Electrical Stimulation Of The Lateral Hypothalamus Research Articles

Electrically induced behavior and neural specificity in ground squirrels and dormice

Electrical stimulation of the lateral hypothalamus in 2 species of hibernator, dormice (Glis glis) and ground squirrels (Spermophilus lateralis), suggests that induced behaviors may reflect activation of specific neural systems, rather than merely activation of a single central mechanism interacting with internal and external cues and past experience (prepotency hypothesis). In dormice, the stimulation induced feeding on powdered food; in squirrels it induced either feeding or picking up of food pellets. Consistent with neural specificity in both species were high probabilities of emergence (78–81%) of a behavior during stimulation at an electrode site, with no greater ease of emergence at a second site tested. In squirrels, only 1 of the 2 behaviors emerged at a site, and there was independence between behaviors emerging at contralateral sites. Long-term reliability of the behavior initially observed at an electrode site was 100% despite infradian (dormice) or circannual (squirrels) cycles of body weight and food intake. Some squirrels consistently showed different induced behaviors at contralateral electrode sites throughout their circannual cycle. These observations suggest that feral species are valuable in investigations of mechanisms underlying electrically induced behaviors, and that reevaluation of the prepotency hypothesis may be in order.

Individual differences in non-regulatory ingestive behavior and catecholamine systems

Animals that eat and/or drink in response to electrical stimulation of the lateral hypothalamus (ESLH-pos) are more responsive to both schedule-induced polydipsia (SIP) tests and a series of amphetamine (AMPH) injections than animals that do not exhibit these behaviors (ESLH-neg). Moreover, prior exposure to the behaviorally activating SIP experience, or to AMPH, permanently transformed the ESLH-neg animals into animals that reliably ate or drank during ESLH. Prior treatment with AMPH also increases the water consumed during subsequent SIP tests. Thus, initial of induced differences in sensitivity to activating experiences can determine behavioral propensities.

Asymmetry in the effects of unilateral 6-OHDA lesions on eating and drinking evoked by hypothalamic stimulation

The present experiment investigated the effects of unilateral 6-hydroxydopamine lesions of the caudate nucleus and nucleus accumbens on eating and drinking evoked by electrical stimulation of the lateral hypothalamus (ESLH). Lesions were made on either the ‘dominant’ or ‘non-dominant’ hemisphere as defined by an amphetamine-rotation test. We report here that lesions of the ‘dominant hemisphere’ were significantly more effective in disrupting ESLH-evoked behavior as well as producing longer-lasting deficits in somatosensory responsiveness as measured by the ‘tactile extinction test’.

Involvement of nigrostriatal dopamine neurons in the contraversive rotational behavior evoked by electrical stimulation of the lateral hypothalamus

This experiment was conducted to determine if nigrostriatal dopamine (DA) neurons are necessary for the contraversive rotational behavior evoked by electrical stimulation in the lateral hypothalamus. Rats were tested daily for electrical stimulation-induced rotational behavior (ESRB) for 5 days, and then given an injection of 6-hydroxydopamine (6-OHDA) or saline into the ipsilateral substantia nigra. The nearly total depletion of striatal DA (> 96%) completely abolished contraversive ESRB and resulted in the appearance of ipsiversive ESRB. Partial DA depletion (< 95%) had no effect on contraversive ESRB. In animals with a partial DA depletion subsequent treatment with a low dose of α-methyl- p-tyrosine (40 mg/kg) attenuated contraversive ESRB, while having no effect on control animals, or the ipsiversive turning in animals with > 96% DA depletion. We conclude that the nigrostriatal DA system is necessary for contraversive rotational behavior evoked by lateral hypothalamic stimulation, but that only a small percentage of DA fibers are required to maintain apparently ‘normal’ function—at least as indicated by contraversive ESRB.

