Identification of differently timed motor components of conditioned blink responses.

Electromyographic recordings were made from the orbicularis oculi muscles of cats in order to identify differently timed motor components of conditioned eye blink responses (CRs). Conditioning was established rapidly by pairing electrical stimulation of the hypothalamus (HS) with a click conditioned stimulus (CS) and a glabella tap unconditioned stimulus (US). Analysis of the EMG responses disclosed five different motor components of the CR that could be distinguished and characterized according to their latencies of occurrence. Four were associated with an increase in EMG activity elicited by the CS (16-48 ms, alpha(1); 48-80 ms, alpha(2); 80 to 120 ms, beta; >/=120 ms, gamma), and one was associated with a decrease in activity (16 to 60 ms, alpha(i)). Analysis of the amplitudes of the different components of the CR during the course of conditioning and extinction disclosed that short latency, alpha(1) components of the CRs were acquired and extinguished in a manner equivalent to longer latency components of the CRs. The observations supported the hypothesis that short and long latency components of blink responses represented comparable rather than substantially different forms of Pavlovian conditioning. The alpha(2) response was present before conditioning began, and increased with other components after conditioning. The alpha(i) response component was also observed prior to conditioning, and represents a previously undetected, inhibitory consequence of presenting weak (70 dB) acoustic stimuli. It could play a role in conditioned inhibition, latent inhibition and blocking as well as suppression of the conditioned motor response during extinction.

IL-1beta increases norepinephrine level in rat frontal cortex: involvement of prostanoids, NO, and glutamate.

The effects of local administration of interleukin-1beta (IL-1beta) were studied by using an intracerebral microdialysis technique in rats. A local injection of IL-1beta (3 and 10 ng) induced an elevation of norepinephrine (NE) concentration in the medial prefrontal cortex (mPFC). IL-1-receptor antagonist (800 ng) completely blocked the IL-1beta-induced NE increase. Diclofenac, a cyclooxygenase inhibitor (500 microM), and Nomega-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor (100 microM), applied through the dialysis probe, did not affect the initial rise in NE levels observed 20 min after injection of IL-1beta but completely suppressed the late phase of IL-1beta-induced NE increase at 40 min and thereafter. In contrast, local perfusion of 6-cyno-7-nitroquinoxaline-2,3-dione, a non-N-methyl-D-aspartic acid (NMDA) glutamate-receptor antagonist (50 microM), but not DL-2-amino-5-phosphonovaleric acid, an NMDA-receptor antagonist (100 microM), blocked both phases of IL-1beta-induced NE increase. Furthermore, a microinjection of IL-1beta elevated the extracellular concentration of glutamate in the mPFC. These findings suggest that the IL-1beta-induced rise in NE levels in the mPFC is caused by activation of the glutamatergic system and the glutamate-induced increases in prostanoids and NO.

Fibroblast growth factor receptor-1 in the lateral hypothalamic area regulates food intake.

Previous studies have shown that acidic and basic fibroblast growth fa ctor (aFGF and bFGF) and certain fragments of the aFGF N-terminal suppress food intake in rats due to their inhibitory actions on the glucose-sensitive neurons in the lateral hypothalamic area (LHA). The present study was planned to determine the role of FGF receptor-1 (FGFR-1), which was found in the LHA neurons of rats, on feeding regulation. The structure-activity relationship of aFGF fragments in feeding suppression was also investigated. An injection of anti-FGFR-1 antibody (250 and 350 ng) into the bilateral LHA significantly increased food intake. Synthesized aFGF fragments were infused into the III ventricle to elucidate the structure-activity relationship on the inhibition of feeding. Although aFGF-(1-29) did not affect food intake, [Ser16]aFGF-(1-29) (400 ng) and [Glu16]aFGF-(1-29) (400 NG), in which the cysteine residue at position 16 of aFGF(1-29) was replaced with structurally similar serine and glutamic acid, were observed to significantly inhibit food intake. These findings suggest that endogenous FGFR-1 in the LHA plays an important role in FGF-induced feeding suppression, while, in addition, the dissolving disulfide bond formation in aFGF fragments enhances their inhibitory effects on feeding.

Hypothalamic linkage in stress-induced hypocalcemia, gastric damage, and emotional behavior in rats.

The effects of hypothalamic lesions on stress-induced hypocalcemia, gastric damage, and swim test-evoked behavior were examined in rats. Bilateral lesions of the ventromedial nucleus in the hypothalamus (VMH) eliminated water-restraint stress-induced hypocalcemia and attenuated any gastric damage compared with those in the sham-operated rats. In contrast, lesions in the paraventricular nucleus (PVN) exacerbated both the stress-induced hypocalcemia and gastric lesions in comparison with those in the control rats. In a forced-swimming test, the VMH-lesioned rats showed a significantly shorter time of immobility as well as a longer duration of struggling than the control rats, respectively, while the PVN-lesioned animals spent a longer time in immobility and a shorter period struggling than the control rats. These results suggest that the VMH has an accelerative action in stress-induced hypocalcemia, gastric lesions, and behavioral despair, while the PVN has an opposite effect.

