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Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra compacta (SNpc) and the only risk factor is aging. We showed that in 6-hydroxydopamine (6-OHDA)-model of PD there is a reduction in the neuronal profile within the brainstem ventral respiratory column with a decrease in the hypercapnic ventilatory response. Here we tested the involvement of orexin cells from the lateral hypothalamus/perifornical area (LH/PeF) on breathing in a 6-OHDA PD model. In this model of PD, there is a reduction in the total number of orexinergic neurons and in the number of orexinergic neurons that project to the RTN, without changing the number of CO2-activated orexinergic neurons during the dark phase. The ventilation at rest and in response to hypercapnia (7% CO2) was assessed in animals that received 6-OHDA or vehicle injections into the striatum and saporin anti-Orexin-B or IgG saporin into the LH/PeF during the sleep and awake states. The experiments showed a reduction of respiratory frequency (fR) at rest during the light phase in PD animals only during sleep. During the dark phase, there was an impaired fR response to hypercapnia in PD animals with depletion of orexinergic neurons in awake and sleeping rats. In conclusion, the degeneration of orexinergic neurons in this model of PD can be related to impaired chemoreceptor function in the dark phase.

Our group has reported on the cloning of a novel rat neuropeptide Y (NPY) receptor involved in NPY-induced food intake, the Y5 receptor. The distribution in rat brain of the mRNA encoding this receptor has been determined by in situ hybridization histochemistry, using radiolabeled oligonucleotide probes. Control experiments were carried out in cell lines transfected with either rat Y1 or rat Y5 cDNAs. With the exception of the cerebellum, only the antisense probes yielded hybridization signal in rat brain tissue sections. A number of brain regions contained hybridization signals indicative of Y5 mRNA localization. Chief among these were various hypothalamic nuclei, including the medial preoptic nucleus, the supraoptic nucleus, the paraventricular nucleus, and the lateral hypothalamus. Other regions with substantial hybridization signals included the midline thalamus, parts of the amygdala and hippocampus, and some midbrain and brain-stem nuclei. In general a low density of Y5 mRNA was observed in most cortical structures, with the exception of the cingulate and retrosplenial cortices, each of which contained a moderate abundance of Y5 hybridization signal. The distribution of this receptor mRNA is consistent with a role for the Y5 receptor in food intake and also suggests involvement in other processes mediated by NPY.

We are using wheat germ agglutinin-conjugated horseradish peroxidase (WIiRP) to study reconnectivity in the transplanted (TX) olfactory bulb (OB) in Sprague-Dawley rats. Tritium-labeled OBs from fetal rat donors of Embryonic Days 14–15 were immediately grafted into neonatal rats in the site from which the host OB had been removed. Following survival times of 7 weeks and longer, WHRP solution was injected into the TX OB, and subjects were perfused after 24 h. The WHRP transport is seen in fibers from the TX OB into layer I of the host olfactory peduncle (OP) and olfactory cortex (OC) and in cell bodies in layers II and III of the OP and OC, the lateral hypothalamus, and the contralateral anterior olfactory nucleus (AON). These findings reaffirm that the axons from a TX OB make connections with some appropriate areas of the host brain and also indicate that axons from cells in the target areas of the host brain, including contralateral AON, reinnervate the TX OB.

Neurons in the lateral hypothalamus (LH) that synthesize hypocretins (Hcrt-1 and Hcrt-2) are active during wakefulness and excite lumbar motoneurons. Because hypocretinergic cells also discharge during phasic periods of rapid eye movement (REM) sleep, we sought to examine their action on the activity of motoneurons during this state. Accordingly, cat lumbar motoneurons were intracellularly recorded, under alpha-chloralose anesthesia, prior to (control) and during the carbachol-induced REM sleep-like atonia (REMc). During control conditions, LH stimulation induced excitatory postsynaptic potentials (composite EPSP) in motoneurons. In contrast, during REMc, identical LH stimulation induced inhibitory PSPs in motoneurons. We then tested the effects of LH stimulation on motoneuron responses following the stimulation of the nucleus reticularis gigantocellularis (NRGc) which is part of a brainstem-spinal cord system that controls motoneuron excitability in a state-dependent manner. LH stimulation facilitated NRGc stimulation-induced composite EPSP during control conditions whereas it enhanced NRGc stimulation-induced IPSPs during REMc. These intriguing data indicate that the LH exerts a state-dependent control of motor activity. As a first step to understand these results, we examined whether hypocretinergic synaptic mechanisms in the spinal cord were state dependent. We found that the juxtacellular application of Hcrt-1 induced motoneuron excitation during control conditions whereas motoneuron inhibition was enhanced during REMc. These data indicate that the hypocretinergic system acts on motoneurons in a state-dependent manner via spinal synaptic mechanisms. Thus, deficits in Hcrt-1 may cause the coexistence of incongruous motor signs in cataplectic patients, such as motor suppression during wakefulness and movement disorders during REM sleep.

In the embryonic brain, the transcription factor Nkx2.1 is localized in the medial ganglionic eminence and the ventromedial part of the hypothalamus. In the present study, we examined the development of mesencephalic dopamine (DA) neuron system in mice lacking Nkx2.1. In normal mice, tyrosine hydroxylase-immunoreactive axons from mesencephalic DA cells extended bilaterally in the lateral hypothalamus at embryonic day 12.5 (E12.5) and project to the ipsilateral striatum by E14.5. In the mutant brain, mesencephalic DA cell groups appeared to develop normally, but the majority of their ascending axons were observed to cross the ventral midline of the caudal hypothalamus and project to the contralateral striatum. DiI, a fluorescent dye, placed in the ventrolateral mesencephalon of E14.5 mutant mice, further revealed that majority of DiI-labeled axons projected to the contralateral striatum, while a minor ipsilateral projection was also observed. In the ventromedial hypothalamus of mutants, the neuroepithelium of third ventricle was missing, and immunoreactivity of semaphorin 3A, a soluble type of axon repellent, which was normally localized in the neuroepithelium, was remarkably reduced. Together with the recent evidence that the expression of slit2, another axon-repellent diffusible factor, is also eliminated in the hypothalamic neuroepithelium of Nkx2.1-deficient mice, the abnormal crossing of ascending DA axons observed may be attributed to the elimination of these chemorepulsive signals in the medial part of the mutant hypothalamus.