Locomotor stepping elicited by electrical stimulation of the lateral hypothalamus requires an ipsilateral descending pathway

The effects of unilateral midbrain lesions on stepping produced by ipsilateral medial forebrain bundle (mfb) stimulation was determined in acute experiments. Rats were anesthetized with nembutal, mounted in a stereotaxic apparatus and suspended over a wheel which rotated when the rat stepped. Stimulation consisted of 10-sec trains of 50 Hz cathodal pulses (0.5 msec) at currents up to 200 μA delivered through monopolar electrodes. The stimulation sites were in the mfb at the level of the subthalamic nucleus. One side of the midbrain was randomly selected to receive a radio-frequency lesion. Certain midbrain lesions (N=11) abolished or severely reduced stepping elicited from ipsilateral mfb stimulation but produced no effect on contralaterally elicited stepping. Areas of common damage in these lesions included the medial half of the medial lemniscus and the ventral tegmental area (VTA). Lesions that were without effect (N=18) generally spared the dorsal VTA but damaged extensively either the ventrolateral VTA, medial lemniscus, substantia nigra, red nucleus, or central gray. A supplemental experiment further implicated a critical descending system since neither unilateral nor bilateral mfb lesions blocked stepping elicited by VTA stimulation. Together these results suggest that a descending path through the ipsilateral dorsal VTA mediates stepping elicited by mfb stimulation in the anesthetized rat.

Proliferation of arterial smooth muscle cells incubated in serum from brain-stimulated rats

Platelet deficient serum prepared from rats subjected to acute electrical stimulation of the lateral hypothalamus demonstrated mitogenic activity when added to incubating media supporting growth of homologous arterial smooth muscle cells in vitro . This activity did not appear to be related to the presence of platelet-derived growth factor, hyperlipidemic lipoproteins or increased amounts of insulin. Plasma arginine vasopressin concentration was elevated in these animals, but further investigation is required to determin if this elevation is causally related. Since hypothalamic stimulation is also associated with severe endothelial injury in vivo , the mitogenic activity of the blood of such animals could induce proliferation of SMC which have migrated into the arterial intima. Such features have been observed in chronically stimulated animals and may be of relevance for the role of neural factors in atherogenesis.

Different effects of cholecystokinin and satiety on lateral hypothalamic self-stimulation

The effects of cholecystokinin (CCK) and satiety were compared in animals lever-pressing for rewarding electrical stimulation of the lateral hypothalamus. For some rats, conditions of food deprivation and satiation, respectively, increased or decreased responding whereas the self-stimulation behavior of other rats was unresponsive to these feeding manipulations. CCK, at doses thought to signal satiety, reduced the responding of all rats independent of whether they were, or were not, responsive to real satiety. This same result was obtained with the aversive agent lithium chloride. These data suggest that the reduced feeding observed following CCK administration is due to aversive consequences and not satiety.

Dissociating the determinants of self-stimulation

Four experiments were conducted to elucidate the determinants of the initiation of and escape from electrical stimulation of the lateral hypothalamus under several different reinforcement schedules. The first experiment of this series used correlational and factor analytic techniques to show that, under continuous reinforcement, the vigour of initiation is determined more by forcement than by positive reinforcement. Forcement is defined as all of the performance changes directly elicited and potentiated by the stimulation. Escape is determined by adaptation of positive reinforcement, not by negative reinforcement or aversion. Continuous reinforcement schedules are, therefore, not appropriate for studying either the positive or negative reinforcement produced by brain stimulation. The second experiment used fixed-interval reinforcement schedules to eliminate the effects of forcement on initiation and adaptation of positive reinforcement on escape. Parametric manipulations indicate that activity in the positive reinforcement and escape systems is a simple function of stimulation charge. The combination of parameters which make up a given charge is of relatively little importance. However, the positive reinforcement system becomes maximally activated at far lower charges than does the escape system. The third experiment used a T-maze technique to show that, after 5 sec, anterior hypothalamic stimulation becomes negatively reinforcing, but posterior hypothalamic stimulation does not. Since the escape from posterior hypothalamic stimulation on a fixed-interval schedule can be dissociated from both negative reinforcement and adaptation of positive reinforcement, it is suggested that such escape is reinforced by a positive process triggered by the offset of stimulation (OFF positive reinforcement). The fourth experiment showed that stimulation trains longer than 10 sec are significantly less positively reinforcing than much shorter trains. This reduction in positive reinforcement confirms the development of negative reinforcement in long trains of hypothalamic stimulation, even at posterior electrodes. Negative reinforcement appears to be as general a property of hypothalamic stimulation as is positive reinforcement. Thus, depending on the reinforcement schedule and electrode site, the initiation of lateral hypothalamic stimulation may be determined by ON positive reinforcement, OFF positive reinforcement and forcement. Escape may be determined by OFF positive reinforcement, adaptation of positive reinforcement and negative reinforcement. The new procedures presented here allow the dissociation of these diverse determinants and the reliable quantification of the reinforcement produced by hypothalamic stimulation.