Ventromedial hypothalamus mediates stress-induced hypocalcemia via the gastric vagus in rats.

A hypothalamo-vagal mechanism of immobilization (IMB) stress-induced hypocalcemia was investigated in rats. Bilateral lesions in the ventromedial nucleus of the hypothalamus (VMH), but not those of the lateral hypothalamic area (LHA) or the paraventricular nucleus (PVN), eliminated the calcium-lowering effect of IMB. None of these lesions, however, affected the basal levels of the blood calcium. An electrical stimulation of the VMH induced a significant decrease in the blood calcium level (0.07 mM fall) 60 min after stimulation. The hypocalcemic response was eliminated by a vagotomy of the gastric branches but not by that of the thyroid/parathyroid branches. These results suggest that the VMH mediates IMB-induced hypocalcemia through its influence on the gastric vagus.

Hypothalamic stimulation induces vagally mediated hypocalcemia in the rat.

To elucidate hypothalamic involvement in blood calcium homeostasis, the effects of unilateral electrical stimulation (0.1 mA, 0.5 ms, 30 Hz, 60 min) of the lateral hypothalamic area (LHA), the paraventricular nucleus (PVN), and the ventromedial nucleus of the hypothalamus (VMH) on the blood concentration of ionized calcium were examined in the anesthetized rats. LHA stimulation induced a sustained decrease (0.05-0.07 mM fall) in the blood calcium level during the period of 60 to 150 min (end of the measurements) after stimulation. In contrast, PVN stimulation elicited a transient hypocalcemia (0.07 mM decrease) 60 min after stimulation. The hypocalcemic effects of LHA and PVN stimulation were eliminated by vagotomy of the gastric branches and the thyroid/parathyroid branches, respectively. VMH stimulation, using the same parameters, did not induce any significant change in blood calcium. The results suggest that the LHA and the PVN have a hypocalcemic function that is mediated, at least in part, by the vagus nerve innervating the stomach and the thyroid/parathyroid glands, respectively.

Hypothalamic involvement in stress-induced hypocalcemia in rats.

Although hormonal regulation of blood calcium homeostasis has been intensively investigated in the peripheral organs, the involvement of the central nervous system in calcium regulation is still poorly understood. In the present study, we found that (1) bilateral lesions of the ventromedial nucleus of the hypothalamus (VMH), but not those of the paraventricular hypothalamic nucleus or the lateral hypothalamic area, eliminated immobilization (IMB)-induced hypocalcemia, and (2) electrical stimulation of the VMH decreased the blood calcium level. The results suggest that the VMH has a hypocalcemic function and plays a role in IMB-induced hypocalcemia.

Feeding suppression elicited by electrical and chemical stimulations of monkey hypothalamus.

The effects of electrical (ES) and chemical stimulations of the hypothalamus were investigated in monkeys during bar-press feeding. ES elicited both prolonged and nonprolonged types of suppression of bar-press feeding in hungry animals. Prolonged type suppression persisted for greater than 1 min beyond one or more post-ES trials and was found after ES of the dorsomedial hypothalamus (DMH), the ventromedial hypothalamus (VMH), and the ventromedial part of the lateral hypothalamic area (LHA). Non-prolonged type suppression was observed only during ES at some sites of both in hypothalamic and extrahypothalamic areas. A microinjection of glutamate into the VMH and the DMH, but not into the LHA, was able to reproduce the ES-induced prolonged type suppression. In contrast, the ES of the LHA, but not the VMH and DMH, in a satiated state provoked feeding. The results, together with the previous findings, suggest that the neuronal inhibitory mechanism of feeding exists in the VMH and DMH, while both the neuronal facilitatory and axonal inhibitory mechanisms in the LHA are involved in the feeding regulation, and these mechanisms of the LHA are affected by the hunger/satiety state.

Electrical stimulation of male monkey's midbrain elicits components of sexual behavior.

We electrically stimulated the midbrain of male rhesus monkeys seated in a restraint chair facing the female partners and examined whether sexual behavior could be induced. When the midbrain was stimulated (0.2 ms, 50-500 microA and 50 Hz for 2.5 s), the male monkey touched and held the waist of his partner (latency; 0.9 +/- 0.4 s, mean +/- SD, n = 225), and then mounted her when she responded with presenting her hip toward him. However, this mounting, unlike when the hypothalamus was stimulated, did not lead to thrusting or ejaculation even if the stimulation continued. The sites in the midbrain where the stimulation elicited touching and mounting were the ventral tegmental area, the substantia nigra, the nucleus reticularis mesencephali and the nucleus reticularis pontis oralis et caudalis. Touching and mounting were not elicited when the partner was put away from the male or replaced by submissive male monkeys or humans. The findings suggest that the stimulation-evoked touching and mounting are components of copulatory behavior and that the midbrain structures may be involved in the sexual behavior of male monkeys.