The sleep disorder narcolepsy may now be considered a neurodegenerative disease, as there is a massive reduction in the number of neurons containing the neuropeptide, hypocretin (HCRT). Most narcoleptic patients have low to negligible levels of HCRT in the cerebrospinal fluid (CSF), and such measurements serve as an important diagnostic tool. However, the relationship between HCRT neurons and HCRT levels in CSF in human narcoleptics is not known and cannot be directly assessed. To identify this relationship in the present study, the neurotoxin, hypocretin-2-saporin (HCRT2-SAP), was administered to the lateral hypothalamus (LH) to lesion HCRT neurons. CSF was extracted at circadian times (ZT) 0 (time of lights-on) or ZT8 at various intervals (2, 4, 6, 12, 21, 36, 60 days) after neurotoxin administration. Compared to animals given saline in the LH, rats with an average loss of 73% of HCRT neurons had a 50% decline in CSF HCRT levels on day 60. The decline in HCRT levels was evident by day 6 and there was no recovery or further decrease. The decline in HCRT was correlated with increased REM sleep. Lesioned rats that were kept awake for 6 h were not able to release HCRT to match the output of saline rats. As most human narcoleptics have more than 80% reduction of CSF HCRT, the results from this study lead us to conclude that in these patients, virtually all of the HCRT neurons might be lost. In those narcoleptics where CSF levels are within the normal range, it is possible that not all of the HCRT neurons are lost and that the surviving HCRT neurons might be increasing output of CSF HCRT.

Earlier studies have demonstrated that electrical stimulation of the lateral hypothalamus (LH) produces analgesia in tests of brief, phasic pain and more prolonged tonic pain. The present experiment examined the effect of morphine microinjection into the LH on formalin-induced pain. The results show that a 10-micrograms morphine microinjection significantly decreases pain responses. Moreover, the decrease persists for the duration of the 25-min test period, which began 25 min after the formalin injection. These findings suggest that electrical stimulation of the LH engages an endogenous opiate system which is capable of producing prolonged analgesia.

Immunohistochemical localization of the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) was employed to reveal the anatomical organization of the A1 noradrenergic cell group in the caudal ventrolateral medulla oblongata of the rat. Subsequently, the supraspinal efferent axonal projections of A1 were investigated with a view to elucidating the anatomical substrates underlying its postulated function in central fluid and cardiovascular homeostasis. Within the caudal medulla, DBH-positive/PNMT-negative (noradrenergic) neurons were observed extending bilaterally through the ventrolateral medullary reticular formation from upper cervical spinal cord levels to the level of the area postrema. At the rostral pole of A1, its neurons intermingled with PNMT-immunoreactive perikarya of the more rostrally situated C1 adrenergic cell group. Discrete injections of the anterogradely transported plant lectin Phaseolus vulgaris leucoagglutinin (PHA-L) into A1 resulted in terminal labeling in a number of presumptive efferent target sites including the nucleus of the solitary tract, rostral ventrolateral medulla, dorsal parabrachial nucleus, Kolliker-Fuse nucleus, central grey, dorsomedial nucleus of the hypothalamus, perifornical region, zona incerta, lateral hypothalamus, paraventricular nucleus of the hypothalamus, supraoptic nucleus, bed nucleus of the stria terminalis, and organum vasculosum of the lamina terminalis. Tissue sections adjacent to those reacted for PHA-L were processed immunohistochemically for DBH to determine if anterogradely labeled terminals were localized in regions that demonstrated appropriate immunoreactivity. The majority of regions in which PHA-L terminal labeling was present also exhibited moderate to intense DBH activity. These experiments provide neuroanatomical evidence for direct efferent pathways from the A1 noradrenergic cell group to a number of supraspinal sites that have been reliably implicated in the neural circuitry underlying the central regulation of fluid and cardiovascular homeostasis. Furthermore, the results suggest a selective anatomical interrelation between A1 and sites in the basal forebrain and hypothalamus in which vasopressinergic neurons have been previously demonstrated. It is postulated that the noradrenergic A1 projections observed in this investigation represent the morphological substrate through which A1 exerts a significant influence on cardiovascular regulatory mechanisms.

The purpose of this study was to gather anatomical data concerning sites for selfstimulation in the lateral hypothalamus in the cat. The study was conducted on 25 adult cats. In each cat, one to three monopolar stimulating electrodes were implanted bilaterally in the lateral hypothalamus in a region between sections Fr 10.0 and Fr 13.0, L 2.0 and L 5.0, and H −2.0 and H −6.0. A reference electrode was placed in the calvaria over the frontal sinus. Twenty-two of these cats learned to press a lever when each press was rewarded by a brief (0.3 s) electrical stimulus (2.0 to 7.0 V, 100/s, 1 ms duration per pulse) delivered to the hypothalamus. Postmortem anatomical analysis of the brains revealed that most of the positive rewarding sites were located in a midlateral hypothalamic zone, which included the medial forebrain bundle, and were localized to section Fr 11.5, between L 2.0 and L. 5.0, and H −3.0 and H −5.5.

Nest-coo (courtship) vocalization is an estrogen-dependent component of a sequence of behaviors leading to egg-laying in the ring dove (Streptopelia risoria). Implantation of estrogen in the nucleus intercollicularis of ovariectomized females restores the ability to produce nest-coos. Lesion of n. intercollicularis specifically disrupts nest-cooing and inhibits follicular development. We used anterograde transport of tritiated leucine to identify regions that receive input from n. intercollicularis. As a control, isotope was injected in an auditory nucleus (nucleus mesencephalicus lateralis, pars dorsalis) neighboring the n. intercollicularis. A strong projection to the nucleus was observed, demonstrating a potential interaction between auditory and vocalization systems at the level of the midbrain. Local projections of n. intercollicularis were observed in midbrain and hind brain nuclei including the nucleus tegmenti pedunculo-pontinus, pars compacta and nucleus papillioformis. A conspicuous projection ascended centrally via the mesencephalic central gray. Proceeding rostrally, this pathway was traced to the nucleus periventricularis magnocellularis and tissue surrounding it. At its rostral extent, the pathway was found to project to the nucleus preopticus medialis, the anterior medial hypothalamus, and the lateral hypothalamus. These results are consistent with the possibility of a nucleus intercollicularis projection to regions that regulate reproductive function.