Opioid antinociception and positive reinforcement are mediated by different types of opioid receptors

Fentanyl (FEN) and diprenorphine's (DIPR) potentials for analgesia and reinforcement were assayed using rats. Analgesia was measured by the classic tail-flick test. The test germane to opioid reinforcement involved measuring pressing rates for direct electrical stimulation of the lateral hypothalamus and ventral tegmental area. FEN, as does morphine and heroin, produced strong analgesia and enhanced pressing rates for brain stimulation. DIPR produced no analgesia and antagonized FEN's analgesia. DIPR, at doses antagonizing FEN's analgesia, enhanced pressing for brain stimulation. DIPR's enhancement of pressing was antagonized by naloxone (100 microg/kg). When FEN and DIPR were given concurrently, pressing for brain stimulation was not reduced and was greater than after FEN alone was given. These data support a conclusion that different types of receptors are associated with opioid analgesia and reinforcement.

Effects of chlordiazepoxide on the self-regulated duration of lateral hypothalamic stimulation in rats.

Rats were exposed to a fixed-interval 60-s schedule under which responding was maintained by electrical stimulation of the lateral hypothalamus. The duration of stimulation was controlled by the duration of each lever press that initiated reinforcement. The effects of variation in current intensity and administration of several chlordiazepoxide (CDP) doses (2.5--20 mg/kg IP) were investigated. The duration of stimulation was inversely related to current intensity. Administration of CDP resulted in increases in response rate and the durations of reinforced and non-reinforced responses. CDP increased the response duration reliably more with non-reinforced responses than with responses that served to regulate the duration of stimulation. Thus CDP-induced increases in the duration of brain stimulation with the single lever self-regulation procedure may not be attributed to a specific effect of this compound on neural processes underlying reinforcement. The present results indicate the utility of intermittent schedules in establishing the specificity of drug effects on self-regulated duration of brain stimulation in the single-lever condition.

Probable independence between the genetic determinants of approach and escape responses induced by lateral hypothalamic stimulation in the mouse

A previous study demonstrated that, in a shuttlebox, BALB/c mice triggered and interrupted continuous electrical stimulation of the lateral hypothalamus (LH) more rapidly than did DBA/2 animals ( Cazala & Garrigues, Physiol. Behav. 25, 357–361 (1980) ). Using identical experimental conditions in the present experiment, we measured the approach and escape latencies induced by LH stimulation in F1 hybrids of DBA/2 × BALB/c crosses, as well as in five recombinant inbred strains (RIS : CXD2C, CXD2D, CXD2E, CXD2F, and CXD2K) originating from DBA/2 and BALB/c parental strains. In F1 animals, the latency to initiate the stimulus (OFF duration) was short, as in the BALB/c strain, whereas the latency to interrupt the stimulation (ON duration) was long, as in the DBA/2 strain. The behavior exhibited by the five RIS permitted us to sort them into four groups. In CXD2D and CXD2F ON and OFF durations were of BALB/c type. In CXD2E ON times were of the BALB/c type; OFF times which were essentially of the DBA/2 type for intensities in the 2- to 10-μA range, clearly exceeded the values recorded in DBA/2 and BALB/c parents for intensities above 10 μA. In CXD2K, ON times were similar to those recorded in the DBA/2 parents, whereas OFF times were of the BALB/c type. The CXD2C offspring, in which mixed results were obtained with regard to ON duration (DBA/2 type for current intensities in the 2- to 8-μA range, and BALB/c type for higher intensities) showed OFF values identical to those observed in the BALB/c strain. The different forms of associations observed between DBA/2 and BALB/c phenotypes, in terms of the two behavioral variables studied, suggest (1) that the two components of LH stimulation are controlled by distinct genetic factors and (2) that there exists in the parental strains BALB/c and DBA/2 a quantitative relationship between the mechanisms respectively involved in the control of approach and escape responses induced by LH stimulation.

