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This study used acetylcholinesterase (AChE) histochemistry to reveal the organization of the dorsomedial hypothalamic nucleus (DM) in the human. Topographically, the human DM is similar to DM in the monkey and rat. It is wedged between the paraventricular nucleus, dorsally, and the ventromedial nucleus, ventrally. Laterally, DM borders the lateral hypothalamic area while medially it approaches the 3rd ventricle. The AChE staining distinguished two subcompartments of the human DM: the larger diffuse and the smaller compact DM. The subcompartmental organization of the human DM appears homologous to that found in the monkey and less complex than that reported in rats. Understanding of the organization of DM creates meaningful anatomical reference for physiological and pharmacological studies in the human hypothalamus.

Activation of the neuropeptide Y (NPY) neuronal system in the dorsomedial nucleus of the hypothalamus (DMH) during lactation in the rat is in part due to neural impulses arising from the suckling stimulus. However, the afferent neuronal input to the DMH that is activated during lactation and is responsible for activation of NPY neurons is currently unknown. Previously, using cFos as a marker for neuronal activation, we identified several brain areas in the lactating animals that were activated by the suckling stimulus. Thus, the objective of the present study was to determine if any of these suckling activated areas project directly to the DMH. The retrograde tracer, fluorogold (FG), was injected into the DMH on day 4 postpartum. FG-injected lactating rats were then deprived of their eight-pup litters on day 9 postpartum, and 48 h later, the pups were returned to the females to reinitiate the suckling stimulus for 90 min and induce cFos expression. The animals were then perfused and the brains were subjected to double-label immunohistochemistry to visualize both FG- and cFos-positive cells. Substantial numbers of FG/cFos double-labeled cells were found in forebrain regions, including the preoptic area, lateral septal nucleus, ventral subiculum, and supramammillary nucleus, and in brainstem regions, including the lateral parabrachial nucleus, periaqeductal gray, and ventrolateral medulla. In conclusion, these areas are potentially important candidates for mediating the activation of the NPY neuronal system in the DMH during lactation.

Unilateral microinjection of calcitonin gene-related peptide (CGRP, 1.6 pmol; 0.2 microl) into the ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH) immediately increased oxygen consumption (VO2), heart rate (HR), colonic temperature (Tco), and temperature of interscapular brown adipose tissue (TIBAT) in urethane-anesthetized rats, whereas vehicle saline injection into the VMH and CGRP injection into other hypothalamic regions such as the preoptic area, lateral hypothalamic area, paraventricular nucleus, and bed nucleus of the stria terminalis had no effect. The effects of CGRP injection into the VMH were dose-dependent over the range of 0.016-1.6 pmol. CGRP administration to the lateral ventricle (LV) required 16-320 pmol to elicit similar degrees of responses that were observed after the injection into the VMH. The increase in TIBAT was always higher than that in Tco after CGRP injection. Injection of [Cys(ACM)2,7]hCGRPalpha, a selective CGRP2 receptor agonist, did not induce any thermogenic effects. Human CGRP8-37, a proposed CGRP1 receptor antagonist, by itself induced heat production responses with no signs of inhibition of CGRP-induced responses. Thus, the receptor subtype of the thermogenic effect of CGRP could not be determined by the available pharmacological tools. The present results show that centrally administrated CGRP induces heat production in the BAT specifically through the VMH or DMH., (Copyright 1999 Elsevier Science B.V.)

Alterations of hypothalamic neuropeptide Y(NPY) and melanocortinergic functions in diet-induced obese (DIO) C57BL/6J mice were investigated by in situ hybridization. Compared with controls, the DIO mice displayed a profound induction (approximately 40-fold) of NPY expression in the dorsomedial (DMH) and ventromedial (VMH) hypothalamic nuclei, whereas the level of NPY mRNA in the arcuate nucleus (ARC) was reduced by 44%. The expression of pro-opiomelanocortin (POMC) and agouti-related protein was not significantly altered in the ARC of obese mice. Both excess body weight gain and altered hypothalamic NPY expression were reversible. We propose that the highly induced NPY expression in DMH and/or VMH may be a contributing etiological factor for the development of obesity and leptin resistance in the DIO mice.