This study demonstrated, in seven guinea pigs, intact self-stimulation in the lateral hypothalamus after (a) ipsilateral removal of the telencephalon plus (b) transection of the diencephalic and mesencephalic interhemispheric connections down to the brachium conjunctivum. We conclude that ipsilaterally descending fibers suffice to mediate or convey the reinforcing effects of lateral hypothalamic stimulation. The normal extinction that followed withholding of reinforcement indicated a functional interaction between the two hemispheres via surviving brain-stem connections.

Previous studies showed that projections from the cells in the substantia innominata to the sensorimotor cortex exist in the monkey and rat and that this group of cortical afferent fibers utilizes acetylcholine as a neurotransmitter. Because similar studies have not been made in the cat, the following study was undertaken to analyze the extent and distribution of this projection from the basal forebrain. Horseradish peroxidase (HRP) injections were made into the anterior and posterior sigmoid gyri 24 h before, and diisopropyl fluorophosphate was injected intramuscularly 3 h before the anesthetized cats were perfused. Brain sections from these cats were incubated in solutions to simultaneously detect retrogradely transported HRP and acetylcholinesterase (AChE) reaction product within the somata. The cell bodies that contained reaction product for both HRP and AChE were mostly large (25 to 30 μm) and multipolar. These double-labeled cells were located in (i) the nucleus of the diagonal band in rostral sections, (ii) the globus pallidus, entopeduncular nucleus, and substantia innominata at the level of the anterior commissure, and (iii) the lateral hypothalamus in the most caudal sections. Many of these sites corresponded to that for the basal nucleus of Meynert, an aggregation of large multipolar neurons scattered throughout the basal forebrain. Although the presence of AChE within a cell does not define a cholinergic neuron, recent studies indicated that its presence is a requirement for this neurotransmitter. These data together with biochemical and immunocytochemical data indicate that a cholinergic projection to the sensorimotor cortex of cats arises from the basal forebrain. This pathway may play a vital role in memory and cognition.

Contraversive rotation evoked by electrical stimulation of the rat substantia nigra (nigral-evoked rotation, NER) was not reduced by 6-hydroxydopamine (6-OHDA, 4 μg in 2 μl or 1 μg in 0.5 μl) at the ipsilateral lateral hypothalamus. These lesions produced striatal dopamine depletions equivalent to those produced by electrolytic lesions at that site which reduced NER. Electrolytic lesions at the lateral hypothalamus produced equivalent reduction in NER in rats with prior microinjection of either 6-OHDA (8 μg in 4 μl) or vehicle at that site. Thus, the decrease in NER after electrolytic lesions at the lateral hypothalamus appears to be entirely due to destruction of nondopaminergic fibers. Small electrolytic lesions at the ipsilateral caudate-putamen did not significantly change NER. Large electrolytic lesions at the caudate-putamen did not alter NER at 2 h after lesion but did reduce it at 3, 7, and 14 days postlesion. Electrolytic lesions at the ipsilateral globus pallidus significantly reduced contraversive NER at all times tested (2, 3, 7, and 14 days after lesion). Some rats with pallidal lesions responded to nigral stimulation with ipsiversive rotation. The difference in time course of the reduction in contraversive NER after caudate-putamen and pallidal lesions suggests that NER might be mediated by antidromic activitation of striatonigral neurons that send axonal collaterals to the pallidum.

A long-standing problem in understanding the neural substrates subserving behavior is to determine the extent that function can be precisely localized in the brain. The commonly asserted one-to-one relation between function and structure is directly challenged here and a more relativistic model is proposed. In brief, rats were rendered adipsic by a lesion in the lateral hypothalamus and, on careful measure, were found post-operatively to have a very low probability of drinking. At the same time, they showed a much higher probability of running. When the two behaviors were made contingent, such that in order to run the animal had to first drink, drinking immediately commenced. Yet, when the contingency was removed, no spontaneous drinking occurred. The results are consistent with the view that specific psychological processes, such as the motivation to drink, cannot be easily localized to specific brain structures. Rather, it would appear the entire cerebrum is involved in the process of determining motivational states.

Recordings were made from single neurons in the lateral hypothalamus and substantia innominata of the rhesus and squirrel monkey during feeding. A population of these neurons which altered their firing rates while the monkeys looked at food but not at nonfood objects was investigated. Because the responses of these neurons must have been affected by the previous experience of the animals, the activity of the neurons was measured during tasks in which the monkeys learned whether or not objects which they saw were associated with food. During visual discrimination tests these neurons came to respond when the monkey saw one stimulus associated with food (e.g., a black syringe from which the animal was fed glucose), but not when the monkey saw a different stimulus which was not associated with food (e.g., a white syringe from which the animal was offered saline). During extinction tests these units ceased to respond when the monkey saw a visual stimulus such as a peanut if the peanut was repeatedly not given to the monkey to eat. The learning or extinction behavior approximately paralleled the response of the neurons. The findings that the neurons in the lateral hypothalamus and substantia innominata respond when a monkey is shown food only if he is hungry, and as shown here, if as a result of learning the visual stimulus signifies food, provide information on a part of the brain which may be involved in feeding. The findings are consistent with other data which suggest that the responses of these neurons are involved in the autonomic and/or behavioral reactions of the animal to the sight of food.

Split-brain monkeys were delivered noncontingent unilateral stimulation at sites in the vicinity of the lateral hypothalamus and the internal capsule. At self-stimulation sites, this produced suppression of alpha rhythm in both hemispheres of animals with either telencephalic or diencephalic commissurotomies. The time course of the alpha suppression in each hemisphere was identical and no habituation was seen with prolonged repetition of stimulation. Bilateral nonhabituating arousal was still obtained after lesion of the hypothalamus, including the medial forebrain bundle, contralateral to the self-stimulation site. Non-self-stimulation sites showed habituation. Bilateral nonhabituating cortical arousal may be involved in the bilateral reinforcement of learning produced by unilateral intracranial self-stimulation in split-brain animals.