Effect of ethanol on central mechanisms of the food response to electrical stimulation of the lateral hypothalamus

Effect of ethanol on central mechanisms of the food response to electrical stimulation of the lateral hypothalamus

Dissociation of hunger and self-stimulation by trigeminal deafferentation in the rat

Section of trigeminal orosensory or oromotor nerves reduces food intake and disrupts performance of a food-reinforced lever pressing response but increases the rate of an identical lever pressing response reinforced by electrical stimulation of the lateral hypothalamus. Our findings suggest that trigeminal orosensation plays a critical role in the neural control of hunger in the rat. These results also fail to support a response-oriented theory of intracranial self-stimulation where the latter is thought to involve selective facilitation of sensorimotor circuits underlying species-typical consummatory behavior.

Lateral hypothalamic stimulation: Stimulus-bound eating and self-deprivation

Research was undertaken in an attempt to clarify the relationship between stimulus-bound eating and self-deprivation produced by electrical stimulation of the lateral hypothalamus. It was hypothesized that if these two phenomena are mediated through a common population of feeding-related neurons, a significant correlation should be observed between these two behaviors. No significant relationship was discovered among the rats tested for both stimulus-bound eating and self-deprivation. Although this finding by itself does not rule out some role for feeding-related neural elements in stimulus-bound eating and self-deprivation, the present results provide no support for this view and suggest alternative explanations should be sought.

Development of brain stimulation reward in the medial prefrontal cortex: Facilitation by prior electrical stimulation of the sulcal prefrontal cortex

Electrical stimulation of the medial prefrontal cortex (MC) in rats delivered daily for seven days causes a marked improvement in the rate of acquisition of a self-stimulation response. In the present experiment, we looked at whether we could get the same facilitatory effect on self-stimulation of the MC by delivering pre-training stimulation to other points in the brain anatomically related to the MC. Electrical stimulation of the lateral hypothalamus was without effect. However, electrical stimulation of the sulcal prefrontal cortex (SC) either contralateral or ipsilateral to the MC electrode did facilitate acquisition of self-stimulation of the MC. Thus the SC and MC would appear to be part of the same substrate controlling the development of positive reinforcement in the MC.

Relation between eating evoked by lateral hypothalamic stimulation and tail pinch in different rat strains

The similarity between the behaviors evoked by tail pinch (TP) and electrical stimulation of the lateral hypothalamus (ESLH) has been noted by many investigators. Evidence is presented for a possible inverse relationship between the probability that ESLH would evoke eating and the readiness to eat in response to TP in six different rat populations (High and Low lines of the LC1 and LC2 Hebrew University Strains, Sprague—Dawley, and Long—Evans). Discussion of these results emphasizes differences in intensity between ESLH and TP stimulation and differences in emotionality among rat populations.

