Adult Human Hypothalamus Research Articles

Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus.

The development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. To address this, we integrated transcriptomic data from 241,096 cells (126,840 newly generated) in the prenatal and adult human hypothalamus to reveal a temporal trajectory from proliferative stem cell populations to mature hypothalamic cell types. Iterative clustering of the adult neurons identified 108 robust transcriptionally distinct neuronal subtypes representing 10 hypothalamic nuclei. Pseudotime trajectories provided insights into the genes driving formation of these nuclei. Comparisons to single-cell transcriptomic data from the mouse hypothalamus suggested extensive conservation of neuronal subtypes despite certain differences in species-enriched gene expression. The uniqueness of hypothalamic neuronal lineages was examined developmentally by comparing excitatory lineages present in cortex and inhibitory lineages in ganglionic eminence, revealing both distinct and shared drivers of neuronal maturation across the human forebrain. These results provide a comprehensive transcriptomic view of human hypothalamus development through gestation and adulthood at cellular resolution.

A comparative study of the neural stem cell niche in the adult hypothalamus of human, mouse, rat and gray mouse lemur (Microcebus murinus)

The adult brain contains niches of neural stem cells that continuously add new neurons to selected circuits throughout life. Two niches have been extensively studied in various mammalian species including humans, the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus. Recently, studies conducted mainly in rodents have identified a third neurogenic niche in the adult hypothalamus. In order to evaluate whether a neural stem cell niche also exists in the adult hypothalamus in humans, we performed multiple immunofluorescence labeling to assess the expression of a panel of neural stem/progenitor cell (NPC) markers (Sox2, nestin, vimentin, GLAST, GFAP) in the human hypothalamus and compared them with the mouse, rat and a non-human primate species, the gray mouse lemur (Microcebus murinus). Our results show that the adult human hypothalamus contains four distinct populations of cells that express the five NPC markers: (a) a ribbon of small stellate cells that lines the third ventricular wall behind a hypocellular gap, similar to that found along the lateral ventricles, (b) ependymal cells, (c) tanycytes, which line the floor of the third ventricle in the tuberal region, and (d) a population of small stellate cells in the suprachiasmatic nucleus. In the mouse, rat and mouse lemur hypothalamus, co-expression of NPC markers is primarily restricted to tanycytes, and these species lack a ventricular ribbon. Our work thus identifies four cell populations with the antigenic profile of NPCs in the adult human hypothalamus, of which three appear specific to humans.

Effects of testosterone treatment on hypothalamic neuroplasticity in female-to-male transgender individuals

Diffusion-weighted imaging (DWI) is used to measure gray matter tissue density and white matter fiber organization/directionality. Recent studies show that DWI also allows for assessing neuroplastic adaptations in the human hypothalamus. To this end, we investigated a potential influence of testosterone replacement therapy on hypothalamic microstructure in female-to-male (FtM) transgender individuals. 25 FtMs were measured at baseline, 4 weeks, and 4 months past treatment start and compared to 25 female and male controls. Our results show androgenization-related reductions in mean diffusivity in the lateral hypothalamus. Significant reductions were observed unilaterally after 1 month and bilaterally after 4 months of testosterone treatment. Moreover, treatment induced increases in free androgen index and bioavailable testosterone were significantly associated with the magnitude of reductions in mean diffusivity. These findings imply microstructural plasticity and potentially related changes in neural activity by testosterone in the adult human hypothalamus and suggest that testosterone replacement therapy in FtMs changes hypothalamic microstructure towards male proportions.

Aromatic l-amino acid decarboxylase- and tyrosine hydroxylase- immunohistochemistry in the adult human hypothalamus

The distribution of cell bodies immunoreactive for tyrosine hydroxylase and aromatic l-amino acid decarboxylase was studied in the adult human hypothalamus. Many neurons in the posterior (A11) and caudal dorsal hypothalamic areas (A13) as well as in the arcuate (A12) and periventricular (A14) zone were immunoreactive for the two enzymes, suggesting that they were dopaminergic. Numerous tyrosine hydroxylase-immunoreactive neurons, which were not immunoreactive for aromatic l-amino acid decarboxylase, could be seen in the paraventricular, supraoptic and accessory nuclei (A15) as well as in the rostral dorsal hypothalamic area. These were considered to be non-dopaminergic. Conversely, large numbers of small neurons immunoreactive for aromatic l-amino acid decarboxylase but not for tyrosine hydroxylase, were identified in the premammillary nucleus (D8), zona incerta (D10), lateral hypothalamic area (D11), anterior portion of the dorsomedial nucleus (D12), suprachiasmatic nucleus (D13), medial preoptic area and bed nucleus of the stria terminalis (D14). In the human hypothalamus, besides dopaminergic cell bodies, there exists a large number of tyrosine hydroxylase-only and aromatic l-amino acid decarboxylase-only neurons, whose physiological roles remain to be determined.

