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The hypothalamus plays especially important roles in various endocrine, autonomic, and behavioral responses that guarantee the survival of both the individual and the species. In the rat, a distinct hypothalamic defensive circuit has been defined as critical for integrating predatory threats, raising an important question as to whether this concept could be applied to other prey species. To start addressing this matter, in the present study, we investigated, in another prey species (the mouse), the pattern of hypothalamic Fos immunoreactivity in response to exposure to a predator (a rat, using the Rat Exposure Test). During rat exposure, mice remained concealed in the home chamber for a longer period of time and increased freezing and risk assessment activity. We were able to show that the mouse and the rat present a similar pattern of hypothalamic activation in response to a predator. Of particular note, similar to what has been described for the rat, we observed in the mouse that predator exposure induces a striking activation in the elements of the medial hypothalamic defensive system, namely, the anterior hypothalamic nucleus, the dorsomedial part of the ventromedial hypothalamic nucleus and the dorsal premammillary nucleus. Moreover, as described for the rat, predator-exposed mice also presented increased Fos levels in the autonomic and parvicellular parts of the paraventricular hypothalamic nucleus, lateral preoptic area and subfornical region of the lateral hypothalamic area. In conclusion, the present data give further support to the concept that a specific hypothalamic defensive circuit should be preserved across different prey species.

The present study investigated the hypothesis that social isolation increases aggression by increasing the number of V1a vasopressin receptors in the anterior hypothalamus (AH). Male hamsters were randomly assigned to a group that was allowed to interact with a small nonaggressive hamster three times each week for 3 weeks (socially experienced) or to a group that did not interact socially with other hamsters (social isolates). On the final day of the experiment, hamsters in both groups were placed in a neutral arena with a small, nonaggressive intruder, and agonistic behavior was scored for 10 min. In social isolates, the duration of aggression and the number of attacks were significantly greater than in socially experienced hamsters. There were no significant between-group differences in the latency to the onset of aggression, the number of flank marks or in the duration of defensive/submissive, social or nonsocial behavior. The amount of V1a receptor binding was significantly greater in the AH, the paraventricular nucleus of the hypothalamus and the lateral hypothalamus in the social isolates than in the socially experienced hamsters. The amount of V1a receptor binding was significantly greater in the central amygdala of socially experienced hamsters than in socially isolated hamsters. Serum concentrations of testosterone were significantly higher in the socially experienced hamsters than in social isolates. These data support the hypothesis that social isolation increases aggression by increasing the number of V1a vasopressin receptors in the AH.

The link between the state of energy balance and reproductive function is well known. Thus, signals denoting negative energy balance and the accompanying hyperphagic drive are likely to be factors in the suppression of gonadotropin releasing hormone (GnRH) activity. We have previously found that appetite-regulating systems, such as neuropeptide Y (NPY) in the arcuate nucleus (ARH) and orexin in the lateral hypothalamic area (LHA), send fiber projections that come in close apposition with GnRH neurons. Furthermore, the appropriate receptors, NPY Y5 and OR-1, respectively, are coexpressed on GnRH neurons, providing neuroanatomical evidence for a direct link between the NPY and orexin systems and GnRH neurons. Therefore, these orexigenic neuropeptide systems are potential candidates that convey information about energy balance to GnRH neurons. The current studies focused on melanin concentrating hormone (MCH), another orexigenic neuropeptide system located in the LHA that is sensitive to energy balance. The results showed that MCH fiber projections came in close apposition with approximately 85-90% of GnRH cell bodies throughout the preoptic area and anterior hypothalamic area in the rat. In addition, the MCH receptor (MCHR1) was coexpressed on about 50-55% of GnRH neurons. These findings present evidence for a possible direct neuroanatomical pathway by which MCH may play a role in the regulation of GnRH neuronal function. Thus, MCH is another potential signal that may serve to integrate energy balance and reproductive function.

We studied the effect of gustatory stimulation on hypothalamic histamine release. Administering a four-basic taste mixture significantly increased histamine release, but not in the chorda tympani-transected rats. 0.1 M NaCl significantly increased histamine release, whereas 0.5 M sucrose, 0.02 M quinine HCl and 0.01 M HCl had no effect. However, when the concentration of HCl was increased to 0.03 M, a significant increase in histamine release was seen. These results suggest that taste information via the chorda tympani activates the histaminergic system.