Endothelial morphology and plasma total and high density lipoprotein cholesterol changes in hypothalamically stimulated squirrel monkeys fed a modified atherogenic diet

Experimental animals fed atherogenic diets show endothelial damage, impairment of endothelial regeneration and plasma lipid changes characterized by elevation of LDL and decrease of HDL cholesterol concentrations. Previous studies in this laboratory disclosed that chronic electrical stimulation of the lateral hypothalamus was associated with electron-microscopic evidence of endothelial injury in rats and squirrel monkeys maintained on basal (low fat/cholesterol-free) diets. In the present investigation squirrel monkeys fed similar diets supplemented with “modest” amounts of caloric fat and cholesterol were subjected to chronic lateral hypothalamic stimulation for periods as long as 20 months with the expectation that endothelial injury would be greater than in the absence of the supplements. These expectations were not substantiated. Endothelium was found to be surprisingly intact by electron microscopy and similar to that of implanted nonstimulated controls. A further observation of interest was the cholesterolemic response, notably in the HDL fraction, observed in both groups, but more striking in experimental animals. The data suggest that an interaction between a modified lipid/cholesterol diet and hypothalamic stimulation may lead to elevation of plasma HDL cholesterol concentration and preservation of endothelial integrity. Further investigation is required to determine whether these two events are causally related.

Morphological identification of brain stem neurones associated with predatory behaviour elicited by lateral hypothalamic electrical stimulation in the cat: a retrograde transport study using horseradish peroxidase subsequent to an electrolytic lesion

The combination of electrical stimulation of the lateral hypothalamus to elicit predatory behaviour, an electrolytic lesion and a subsequent HRP injection was used to identify brain stem neurones whose axons were affected by such hypothalamic stimulation. In contrast, the injection of HRP into such hypothalamic sites, without a prior lesion, resulted in a significant reduction in the number of labelled neurones. This suggests that an important contribution, namely those neurones which give rise to fibres which pass through the stimulated region, is underestimated by the later procedure.

The Effects of D-Amphetamine and Chlordiazepoxide on Responding Maintained by a Multiple Schedule of Food and Electrical Brain Stimulation in Rats

Rats were exposed to a multiple variable-interval schedule of food or electrical stimulation of the lateral hypothalamus. When stable behavioral baselines had developed, the effects of several doses of chlordiazepoxide (2.5, 5, 10, and 20 mg/kg) and of d-amphetamine (.25, .5, and 1 mg/kg) were assessed. Chlordiazepoxide was found to have similar effects on responding maintained by both reinforcers, low doses increasing response rates and the highest dose reducing them. This drug also increased the duration of brain stimulation, which was under the control of the rats. The effects of d-amphetamine, in contrast, were different in the two schedule components. Responding maintained by brain stimulation was substantially increased by d-amphetamine which, however, produced either only small increases or even decreases in response rates maintained by food. The different effects of d-amphetamine in the two schedule components could not be explained in terms of differences in baseline response rates. It is therefore concluded that in some circumstances the actions of d-amphetamine are dependent on the reinforcing event maintaining behavior.

Effect of hypothalamic stimulation on the endothelial morphology of the aorta in the conscious squirrel monkey

The role of neurogenic factors in the development of atherosclerosis has not previously been studied in detail. In recent years evidence has accumulated to implicate endothelial injury as a primary stimulus for the proliferation of myointimal cells resulting in the formation of the early morphologic lesion. In the present investigation, the effect on aortic endothelial morphology of repetitive electrical stimulation of the lateral hypothalamus in the conscious, unrestrained squirrel monkey, maintained on a cholesterol-free low-fat diet, has been studied. Stimulation was performed with a self-powered, miniaturized electronic stimulator connected to indwelling electrodes. Implanted nonstimulated animals served as controls. Endothelial injury in the form of cell degeneration, denudation, with plasma insudation and partial junctional separation were observed electron-microscopically in stimulated animals compared with controls. These alterations were found to be independent of hypercholesterolemia and/or hypertension. Possible pathways for the induction of injury in this neurogenic model are: (1) direct, through neural circuits from the brain to the vessel wall, and (2) indirect, by elaboration of angiopathic substances inside or outside of the CNS, released into the circulation and transported to the vessel wall where they exert their effects. Reversibility of the endothelial injury or progression to established lesions and mechanisms involved remain to be determined in further investigations.