The human suprachiasmatic nucleus (SCN) is located in the basal part of the anterior hypothalamus and is considered as the biological clock that generates circadian rhythms and synchronizes the daily activity pattern with the environmental light-dark cycle. However, the mechanisms and pathways by which the SCN transmits its information to the other brain areas are unknown. Therefore, in the present study, we investigated the efferent projections of the SCN by the immunocytochemical staining of two major peptidergic SCN neurotransmitters: vasopressin (VP) and vasoactive intestinal polypeptide (VIP). It confirmed that these peptides are present in different subdivisions of the SCN. The results of this investigation show that VP and VIP fibers arising from the SCN were detected to branch extensively and hence seem to innervate the SCN itself and the central and medial part of the anteroventral hypothalamic area (AVH), the area below the paraventricular nucleus (sub-PVN), the ventral part of the paraventricular nucleus (PVN), and the dorsomedial nucleus of the hypothalamus (DMH). There appeared to be substantial congruity between the presumptive human SCN projections and those as observed by tracing in rat or hamster. Regarding the anatomical organization of the human SCN projections, the main projection areas appeared to be the AVH, the sub-PVN, the ventral part of the PVN, and the DMH. The observation that VIP and in particular VP fibers pass between the SCN and the PVN suggests that the human SCN and the PVN may have a direct anatomical connection. In addition, VP and VIP fibers were detected in several other hypothalamic areas that are not known to have clear direct connections to the SCN. The possible origin of these VP and VIP fibers is discussed.

The distribution of the neuronal nitric oxide synthase (nNOS), androgen receptor (AR), estrogen receptor (ER) and aromatase (ARO) was studied in the dorsal and ventral premammillary nuclei (PMd and PMv) of the newborn rat by immunohistochemistry. In the intact male pups, nNOS immunoreactivity (-IR) was present both in the PMd and the PMv, while AR-IR was detected only in the PMv. On the other hand, ER-IR and ARO-IR were scarcely encountered in the both PMd and PMv. By double immunostaining of nNOS and AR, all the nNOS-IR cells in the PMv were revealed to contain AR-IR. In the intact female pups, nNOS-IR was present in the both PMd and PMv, but neither ER-, nor ARO-IR were detected in the PM region. In the PMv of the intact female rat, no AR-IR was detected at 6 days of age, while it was detected as only a faint staining within 12 h after birth. When the male pups were castrated neonatally, no AR-IR was detected in the PMv. Subcutaneous injections of 5alpha-dihydrotestosterone (DHT) induced strong AR-IR in the castrated male and the intact female pups. On the contrary, the intensity of nNOS-IR stayed unchanged among these animals. Neonatal androgen and nitric oxide has been considered important to brain development. Moreover, involvement of the PMv in aggressive and mating behavior of male animals has been reported. Together with the fact that the AR-IR and nNOS-IR were found in the same neurons in the PMv, involvement of this nucleus in masculinization of the brain by non-aromatizable androgen is postulated.

1. Disinhibition of the dorsomedial hypothalamus (DMH) in rats by local microinjection of GABAA receptor antagonists evokes behavioural and physiological changes resembling those seen in acute experimental stress. 2. Conversely, similar microinjection of muscimol, a potent agonist at inhibitory GABAA receptors, virtually abolishes stress-induced increases in heart rate and arterial pressure. 3. Blockade of excitatory amino acid (EAA) receptors in the DMH also attenuates [correction of attentuates] stress-induced cardiovascular changes and microinjection of kainate, AMPA or NMDA at low doses elicits cardiovascular effects resembling those seen in stress. Paradoxically, injection of higher doses of NMDA or of glutamate into this region has no consistent effect. 4. The cardiovascular effects of bicuculline methiodide, a GABAA receptor antagonist, as well as those of NMDA and/or kainate were assessed after identical injection into either the DMH, the paraventricular nucleus (PVN) or the area between the two nuclei in both anaesthetized and conscious rats. For each agent, a similar pattern was seen, with the largest increases in heart rate and arterial pressure occurring after injection into the DMH and the smallest changes resulting from injection into the PVN. 5. In a parallel study, bilateral microinjection of muscimol into the DMH dramatically reduced air stress-induced cardiovascular changes; similar injection into the area of the PVN had no effect, while injection into the area between the nuclei produced an intermediate effect. 6. Our findings suggest that activation of neurons in the region of the DMH mediates stress-induced cardiovascular changes and that the activity of these neurons may be determined by the balance of tone at inhibitory GABAA receptors and EAA receptors.