Localization and developmental pattern of vasoactive intestinal polypeptide binding sites in the human hypothalamus

Using a quantitative in vitro autoradiographic approach, vasoactive intestinal polypeptide (VIP) binding site densities were compared in the post-mortem hypothalamus of human neonate/infant and adult. The densities were similar during development in most of the hypothalamic nuclei and areas examined underlying the stability of 125I-VIP binding sites in the post-mortem hypothalamus of young and adult individuals. However, the ventral part of the medial preoptic area, the medial, lateral, and supramammillary nuclei were characterized by an increase of 125I-VIP binding with age. In young and adult individuals, the highest densities of hypothalamic 125I-VIP binding sites were detected in the supraoptic and infundibular nuclei; the ependyma; the organum vasculosum of the lamina terminalis; the horizontal limb of the diagonal band of Broca; the ventral part of the medial preoptic area (in adult); the suprachiasmatic, paraventricular, and periventricular nuclei; and the medial and lateral mammillary nuclei in adult. Moderate densities were found in the vertical limb of the diagonal band of Broca, the bed nucleus of the stria terminalis, the ventral part of the medial preoptic area in neonate/infant, the medial and lateral mammillary nuclei in neonate/infant, the supramammillary nucleus in adult, the dorsal hypothalamic area, and the ventromedial nucleus. Low to moderate binding site densities were observed in the other hypothalamic regions of young or adult individuals. The nonspecific binding ranged from 15% of the total binding in the anterior hypothalamus to 20% in the mediobasal and posterior hypothalamic levels. Taken together, these results provide evidence for a large distribution of VIP binding sites in neonate/infant and adult human hypothalamus suggesting the implication of VIP in the development of this brain structure and the maintenance of its various functions.

Gender and sexual orientation in relation to hypothalamic structures.

Animal experiments have provided evidence for the presence of sex differences from the synaptic level up to behaviour. Although sex differences in the human brain may have been presumed implicitly since the days of Aristotle, research on the presence of functional and structural sex differences of the human brain started only relatively recently. The most conspicuous sex difference in the mammalian brain was described by Gorski et al. [1978] in the preoptic area (POA) of the rat hypothalamus. We found that the volume of a putative homologue of this sexually dimorphic nucleus (SDN) in the adult human hypothalamus was more than twice as large in men as in women and contained about twice as many cells. Recently a similar sex difference and volume has been described for the human bed nucleus of the stria terminalis and 'interstitial nuclei of the hypothalamus' (INAH). Sexual differentiation of the hypothalamus was generally believed to take place between 4 and 7 months of gestation. A life span study on the SDN of more than 100 subjects revealed, however, that only after the age of 2-4 years postnatally sexual differentiation becomes manifest by a decrease in volume and cell number in the female SDN. If sexual differentiation of the brain indeed takes place postnatally, not only chemical and hormonal factors may influence this process but also social factors. A prominent theory on the development of sexual orientation is that it develops as a result of an interaction between the developing brain and sex hormones. According to Dörner's hypothesis, male homosexuals have a female differentiation of the hypothalamus. This hypothesis was not supported by our observations on the SDN. Neither the SDN volume nor the cell number in the hypothalamus of homosexual men differed from that of heterosexual men. However, a difference in SCN cell number was observed in relation to sexual orientation. The volume and cell number of the SCN of homosexual men was twice as large as that of a reference group. During development, the SCN volume and cell counts reach peak values around 13-16 months after birth. At this age the SCN contains about the same number of cells as the SCN of adult male homosexuals, whereas in the reference group the cell numbers subsequently decline to the adult value, which is about 35% of the peak value.(ABSTRACT TRUNCATED AT 400 WORDS)

