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There are sexual differences in several parameters of the nigrostriatal dopamine neurons, as well as in the progression of diseases associated with this system, e.g., Parkinson's disease and dementia. These differences, as well as direct experimental data in rodents, suggest that gonadal hormones play a role in modulating this system. To determine whether circulating estrogen might have long-term effects by altering the number of dopamine neurons, the density of dopamine neurons was calculated in the compact zone of the substantia nigra of male and intact female short- (10 d) and longer-term (30 d) ovariectomized and short- and longer-term ovariectomized but estrogen-replaced nonhuman primates (African green monkeys). Furthermore, the number of tyrosine hydroxylase-expressing neurons, the total number of all types of neurons, and the volume of the compact zone of the substantia nigra were calculated in 30 d ovariectomized and in 30 d ovariectomized and estrogen-replaced monkeys. Unbiased stereological analyses demonstrated that a 30 d estrogen deprivation results in an apparently permanent loss of >30% of the total number of substantia nigra dopamine cells. Furthermore, the density calculations showed that brief estrogen replacement restores the density of tyrosine hydroxylase-immunoreactive cells after a 10 d, but not after a 30 d, ovariectomy. Moreover, the density of dopamine cells is higher in females than in males. These observations show the essential role of estrogen in maintaining the integrity of the nigral dopamine system, suggest a new treatment strategy for patients with Parkinson's disease and with certain forms of memory-impairing disorders, and provide another rationale for estrogen replacement therapy for postmenopausal women.

Distinct brain peptidergic circuits govern peripheral energy homeostasis and related behavior. Here we report that mitochondrial uncoupling protein 2 (UCP2) is expressed discretely in neurons involved in homeostatic regulation. UCP2 protein was associated with the mitochondria of neurons, predominantly in axons and axon terminals. UCP2-producing neurons were found to be the targets of peripheral hormones, including leptin and gonadal steroids, and the presence of UCP2 protein in axonal processes predicted increased local brain mitochondrial uncoupling activity and heat production. In the hypothalamus, perikarya producing corticotropin-releasing factor, vasopressin, oxytocin, and neuropeptide Y also expressed UCP2. Furthermore, axon terminals containing UCP2 innervated diverse hypothalamic neuronal populations. These cells included those producing orexin, melanin-concentrating hormone, and luteinizing hormone-releasing hormone. When c-fos-expressing cells were analyzed in the basal brain after either fasting or cold exposure, it was found that all activated neurons received a robust UCP2 input on their perikarya and proximal dendrites. Thus, our data suggest the novel concept that heat produced by axonal UCP2 modulates neurotransmission in homeostatic centers, thereby coordinating the activity of those brain circuits that regulate daily energy balance and related autonomic and endocrine processes.

Hypocretin (orexin) has recently been shown to increase feeding when injected into the brain. Using both rat and primate brains, we tested the hypothesis that a mechanism of hypocretin action might be related to synaptic regulation of the neuropeptide Y (NPY) system. Hypocretin-immunoreactive terminals originating from the lateral hypothalamus make direct synaptic contact with neurons of the arcuate nucleus that not only express NPY but also contain leptin receptors. In addition, hypocretin-containing neurons also express leptin receptor immunoreactivity. This suggests a potential mechanism of action for hypocretin in the central regulation of metabolic and endocrine processes. The excitatory actions of hypocretin could increase NPY release, resulting in enhanced feeding behavior and altered endocrine regulation, whereas leptin, released from adipose tissue as an indicator of fat stores, would have the opposite effect on the same neurons, leading to a decrease in NPY and NPY-mediated hypothalamic functions. On the other hand, the innervation of hypocretin cells by NPY boutons raises the possibility that NPY may exert an effect on hypothalamic functions, at least in part, via mediation or feedback action on these lateral hypothalamic cells. Our data indicate that a direct interaction between leptin, hypocretin, and NPY exists in the hypothalamus that may contribute to the central regulation of metabolic and endocrine processes in both rodents and primates.

Using tract tracing and immunocytochemistry, this study explored the connectivity between lateral geniculate efferents and neurons of the hypothalamus, including those producing dopamine, that have direct access to fenestrated capillaries. It was also determined whether the intergeniculate neurons that give rise to hypothalamic projections are targeted by retinal axons. Within the hypothalamus, Phaseolus vulgaris leucoagglutinin-labeled, lateral geniculate efferents were observed in the suprachiasmatic nucleus, subparaventricular area, periventricular nuclei, medial preoptic areas, and between the arcuate and ventromedial nuclei. In these sites, intergeniculate efferents contacted populations of neurons that were retrogradely labeled from fenestrated capillaries by the intraperitoneal injection of fluorogold. Hypothalamic dopamine neurons, a population of which was neuroendocrine, were also synaptic targets of lateral geniculate efferents. After injection of the retrograde tracer fluorogold into these hypothalamic projection sites in parallel with bilateral enucleation, retrogradely labeled perikarya were restricted to the intergeniculate leaflet. All of the labeled perikarya contained infolded nuclei, and their distal dendrites were frequently found to be contacted by degenerated, retinal fibers. This study provides morphological evidence for a signaling pathway from the retina through the intergeniculate leaflet to hypothalamic cells that participate in neuroendocrine regulations. These observations raise the possibility that visual signals independent of the circadian clock may also influence the hypothalamo-pituitary axis. In light of the overlapping distribution of intergeniculate and suprachiasmatic efferents in the hypothalamus and their similar relationship with neuroendocrine cells, it is suggested that integration of circadian and visual signals can occur outside of the suprachiasmatic nucleus to regulate endocrine rhythms.