Traditional views that thirst is no longer experienced by rats which have recovered spontaneous ingestion after lateral hypothalamic lesions have been questioned by a number of recent observations which emphasize the non-specific stressful aspects of dipsogenic challenges. These issues have now been examined in some detail using novel and nonstressful drinking tests. During long-term intravenous and intragastric NaCl infusions, five out of eight rats with lesions in the lateral hypothalamus increased oral drinking. These five rats, and two of the nondrinkers, decreased oral drinking during complementary experiments in which water was infused. All animals with lesions selected for study showed complete failure to drink within 6 hr of intraperitoneal NaCl injection. It is therefore suggested that previous studies have failed to characterize completely the nature of the drinking impairments in these animals. The implications and difficulties of interpretation of these findings in terms of regulatory deficits are discussed, as well as more general issues relating to recovery of function after central nervous system damage. There may be qualitative differences between animals with larger and smaller lesions, and it appears unwise to posit global explanations for the lateral hypothalamic syndrome.

The purpose of this study was to determine the effect of electrical stimulation of the lateral hypothalamus and preoptic area on second- and higher-order neurons in the ventral tegmental area of the mesencephalon. Single-unit responses were recorded by tungsten microelectrodes in anesthetized cats. Lateral hypothalamic stimulation caused short- and long-latency excitation as well as antidromic activation of ventral tegmental area neurons. However, half of the responsive neurons exhibited a suppression of firing, or inhibition, following stimulation. The short latency of onset of the suppression obtained in some of these neurons suggests the possibility that, in addition to a descending excitatory hypothalamic outflow, descending monosynaptic inhibitory pathways to the ventral tegmental area are also present.

The relation between neocortical and hippocampal electroencephalogram (EEG) activity and behavior was studied in rats with forebrain and brain stem lesions. Atropine-sensitive neocortical low-voltage, fast activity (LVFA) recorded during immobility could be transiently abolished by lateral hypothalamic lesions. Atropine-sensitive hippocampal rhythmical slow activity (RSA) was produced by all brain stem lesions and became the dominant hippocampal EEG pattern in the alert immobile rat after medial pons lesions. Atropine-resistant LVFA and RSA normally associated with movement could be transiently abolished by lateral hypothalamic and orbital frontal lesions. In addition, lateral hypothalamic lesions produced an acute reduction in RSA frequency, during walking and swimming, of 1 to 4 Hz which lasted 1 to 15 days, and a chronic reduction of about 1 Hz. Lesions in the medial frontal neocortex, caudate putamen, medial hypothalamic nuclei, substantia nigra, raphe nuclei, lateral pons, caudal reticular formation, and locus ceruleus produced only slight transient or no change in atropine-resistant neocortical or hippocampal EEG activity. Motor and regulatory deficits could be produced by lesions which disrupted EEG as well as those which did not (i.e., lateral hypothalamus vs substantia nigra). The results support the suggestion that there are two types of LVFA and RSA, one of which is cholinergic, and further suggest that forebrain EEG activity may be related to the higher order control and activation of movement.

The projections of the stria terminalis were traced with the Fink-Heimer stain following lesions at the level of the anterior commissure. The pre-commissural stria terminalis is amygdalofugal only, and projects to the nucleus of the anterior commissure, the medial preoptic area, the ventral portion of the capsule surrounding the ventromedial nucleus, and to the area closely adjacent to the periventricular nucleus by way of the medial corticohypothalamic tract. The postcommissural stria terminalis is both amygdalofugal and amygdalopetal. Its hypothalamic projection is to the lateral preoptic area and the bed nucleus of the stria terminalis, and to the lateral hypothalamus by way of the lateral preoptic area. The amygdaloid projection is mainly to the basolateral nucleus, with fewer terminations to the basomedial nucleus and the area surrounding the central nucleus. The projections of the bed nucleus of the stria terminalis are quite similar to the postcommissural stria, except for an additional projection to the magnocellular paraventricular and dorsal periventricular nuclei by way of the lateral filiform tract. The commissural stria terminalis projects contralaterally to cells within its fiber bundle and the posterior limb of the anterior commissure.

The effect of electrode implantation and unilateral and bilateral intracerebral lesions on the gastric secretory response to insulin-induced hypoglycemia was examined in six unanesthetized, unrestrained cats. Lesions located in the supraoptic nucleus, preoptic area, mamillothalamic tract region of the dorsal hypothalamus, and the supraoptic, medial forebrain bundle and mamillothalamic tract regions of the lateral hypothalamus significantly reduced or completely abolished the increase in gastric secretory volume, titratable acidity, chloride and pepsin output evoked by insulin-induced hypoglycemia. Bilateral lesions located in the superior border of the anterior portion of the caudate nucleus and the lateral region of the corpus callosum did not alter the gastric secretory response of one animal to insulin-induced hypoglycemia. The results suggest that fibers originating in or passing through the supraoptic-preoptic region, mamillothalamic tract region of the dorsal hypothalamus, and various regions of the lateral hypothalamus project directly or indirectly to the dorsal motor nuclei of the vagi. The results also suggest the possibility that the increase in vagal activity observed during insulin-induced hypoglycemia may represent an integrated response involving a number of stimulatory, and possibly inhibitory, pathways in the hypothalamus.

The ascending and descending projections of the lateral preopticohypothalamus were studied with radioautographic methods. Injections of [−3H]leucine were placed throughout the rostral to caudal extent of the lateral preopticohypothalamic zone in adult cats. Ascending fibers of the rostral two-thirds of the lateral preopticohypothalamus terminate primarily in a nonspecific manner within the lateral and intermediolateral parts of septum and to a limited extent in the medial septum. Fibers from the rostral two-thirds of the lateral preopticohypothalamus also project to the lateral habenular nucleus via the stria medullaris. The caudal third of lateral hypothalamus appears to provide little or no contribution to the septum and habenular complex. Neurons from all parts of the lateral hypothalamus contribute to the total projection to both the ventral tegmental region and lateral preoptic region and adjacent structures. Projections from the lateral hypothalamus to midline thalamus could not be identified in the present study.

