls, which may be due to a reduction of DMN neuropeptide Y (NPY). Rats lacking DMN CCK-A receptors are obese and have increased expression of NPY in the DMN, supporting earlier data that CCK may act at the DMN to suppress food intake. Excitotoxin studies showed that loss of DMN cell somata, and not fibers of passage, is important in the development of the DMNL syndrome. The DMN is a site where opioids increase food intake and knife-cut studies have shown that fibers traveling to/from the DMN are important in this response. An interaction of glucose and opioids in DMN may also be involved in the control of food intake. DMN knife cuts interrupting fibers in the posterior and ventral directions additively produce the hypophagia and reduced linear and ponderal growth observed after DMNL. Ventral cuts may interrupt important connections with the arcuate nucleus. Lateral and posterior DMN cuts additively produce the hypodipsic effect seen after DMNL, but DMNL rats respond normally to all water-regulatory challenges, i.e., the hypophagia is not due to a primary hypodipsia. The DMN has been shown to be involved in the rat's feeding response to an imbalanced amino acid diet. These data show the DMN has an important role in many processes that control both food intake and BW regulation.