Central control of sexual behavior.

Neuronal activity changes in the medial preoptic area (MPOA) of the male monkey were related to the commencement of sexual behavior, penile erection and the refractory period following ejaculation. Similarly, changes in the female MPOA were related to the commencement of sexual behavior and presentation. Increased neuronal activity in the dorsomedial hypothalamic nucleus (DMH) in the male monkey and in the ventromedial hypothalamic nucleus (VMH) in the female monkey was synchronized to each mating act. Stimulation study and neuronal activity recordings in the MPOA, DMH and VMH suggest involvement of MPOA neurons in sexual arousal, and of male DMH and female VMH neurons in the copulatory act. Stimulation experiment on the various parts in the hypothalamus of the female monkey also supports the conclusion.

Proceptive presenting elicited by electrical stimulation of the female monkey hypothalamus.

Proceptive presenting by female macaque monkeys was evoked by electrical stimulation of the ventromedial hypothalamic nucleus and the medial preoptic area, under conditions of partial restraint while sitting in a primate chair. This behavior could be elicited only when a male monkey was in close proximity and not when he was removed or was replaced with a female monkey or the human experimenter. This seems to be the first report on the effects of electrical brain stimulation on proceptivity in the female monkey.

Effects of behaviorally rewarding hypothalamic electrical stimulation on intracellularly recorded neuronal activity in the motor cortex of awake monkeys.

Effects of hypothalamic stimulation (HS) were studied in intracellular recordings obtained from 125 neurons of the motor cortex (MC). HS that was effective in reinforcing bar-press behavior, i.e. satisfactory for intracranial self-stimulation (ICSS), evoked short-latency (less than 3 ms) activation of these cortical neurons more frequently (42% of cells tested) than did HS that was ineffective in reinforcing bar-press behavior (7% of cells tested). Longer latency activation (greater than 3 ms) and inhibition (of variable onset) also occurred, but their incidence was not significantly different when HS was effective or ineffective in producing ICSS. Effects of HS that was effective in producing ICSS were also examined in 23 cells in which the spikes were followed by afterhyperpolarization (AHP) of 1.4-10 mV amplitude and 1.7-54 ms duration. The amplitudes of AHPs of greater than 8 ms duration were reduced after presentations of HSs that were effective as a reinforcer for ICSS. These results suggest that: (1) MC neurons receive reward-related hypothalamic information through pathways sufficiently direct to produce short-latency activation; and (2) a modulation of spike afterhyperpolarization can be observed in conjunction with reception of this information.

Pavlovian conditioning of discriminatively elicited eyeblink responses with short onset latency attributable to lengthened interstimulus intervals.

Conditioned eyeblink responses were obtained in cats by pairing click (CS) with glabella tap (US) and electrical stimulation of the hypothalamus (HS). Hiss was used as a discriminative stimulus (DS). Onset latencies of conditioned responses (CRs) of 20-56 ms were obtained by using an interstimulus interval (ISI) of 570-10 ms between CS and US-HS. Longer latency (90-320 ms) blink CRs were obtained with ISIs of 340-240 and 340-10 ms. The timing of associatively learned movements has been thought to increase with lengthening of the intervals between CS and US presentation. The production of shorter latency CRs of this type by lengthening the ISI is a novel result and one unexpected from widely held beliefs.

Responsiveness of monkey preoptic thermosensitive neurons to non-thermal emotional stimuli.

Responsiveness of 143 preoptic neurons to changes in hypothalamic temperature and to non-thermal emotional stimuli were investigated while rewarding (foods) and aversive objects (hypertonic saline, a toy snake, an air puffer) were given. About 71% of thermosensitive neurons and 32% of thermally insensitive neurons changed the activity when emotional stimuli were shown to and/or tasted by the monkey. Such responses were modulated by satiety/hunger state and were dependent on the degree of perturbation of emotional state. About half of the neurons tested responded when the monkey opened the mouth and protruded the tongue or moved fingers in trying to obtain foods with strong motivation, but did not when the animal made such movements less readily or reluctantly with the progress of satiation. This response was most frequently found among warm-units. The results raise a possibility that preoptic thermosensitive neurons, besides their postulated thermoregulatory functions, might be involved in the response of coordination with thermal and non-thermal emotional behaviors controlled in the hypothalamus.

Medial preoptic and hypothalamic neuronal activity during sexual behavior of the male monkey.

Neuronal activity changes in the medial preoptic area of the male monkey were related to the commencement of sexual behavior, penile erection and the refractory period following ejaculation. Increased neuronal activity in the dorsomedial hypothalamic nucleus was found to be synchronized to each mating act. The involvement of medial preoptic neurons in sexual arousal, initial penile erection and that of dorsomedial hypothalamic neurons in the copulatory act are suggested by the present findings.