There is evidence that the inferotemporal visual cortex in the monkey projects to the amygdala, and evidence that damage to this region impairs the learning of associations between visual stimuli and reward or punishment. In recordings made in the amygdala to determine whether or not visual responses were found, and if so how they were affected by the significance of the visual stimuli, neurons were found in the dorsolateral part of the amygdala with visual responses which in most cases were sustained while the animal looked at effective visual stimuli. The latency of the responses was 100 to 140 ms or more. The majority (85%) of these neurons responded more strongly to some stimuli than to others, but physical factors which accounted for the responses of the neurons, such as shape, size, orientation, color, or texture, could not usually be identified. Although 22 (19.5%) of these neurons responded primarily to food objects, the responses were not uniquely food-related. Furthermore, although some neurons responded in a visual discrimination test to a visual stimulus which indicated reward, and not to a visual stimulus which indicated saline, only minor modifications of the magnitude of the neuronal responses to the stimuli were obtained when the reward-related significance of the stimuli was reversed. The visual responses of these amygdaloid neurons were thus intermediate in some respects between those of neurons in the inferotemporal cortex, which are not affected by the significance of visual stimuli, and those of neurons in a region to which the amygdala projects, the lateral hypothalamus and substantia innominata, where neurons respond to visual stimuli associated with food reward.

Experiments were performed in cats to determine the pathway from the thalamic mediodorsal nucleus to the hypothalamus. In the first stage, lesions were placed in the mediodorsal nucleus and degenerating fibers were traced to the posterior half of the midline thalamus but not to the hypothalamus. In the second stage, lesions were placed within the posterior half of the midline thalamus and fibers were traced to the anterior half of midline thalamus, but not to any part of the hypothalamus. In the third stage, lesions were placed in the anterior half of midline thalamus and terminal degeneration was observed in the anterior portion of the perifornical lateral hypothalamus after short survival times were employed. These findings suggest the existence of a fine-caliber fiber system from the anterior midline thalamus to the hypothalamus. The results indicate a multisynaptic circuit from the mediodorsal nucleus of the thalamus to the hypothalamus which can be summarized as follows: mediodorsal nucleus → posterior midline thalamus → anterior midline thalamus → anterior lateral hypothalamus.

Behavioral tests show that noncontingent stimulation of self-stimulation sites in the lateral hypothalamus increases escape and avoidance from central or peripheral stimuli. The present study investigated the possibility that this phenomenon was mediated by an excitatory connection from the lateral hypothalamus to neurons in aversive regions of the brainstem. Most of the 24 rats participated in two phases of the experiment: unit recording under anesthesia; and behavioral tests with intracranial stimulation in the waking state. Recordings of 120 units were obtained from the n. gigantocellularis reticularis (NGC) since stimulation of this region in the awake rat consistently elicited escape behavior. Unit responses could be divided into two catagories: 61% responded to deep pinch or foot shock (or both) but not to light brushing of the hair; and 39% responded to light brushing of the hair or were not responsive. Stimulation of behaviorally confirmed self-stimulation sites in lateral hypothalamus evoked short-latency (2 and 4 msec) excitation of 88% of the NGC units in the first category and only 15% in the second. Nearly all hypothalamic sites not eliciting self-stimulation also failed to excite NGC units. The excitatory hypothalamic-bulboreticular connection may serve to increase the excitability of a nociceptive system during self-stimulation.

Subcortical fiber degeneration in Macaca mulatta was traced by means of Nauta's technique following lesions of behaviorally-defined prefrontal sectors: dorsal, principalis, lateral orbital and medial orbital. All lesions led to degeneration in parts of the anterior basal ganglia, hippocampus, medial, ventral and intralaminar thalamic nuclei, and subthalamic region. Within most of these structures, however, at least two different patterns of degeneration could be distinguished: an “orbital” pattern which differed from a “dorsolateral” one mainly in being more ventral and caudal in the basal ganglia, and more medial and denser in the thalamus and subthalamus. In addition, only orbital lesions sent fibers to the septum, or, in any substantial number, to the lateral hypothalamus. The finest differentiation among the projections was observed in the head of the caudate nucleus where each type of prefrontal lesion distributed fibers to a different locus. An attempt was made to relate the anatomical findings to behavioral studies of prefrontal-subcortical functions.

Drinking and feeding were elicited by stimulation of topographically differentiated sites in the rat brain. When stimulated with low current via small electrodes, drinking was elicited from the zona incerta (ZI) feeding from the lateral hypothalamus (LH), and both responses from a restricted portion of the LH dorsolateral to the fornix. With stimulation of sites outside these regions consummatory responses occurred unreliably. Discrete lesions were made at sites of stimulation and resulting axonal degeneration was stained by the Fink and Heimer technique. Although similar connections existed, the main degeneration from drinking sites in the ZI differed from that arising from feeding sites in LH; degeneration from drinking sites coursed in the ZI and in other structures including the nucleus reuniens, ventromedial thalamus, the region ventral to the globus pallidus and the region near the subcommissural organ; degeneration from feeding sites in the LH coursed in the medial forebrain bundle and in the pathways that extend from it. Degeneration from sites dorsolateral to the fornix where both feeding and drinking were elicited was similar to that from feeding sites. These anatomical differences and similarities suggest the existence of two neural systems for drinking, one being closely related to the system for feeding and the other being independent.