Autoradiographic distribution of TRH binding sites in the human hypothalamus

Using in vitro quantitative autoradiography and [ 3H]3MeTRH, a selective high affinity radioligand, we examined the rostrocaudal distribution of TRH binding sites in both the infant and the adult human hypothalamus. The saturation curve shows that the [ 3H]3MeTRH binds with high affinity to a single class of TRH binding sites and is saturable, the apparent constant of dissociation is in the namomolar range. TRH binding sites showed a wide distribution, principally in the anterior and mediobasal levels of the hypothalamus. TRH binding site concentration was highest within the diagonal band of Broca, the lateral preoptic area, the infundibular and the tuberal nuclei. TRH binding site concentration was moderate in the ventromedial nucleus and the medial preoptic area, whereas we observed low densities in the periventricular, paraventricular and mammillary nuclei. The distribution in the infant and the adult is generally similar. However, it is noteworthy that the infant tuberal nuclei displayed a lower binding site density when compared to the adult. On the other hand, the diagonal band of Broca is relatively more labeled in infant. The analysis of the whole hypothalamus allows us to ascertain the absence of lateral asymmetric distribution both in the infant and the adult. No significant difference is noticed when considering as paremeters of variation age, sex or post mortem delay.

Tyrosine hydroxylase-immunoreactive neurons in paraventricular and supraoptic nuclei of the human brain demonstrated by a method adapted to prolonged formalin fixation

We studied the distribution of tyrosine hydroxylase (TH) immunoreactive (IR) neurons in the adult human hypothalamus using a modification of the peroxidase-antiperoxidase immunohistochemical method which can be applied on autopsy brain material following prolonged formalin fixation. We observed that most of the TH-IR perikarya localized within the paraventricular (PVN) and supraoptic (SON) nuclei were large and showed homogeneous staining over the entire cytoplasm and processes. These results show that in the human brain a large population of neurons within the neurosecretory nuclei are able to synthesize a catecholamine.

Tyrosine hydroxylase-containing neurons in the supraoptic and paraventricular nuclei of the adult human

We have studied the distribution of tyrosine hydroxylase-containing neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the adult human hypothalamus. Large numbers of these neurons were seen in these hypothalamic nuclei; approximately 40% of all the cells within the SON and PVN were immunoreactive for tyrosine hydroxylase (TH-ir). Most of these cells were magnocellular. Their distribution was compared to that of arginine-vasopressin-immunoreactive (AVP-ir) cells. In the SON a greater proportion of magnocellular TH-ir cells was found caudally compared to AVP-ir cells. In the PVN the magnocellular TH-ir cells were larger in mean diameter compared to AVP-ir cells. In double-immunofluorescence experiments some TH-ir cells contained oxytocin immunoreactivity but none contained AVP-ir. In the adult human a large number of PVN and SON magnocellular cells appear to synthesize a catecholamine. A subclass of these neurons also synthesize oxytocin but most cells are distinct from the classically described neurosecretory neurons.

Neurosecretion of human hypothalamic immunoreactive beta-endorphin: in vitro regulation by dopamine.

An in vitro perifusion system was used to investigate immunoreactive beta-endorphin (beta-END-I) release from adult human hypothalami in response to dopamine (DA) and the DA receptor antagonist haloperidol (HAL). Administration of a 1 microM pulse of DA consistently elicited a mean (+/- SE) 88 +/- 9% increase (p less than 0.05, n = 5) in beta-END-I release, whereas 1 microM HAL had no effect. Administration of 1 microM DA during three perifusions in which 1 microM HAL was added to the medium failed to alter basal beta-END-I release. In contrast, DA did evoke an acute 230 +/- 31% increase (p less than 0.05) in beta-END-I release during three matching perifusions with medium containing the alpha-adrenergic antagonist phentolamine. These studies demonstrate that DA can stimulate in vitro release of beta-END-I from the adult human hypothalamus by a DA receptor mediated mechanism.

Gonadotropin-releasing hormone neurosecretion in the human hypothalamus: in vitro regulation by dopamine.

An in vitro perifusion system was used to investigate GnRH release from adult human hypothalami in response to dopamine (DA) and the DA receptor antagonist haloperidol (HAL). Administration of a 1-microM pulse of DA consistently elicited a mean +/- SE 218 +/- 59% increase (P less than 0.05; n = 5) in GnRH release, whereas 1 microM HAL had no effect. Administration of 1 microM DA during three perifusions in which 1 microM HAL was added to the medium failed to alter basal GnRH release. In contrast, DA did evoke an acute 98 +/- 39% increase (P less than 0.06) in GnRH release during three matching perifusions with medium containing the alpha-adrenergic antagonist phentolamine. These studies demonstrate that DA can stimulate in vitro release of GnRH from the adult human hypothalamus by a DA receptor-mediated mechanism.