Using in vitro quantitative autoradiography and [3H]flunitrazepam we examined the rostrocaudal distribution of benzodiazepine binding sites in the human neonate/infant hypothalamus. The autoradiographic analysis shows the presence of a heterogeneous distribution throughout the rostrocaudal extent of this brain structure. High [3H]flunitrazepam binding corresponds primarily to the diagonal band of Broca and the preoptic region. The labelling in the preoptic region showed a rostrocaudal increase, contrasting in that with the other hypothalamic structures. Intermediate densities were present in the septohypothalamic, suprachiasmatic, periventricular and paraventricular nuclei as well as in the mammillary complex. Low binding was observed in the other hypothalamic structures. The benzodiazepine binding sites analyzed belong mostly to type II receptors. In an attempt to unravel possible differences related to age, we compared the autoradiographic distribution in three postnatal age ranges. The topographical distribution of these binding sites was almost identical in each period analyzed. We found, however, that benzodiazepine binding is generally low in the neonatal period and a tendency in increasing densities is observed during development. Taken together, these results provide evidence for a large distribution of benzodiazepine binding sites in neonate/infant hypothalamus, suggesting their implication in the development of this brain structure and the maintenance of its various functions.

The serotonin (5-HT) syndrome is the most serious side effect of antidepressants, and it often necessitates pharmacotherapy. In the present study, the efficacy of several drugs was evaluated in an animal model of the 5-HT syndrome. When 2 mg/kg of clorgyline, a type-A monoamine oxidase inhibiting antidepressant, and 100 mg/kg of 5-hydroxy-L-tryptophan, a precursor of 5-HT, were administered intraperitoneally to rats to induce the 5-HT syndrome, the rectal temperature of the rats increased to more than 40 degrees C, and all of the animals died by 90 min after the drug administration. The noradrenaline (NA) levels in the anterior hypothalamus, measured by microdialysis, increased to 15.9 times the preadministration level. Pretreatment with propranolol (10 mg/kg), a 5-HT(1A) receptor antagonist as well as a beta-blocker, and dantrolene (20 mg/kg), a peripheral muscle relaxant, did not prevent the death of the animals, even though these two drugs suppressed the increase in rectal temperature to some extent. Chlorpromazine and cyproheptadine prevented the lethality associated with the 5-HT syndrome only at high doses. By contrast, pretreatment with ritanserin (3 mg/kg) and pipamperone (20 mg/kg), both potent 5-HT(2A) receptor antagonists, completely prevented the increase in rectal temperature and death of the animals, and the hypothalamic NA levels in these two groups increased less than that in the other groups. These results suggest that potent 5-HT(2A) receptor antagonists are the most effective drugs for treatment of the 5-HT syndrome, and that NA hyperactivity occurs in the 5-HT syndrome.

Basal and psychological stress-induced noradrenaline (NA) release were studied by intracerebral microdialysis in the hypothalamus of rats aged 9 weeks or 12 months. Basal NA output was not significantly different between young (9-week-old; 2.11 +/- 0.22 pg/20 min) and aged (12-month-old; 2.29 +/- 0.34 pg/20 min) rats. Psychological stress for 20 min significantly increased NA release in both groups (186% and 142% of baseline at 9 weeks old and 12 months old, respectively); however, the increase in aged rats was significantly lower than that in young rats (P < 0.01). This finding suggest that the noradrenergic neuronal response to psychological stress is attenuated in aged rats.

Noradrenaline (NA), dopamine (DA); serotonin (5-HT) and their metabolites-3-methoxy, 4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA)-were determined using HPLC in medial vestibular nucleus (MVN), anteroventral cochlear nucleus (AVCN), dorsal+posteroventral cochlear nucleus (DCN+PVCN), locus coeruleus (LC) and raphe dorsalis of Dark Agouti-Hanovre (DA-HAN) rats aged 4, 21 and 24 months. In older rats, the main noradrenergic changes were a decrease of NA content with an increase of the MHPG/NA ratio in MVN and a selective NA increase in AVCN. 5-HT and 5-HIAA levels were increased in all the brainstem nuclei except raphe dorsalis. DA and DOPAC remained unchanged. These data show that noradrenergic neurons in sensory nuclei are differently affected by aging whereas serotonergic activation occurs in most of them possibly as a compensatory response to dysfunction of sensory input and processing. The increase of NA stores in the AVCN of aged rats is in line with the elevated auditory brainstem threshold reported in old rats and could improve the signal-to-noise ratio. Noradrenergic neurons in the MVN seem to be more sensitive to age effect than cochlear nuclei; however, even if neuronal loss occurs, NA synthesis and/or metabolism increase to ensure normal or increased noradrenergic activity.