Strength of motivation for electrical self-stimulation of the brain (ESB) and for a conventional reinforcer (water) was compared in C57BL 6 mice with electrodes in the lateral hypothalamus (LHA) and in the septum. Latency to begin lever pressing was longer and rate slower in septally implanted mice than in mice with LHA electrodes. None of the mice required priming to initiate lever pressing. Extinction tests immediately and 60 min following continuous reinforcement showed that mice with LHA electrodes made fewer responses 60 min later than immediately after continuous reinforcement, while mice with septal electrodes made more responses during extinction after a delay of 60 min than immediately following continuous reinforcement. Resistance to extinction following water reinforcement was similar to that of subjects receiving ESB to the septum. Mice with LHA electrodes worked for ESB and for water reinforcement on schedules up to FR 32. Mice with septal implants worked up to FR 32 for a water reward but would not go beyond FR 8 for ESB. With a progressive ratio reinforcement schedule, the mice with LHA electrodes would make up to 76 presses to obtain a single ESB reinforcement and their performance on this schedule was comparable to that of a food rewarded mouse. These results indicate that in mice motivational similarity of ESB and conventional rewards dependes both on site of stimulation in the brain and the behavioral indices of motivation employed.

Lesions were placed in the major known efferent fiber pathways of the lateral hypothalamic feeding area of rats in an attempt to determine the route by which signals relevant to food-motivated behavior are conveyed to extrahypothalamic structures. The rats with lesions were deprived of food for 24 hr and then placed in a Skinner box where bar presses delivered food pellets. While lesions within the lateral hypothalamic feeding area resulted in gross decrements in bar pressing, large lesions of the medial forebrain bundle rostral or caudal to the lateral hypothalamic feeding area or of the periventricular fiber system produced no decrements in comparison to control rats.

The midbrain course of descending pathways mediating sham rage behavior has been investigated in thalamic cats. Electrical stimulation of the lateral hypothalamus has been tested for rage outbursts before and following various lesions in the midbrain. The following lesions were found not to impair transmission of the descending hypothalamic influences: transection of the rostral third of the central periaqueductal gray and adjacent tegmentum, with interruption of the hypothalamic component of Schutz's dorsal longitudinal fasciculus; midline lesions, including the medial component of the medial forebrain bundle to the ventral tegmental area of Tsai and to the caudal periaqueductal gray; and lateral tegmental lesions involving the lateral component of the medial forebrain bundle to the lateral midbrain tegmentum. Large lesions involving most, though not all, of the tegmentum at the midcollicular level impaired, but did not abolish, rage responses to lateral hypothalamic stimulation. It is concluded that descending connections from the lateral hypothalamus, responsible for the peripheral manifestations of rage, are diffuse through the midbrain, including both the lateral and the medial components of the medial forebrain bundle, and possibly the dorsal longitudinal fasciculus as well.

Electrodes were positioned in the septum and lateral hypothalamus, (LH), and implanted in locations from which evoked potentials could be obtained from the hypothalamic recording site when the septum was stimulated. Animals were then tested for LH self-stimulation at two current levels, threshold and suprathreshold, and the effect of preceding each LH-pulse with a septal pulse at 5 and 15 msec intervals was investigated. At threshold current levels, when the neural activity was low, septal stimulation facilitated the self-stimulation rate whereas at suprathreshold levels, when the neural activity was high, either inhibition or no effect was produced. These data suggest that the same site of stimulation in the septum may exert a dynamic influence on the LH, the direction of which is determined by the level of activity present in the LH. Furthermore the evoked potential data suggest that these influences may be mediated by two functionally antagonistic pathways, the precommissural fornix and the stria terminalis.

Electrolytic lesions centered in the reticular formation or partial hemisections of the brain stem were induced stereotaxically at various levels from the medulla to the diencephalon. Nauta and Fink-Heimer methods were used to reveal degenerated fibers ascending through the upper brain stem. Degenerated fibers coursing rostrally through the subthalamus and ventrally to enter the lateral hypothalamus at tuberal levels were observed after lesions at all levels rostral to the medulla. The trajectory of this ascending pathway through the midbrain and diencephalon was distinct from that of the dorsal longitudinal fasciculus which is medial and that of the medial forebrain bundle which is ventral. Several lines of evidence suggest the hypothesis that this pathway is a component of the ascending reticular system which carries sensory information into the hypothalamus for correlation with hypothalamic visceral and behavioral functions.

Following damage to the lateral hypothalamic region, rats show impairments in orienting their heads toward visual, tactile, and olfactory stimuli, as well as deficits in using their limbs in climbing. When such damage is bilateral, rats also show aphagia, adipsia, akinesia, and catalepsy. Damage to the superior colliculus, in contrast, produces a selective and enduring impairment in head orientation to stimuli. Rats with bilateral collicular lesions show little difficulty in climbing, visually elicited placing, motility, feeding, or drinking. These results support the view that the lateral hypothalamic lesions produce a wide-ranging syndrome of sensorimotor dysfunction, primarily by interrupting basal ganglia fibers. The more restricted impairments in head orientation seen after superior collicular damage are consistent with the limited distribution of tectospinal projections.

The roles of the nigrostriatal dopaminergic system and of the neostriatum in recovery from ingestive behavior deficits and body weight losses after damage to the nigrostriatal bundle in the lateral hypothalamus were investigated. Sequential removals of pairs of neostriatal afferent inputs (from cortex, substantia nigra, and dorsal raphe nucleus) were effected by making an initial lesion of one input followed in 30 days by a test lesion of a second input. The recovery of rats with combination lesions (initial + test) was compared with that of controls with only test lesions. An initial unilateral rostral cortex lesion prior to ipsilateral lateral hypothalamic test damage accelerated recovery of rats with these lesions (initial + test) from the eating behavior deficits and body weight losses suffered by animals with only unilateral hypothalamic test lesions. Because cortical lesions alone had no effect upon neostriatal dopamine content, sparing from subsequent hypothalamic test damage is not dependent on a dopamine increase caused by the initial cortical lesion. Also, this acceleration of recovery from unilateral lateral hypothalamic test damage by a prior lesion is an effect that appears to be specific to the ipsilateral cortex, because initial destruction of the contralateral cortex or of the midbrain dorsal raphe nucleus did not attenuate the deficits caused by hypothalamic test lesions. Furthermore, when an initial unilateral hypothalamic lesion preceded an ipsilateral cortical test lesion, recovery of eating behavior and of body weight was not accelerated. Thus, the order in which our cortical and hypothalamic lesions were made determined whether or not accelerated recovery from eating deficits occurred. Therefore, the ability to make the neuronal alterations underlying this accelerated recovery may be the property of a subcortical system such as substantia nigra, but not of cortex itself.