Contents of adenosine triphosphate (ATP) in the suprachiasmatic nucleus (SCN), anterior hypothalamic area (AH) and caudate putamen (CPu) were determined every 4 h in rats kept under constant dark conditions. All tested regions of the brain exhibited circadian rhythms in ATP content. Among these, the amplitude of the rhythm was largest in the SCN. Peaks of the ATP content were observed at circadian time 18 in the SCN, 6 in the AH and 10 in the CPu. In view of the observation that at around these peak times electrical or glucose uptake activity of each brain region was lowest, the present result suggests that ATP content is negatively correlated with electrical or glucose uptake activity.

A large number of estradiol-concentrating cells were visualized by autoradiography in a subpopulation of large neurons located in and around the sexually dimorphic male nucleus of the preoptic/anterior hypothalamic area (MN-POA/AH) of castrated male ferrets and in a comparable dorsal portion of the POA/AH of ovariectomized females. Considerably fewer estradiol-labelled cells were seen in the non-dimorphic ventral POA/AH nucleus of both sexes. Estrogen binding in cells in or around the MN-POA/AH may contribute to the formation of this sexually dimorphic nucleus in fetal males and may mediate specific estrogen-dependent behavioral functions in adulthood.

Localized intracerebral microinjections of GABA, muscimol, picrotoxin and bicuculline were made in the anterior and basal hypothalamus to determine possible sites of action of GABA in the regulation of prolactin and growth hormone (GH) secretion. Studies were carried out in unanesthetized male rats with chronic indwelling atrial cannulae and intracerebral guide cannulae which permitted stress free blood sampling and intrahypothalamic injections, respectively. Preoptic/anterior hypothalamic area. (PO/AHA) injection of muscimol (0.16 nmol) stimulated both prolactin and GH secretion. GABA (1600 nmol) stimulated prolactin. Bicuculline (0.016 and 0.16 nmol) inhibited GH secretion. Medial basal hypothalamic (MBH) injection of muscimol (0.1 and 1.0 nmol) and GABA (1000 nmol) stimulated prolactin but had no effect on GH secretion. Picrotoxin and bicuculline did not stimulate GH. These findings indicate that activation of PO/AHA GABAergic receptors facilitates secretion of GH and prolactin and activation of MBH GABAergic receptors stimulates secretion of prolactin. It is proposed that GABA inhibits somatostatin neurons in the PO/AHA to facilitate GH and inhibits tuberoinfundibular dopamine or GABA neurons in the MBH to stimulate prolactin.

The chronology of changes in plasma luteinizing hormone (LH) and the distribution of immunoreactive neuronal processes containing LH releasing hormone (LHRH-ir) were studied in the female rat after surgical interruption of anterior neural connections of the mediobasal hypothalamus (MBH). Spontaneous LH surges on the afternoon of proestrus and LH release after estradiol benzoate (EB) followed 48 h later by progesterone (P) administration were studied in ovariectomized (OVX) rats. The maximum increase in plasma concentrations (delta maxLH) after EBP was calculated for each rat at several intervals over 140 days. Control animals given EBP at monthly intervals after OVX had comparably large delta maxLH surges during the first few months of study. However, a gradual decline in control delta maxLH followed becoming significant 3 months after the start of the experiment. In contrast, frontal cuts (FC), which interrupted anterior MBH connections, produced an abrupt decrease in delta maxLH surges after EBP to 11% of preoperative levels. However, during subsequent EBP trials, there was a gradual improvement in LH surges to about 50% of preoperative levels over 100 days. In some cases, individual improvement became equal to preoperative LH surge levels, in others there was no recovery. Examination of LHRH-ir nerve fiber growth responses after FC suggested that sprouting by these peptide-containing neuronal processes may have contributed to the functional improvements observed.