Male and female albino rats sustained bilateral electrolytic destruction of the lateral hypothalamic area (LHA) at 10 days of age. After brain damage, physical growth, the ontogeny of sensorimotor behavioral capacity, and consummatory behavioral responses to specific regulatory challenges were repeatedly and systematically assessed for as long as 375 days of age. Bilateral LHA damage caused immediate cessation of suckling from the dam and necessitated maintenance by hand and tube feeding. The infant LHA rats were incapable of regulating body weight by intake of dry food and water alone when killed at 70 or 375 days of age. Although they eventually could maintain body weight by ad libitum intake of highly palatable wet diets, these rats displayed severe body weight reduction, impaired linear growth, and permanent consummatory deficits to specific regulatory challenges. Multimodal sensorimotor tests failed to reveal “sensory neglect” or “attenuated arousal” in the brain-damaged rats; however, a transient syndrome of motor deficits and hyperreactivity consistently appeared. These findings were in sharp contrast to the sensorimotor deficits seen in animals which sustain LHA damage after weaning or in adulthood. These data argue that sensory neglect or attenuated arousal is not necessary to production of consummatory deficits and, taken with other research, suggest that damage to intrinsic LHA neurons causes consummatory deficits whereas damage to fibers of passage causes sensorimotor impairment.

The telencephalon was removed unilaterally in rats. In addition, the forebrain of the other hemisphere was isolated from its brain stem by a precollicular transverse cut. This preparation was then tested for self-stimulation via electrodes implanted in the region of the lateral hypothalamus and medial forebrain bundle (LH-MFB) of either hemisphere. Self-stimulation was found to be intact in both hemispheres. Possible pathways connecting the LH-MFB region of one hemisphere to the contralateral diencephalon were also investigated in the bilaterally detelencephalized rat. The technique of retrograde transport of horseradish peroxidase was used for this purpose. Some fibers from the LH-MFB of one hemisphere were found to decussate to the other hemisphere by way of the thalamic commissure. The supraoptic decussation as well as diffusely organized interdiencephalic connections provide additional routes for interhemispheric LH-MFB projections.

The effects of morphine (15 mg/kg) on multiple-unit activity in the awake rat were investigated at brain sites previously characterized by their ability to support stimulation-produced analgesia (SPA) and intracranial self-stimulation (ICSS). Of the SPA and SPA + ICSS sites, most of which were located in the periaqueductal gray matter, 91% showed increased multiple-unit activity after morphine administration (median increase = 80%). In contrast, only 50% of the ICSS-only sites, most of which were located in the lateral hypothalamus, and only 29% of sites supporting neither behavior showed this effect. All increases in multiple-unit activity were at least partly reversed by naloxone (1 mg/kg). Latencies to their onset and to analgesia measured by the tail-flick method were significantly correlated. A significant negative correlation was found between ICSS current thresholds and increases in multiple-unit activity after morphine at ICSS-only sites. These data lend further support to the suggestion that morphine exerts its analgesic action by activating an endogenous analgesic system and that the periaqueductal gray constitutes an important part of such a system. Furthermore, it is suggested that morphine's excitatory effect at self-stimulation loci may reflect its rewarding properties.

The possibility that cellular and extracellular thirst signals are transmitted by separate neural pathways in the lateral hypothalamus was investigated by administering peripheral and central thirst challenges and placing electrolytic lesions in two stages in the farlateral and midlateral hypothalamus. Lesions of the farlateral hypothalamus disrupted water intakes elicited by peripheral and central administration of NaCl (doses of 1.0, 2.0, and 4.0 osm) and sucrose (doses of 0.5, 1.0, 2.0 and 4.0 osm) without attenuating drinking to angiotensin II microinjected into the preoptic region (doses of 25, 50, 100, and 500 ng). Although the larger farlateral hypothalamus lesions, which destroyed the ventromedial part of the internal capsule, medial edge of the globus pallidus, and farlateral aspects of the lateral hypothalamus, caused motor impairments and some loss of body weight, these changes were minor and restricted to the immediate postlesion period. Smaller farlateral hypothalamus lesions, in which tissue damage was restricted to the farlateral hypothalamus and medial internal capsule, had little or no effect on rate of body weight gain or motor functions but were as effective as the larger lesions in disrupting water intake to NaCl and sucrose. Lesions of the midlateral hypothalamus attenuated water intake to angiotensin II given centrally without affecting drinking to centrally administered NaCl or sucrose. These observations indicate that the effects of far- and midlateral hypothalamic lesions are due to interruption of neural pathways mediating cellular and extracellular thirst signals, respectively, and not to nonspecific deficits.

Fiber degeneration resulting from medial prefrontal ablations in rhesus and squirrel monkeys was followed through a previously unrecognized trajectory. Degenerating fibers were traced caudally in a path ventromedial to the caudate nucleus. The majority entered and followed the stria terminalis and at midthalamic levels, left this bundle, descended vertically through the dorsolateral internal capsule, and entered the external and internal laminae of the globus pallidus. Some of these fibers turned medially to traverse the dorsal region of both lateral and medial pallidal segments, whereas the majority coursed ventrally into the substantia innominata and amygdaloid complex. Debris suggestive of preterminal degeneration was present in the pallidum, nucleus basalic, lateral hypothalamus, and amygdaloid nuclei. The presence of prefrontal fibers in the pallidal region indicates that previous degenerative studies of pallidal efferents, following lesions in this region, may require reconsideration.

The role of the superior colliculus in multimodal sensory function is unsettled, in large part because a clear distinction between the somatosensory effects and the postural/motor effects of damage to the deep layers of the superior colliculus has not been obtained. Unilateral lesions of the entire superior colliculus impair orienting of the head and eyes to tactile, visual, and auditory stimuli presented on the side of the body contralateral to the lesion; however, even in the absence of sensory stimulation animals with such a lesion tend to circle ipsiversively and fail to make contralateral head movements. To determine whether or not unilateral damage to the superior colliculus produces a somatosensory asymmetry independently of head movement/circling biases, a neurological test was used in which lateral head or trunk movements were not required. Small pieces of adhesive-backed paper were attached to each forelimb and the latencies to contact and remove the stimuli were recorded. A battery of standard neurological tests was administered as well. The entire superior colliculus was removed unilaterally, and for comparison, the sensorimotor cortex or lateral hypothalamus were damaged in additional groups. Lesions of the superior colliculus produced the expected deficit in contralateral orienting and ipsilateral circling/postural biases, but failed to produce a somatosensory asymmetry in the head movement-independent sensorimotor test. In contrast, both sensorimotor cortex and lateral hypothalamus lesions produced a severe asymmetry in the head-movement-independent sensorimotor test. We conclude that the superior colliculus is involved in the control of lateral head movements and that its role in somatosensory function is fundamentally different from that of the sensorimotor cortex or lateral hypothalamus regions.

The effect of intracerebral stimulation on the basal gastric secretory response was examined in unanesthetized, unrestrained cats equipped with a permanent gastric fistula and indwelling electrodes. A consistent gastric acid response was obtained without concomitant behavioral or motor changes when specific regions located in the supraoptic area, the lateral amygdala and the anterior amygdala—globus pallidus area were stimulated for 15 min. The responses first appeared after a latent period of 15 to 30 min and persisted thereafter for periods ranging up to 75 min. Three of these responses were accompanied by an increase in pepsin output, while one showed a significant increase in chloride output and one displayed a significant decrease in secretory volume. All five of these sites failed to evoke a significant increase in total acidity or pepsin output when the intensity of the stimulus was raised to levels which produced gross autonomic, behavioral or motor changes. Stimulation of one of the two sites located in the caudate nucleus elicited a consistent and significant decrease in chloride output without concomitant behavioral and motor changes. The other site in the caudate nucleus and those in the lateral hypothalamus, and the pyriform cortex and putamen areas of the lateral amygdala were consistently negative at sign-free intensities. The results that were obtained with the five placements located in the supraoptic area, the lateral amygdala and the anterior amygdala—globus pallidus area support the view that the amygdala mediates its gastric secretory activity through the anteromedial hypothalamus.

Multi-unit and EEG activity was recorded from discrete hypothalamic loci in anesthetized cats during intravenous injection or infusion of glucose solutions. Glucose diminished multi-unit activity on the lateral hypothalamus and increased activity in the ventromedial hypothalamus. The temporal course of the effects differed in both structures. Similar changes in multi-unit activity were noted in other hypothalamic regions. The EEG effects were found to be generally unreliable or inconsistent. The results support the concept that blood glucose is at least one factor in food intake regulation and further indicate that several hypothalamic regions may be involved in the regulation process.

Rats with chronically implanted electrodes were induced by hypothalamic stimulation to drink water. A second electrode was then implanted in the septum of each rat under electrophysiological control. The main components of the evoked potentials (EP) recorded at the hypothalamic “drinking site” to septal stimulation had latencies of 10–14 and 18–23 msec. In behavioral tests a pulse of stimulation to the septum prior to each pulse of stimulation to the hypothalamus facilitated or suppressed water intake. When septal stimulation facilitated drinking the septal electrodes were in the region of the dorsal fornix and the 10–14-msec component of the EP was prominent, whereas with suppression of elicited drinking the electrodes were at more ventral sites in the vicinity of the bed nucleus of the stria terminalis and the 18–23-msec component was prominent in the EP. We conclude that septal stimulation both facilitates and inhibits drinking elicited by hypothalamic stimulation, and it appears that the effects are mediated by different pathways, facilitation of induced drinking by means of the fornix and suppression of drinking by the stria terminalis.

Rats received electrical stimulation through electrodes implanted chronically in the lateral hypothalamus. The stimulation, controlled either by the experimenter or by the rat pressing on a lever, elicited stimulus-bound drinking in several of the animals. In 1-hr tests the rats drank amounts which, in most cases, equalled or exceeded their normal 24-hr intakes. In longer tests, this induced drinking was quite constant; during a 24-hr period one rat drank 460 ml of water. About 20 to 30 min after stimulation was begun, diuresis was observed and during experiments extending over several hours the excess of water intake over water loss, allowing for the normal extrarenal loss of water, was 20 to 25 ml. In experiments repeated over several months in the same rats hypothalamic stimulation continued to induce water intake.

Evoked potentials recorded in the lateral hypothalamus (LH) of the rat to stimulation of the septum were observed to have response components of 3–6, 10–14, and 18–23 msec. These components were elicited from different regions of the septum; the 3–6 and 10–14 msec components from dorsal and midline regions corresponding to the projection field of the precommissural fornix from the hippocampus and the 18–23 msec component from a ventrolateral region corresponding to projections of the stria terminalis. Stimulation of the hippocampus and stria terminalis evoked responses in the LH of similar configuration but with latencies longer than the 10–14 and 18–23 msec components, respectively. Lesions in the dorsal midline and ventrolateral septum attenuated these responses suggesting that the precommissural fornix and stria terminalis are the pathways mediating the septal evoked components. These data provide a neuroanatomical framework for the dual role of the septum on response patterns elicited from the hypothalamus.

Forty-seven vagotomized monkeys anesthetized with urethane and chloralose were used to study the cardiovascular control mechanism in the brain stem. It was found that a pressor response concomitant with cardioacceleration and cardio-augmentation could be elicited in the lateral hypothalamus, the tegmentum of the mesencephalon, and the dorsal and ventrolateral portions of the pons and medulla. A depressor response, which was at times associated with a decrease in cardiac rate or contractile force, was found in the upper brain stem, but this was more readily elicited in the medulla medial and ventral to the pressor region. The sensitivity of the different structures of the brain stem to electrical stimulation varied. The order of sensitivity descended from dorsal medulla, dorsal pons, ventrolateral portions of the medulla and pons, mesencephalon, and hypothalamus. Stimulation of the medulla, especially, the caudal portion produced a much bigger response and the intensity of stimulation required was half that required for the hypothalamus. This supports the location of a basic cardiovascular control mechanism in the medulla for maintenance of vasomotor and cardiac functions.