Neural Progenitor Cells and the Hypothalamus.

Neural progenitor cells (NPCs) are multipotent neural stem cells (NSCs) capable of self-renewing and differentiating into neurons, astrocytes and oligodendrocytes. In the postnatal/adult brain, NPCs are primarily located in the subventricular zone (SVZ) of the lateral ventricles (LVs) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). There is evidence that NPCs are also present in the postnatal/adult hypothalamus, a highly conserved brain region involved in the regulation of core homeostatic processes, such as feeding, metabolism, reproduction, neuroendocrine integration and autonomic output. In the rodent postnatal/adult hypothalamus, NPCs mainly comprise different subtypes of tanycytes lining the wall of the 3rd ventricle. In the postnatal/adult human hypothalamus, the neurogenic niche is constituted by tanycytes at the floor of the 3rd ventricle, ependymal cells and ribbon cells (showing a gap-and-ribbon organization similar to that in the SVZ), as well as suprachiasmatic cells. We speculate that in the postnatal/adult human hypothalamus, neurogenesis occurs in a highly complex, exquisitely sophisticated neurogenic niche consisting of at least four subniches; this structure has a key role in the regulation of extrahypothalamic neurogenesis, and hypothalamic and extrahypothalamic neural circuits, partly through the release of neurotransmitters, neuropeptides, extracellular vesicles (EVs) and non-coding RNAs (ncRNAs).

Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability.

INTRODUCTION: Deep brain stimulation (DBS) is a surgical technique used to manage aggression in patients who do not improve despite the use of appropriate drug treatment. OBJECTIVE: The objective of this study is to assess the impact of DBS on aggressive behavior refractory to the pharmacological and behavioral treatment of patients with Intellectual Disabilities (ID). METHODS: A follow-up was conducted on a cohort of 12 patients with severe ID, undergoing DBS in posteromedial hypothalamic nuclei; evaluated with the Overt Aggression Scale (OAS), before the intervention, at 6, 12, and 18 months of medical follow-up. RESULTS: After the surgical procedure, there was a significant reduction in the aggressiveness of patients in the follow-up medical evaluation at 6 months (t = 10.14; p < 0.01), 12 months (t = 14.06; p < 0.01), and 18 months (t = 15.34; p < 0.01), respect to the initial measurement; with a very large effect size (6 months: d = 2.71; 12 months: d = 3.75; 18 months: d = 4.10). From 12 months onward, emotional control stabilized and is sustained at 18 months (t = 1.24; p > 0.05). CONCLUSION: DBS in posteromedial hypothalamic nuclei may be an effective treatment for the management of aggression in patients with ID refractory to pharmacological treatment.

Type 1 melanocortin receptors in pro-opiomelanocortin-, vasopressin-, and oxytocin-immunopositive neurons in different areas of mouse brain.

Information on the localization of the Type 1 melanocortin receptors (MC1Rs) in different regions of the brain is very scarce. As a result, the role of MC1Rs in the functioning of brain neurons and in the central regulation of physiological functions has not been studied. This work aimed to study the expression and distribution of MС1Rs in different brain areas of female C57Bl/6J mice. Using real-time polymerase chain reaction, we demonstrated the Mс1R gene expression in the cerebral cortex, midbrain, hypothalamus, medulla oblongata, and hippocampus. Using an immunohistochemical approach, we showed the MС1R localization in neurons of the hypothalamic arcuate, paraventricular and supraoptic nuclei, nucleus tractus solitarius (NTS), dorsal hippocampus, substantia nigra, and cerebral cortex. Using double immunolabeling, the MC1Rs were visualized on the surface and in the bodies and outgrowths of pro-opiomelanocortin (POMC)-immunopositive neurons in the hypothalamic arcuate nucleus, NTS, hippocampal CA3 and CA1 regions, and cerebral cortex. Co-localization with POMC indicates that MC1R, like MC3R, is able to function as an autoreceptor. In the paraventricular and supraoptic nuclei, MC1Rs were visualized on the surface and in the cell bodies of vasopressin- and oxytocin-immunopositive neurons, indicating a relationship between hypothalamic MC1R signaling and vasopressin and oxytocin production. The data obtained indicate a wide distribution of MC1Rs in different areas of the mouse brain and their localization in POMC-, vasopressin- and oxytocin-immunopositive neurons, which may indicate the participation of MC1Rs in the control of many physiological processes in the central nervous system.

Complex negative emotions induced by electrical stimulation of the human hypothalamus.

BACKGROUND: Stimulation of the ventromedial hypothalamic region in animals has been reported to cause attack behavior labeled as sham-rage without offering information about the internal affective state of the animal being stimulated. OBJECTIVE: To examine the causal effect of electrical stimulation near the ventromedial region of the human hypothalamus on the human subjective experience and map the electrophysiological connectivity of the hypothalamus with other brain regions. METHODS: We examined a patient (Subject S20_150) with intracranial electrodes implanted across 170 brain regions, including the hypothalamus. We combined direct electrical stimulation with tractography, cortico-cortical evoked potentials (CCEP), and functional connectivity using resting state intracranial electroencephalography (EEG). RESULTS: Recordings in the hypothalamus did not reveal any epileptic abnormalities. Electrical stimulations near the ventromedial hypothalamus induced profound shame, sadness, and fear but not rage or anger. When repeated single-pulse stimulations were delivered to the hypothalamus, significant responses were evoked in the amygdala, hippocampus, ventromedial-prefrontal and orbitofrontal cortices, anterior cingulate, as well as ventral-anterior and dorsal-posterior insula. The time to first peak of these evoked responses varied and earliest propagations correlated best with the measures of resting-state EEG connectivity and structural connectivity. CONCLUSION: This patient's case offers details about the affective state induced by the stimulation of the human hypothalamus and provides causal evidence relevant to current theories of emotion. The complexity of affective state induced by the stimulation of the hypothalamus and the profile of hypothalamic electrophysiological connectivity suggest that the hypothalamus and its connected structures ought to be seen as causally important for human affective experience.

Structural and molecular characterization of paraventricular thalamic glucokinase-expressing neuronal circuits in the mouse.

The thalamic paraventricular nucleus (PVT) is a structure highly interconnected with several nuclei ranging from forebrain to hypothalamus and brainstem. Numerous rodent studies have examined afferent and efferent connections of the PVT and their contribution to behavior, revealing its important role in the integration of arousal cues. However, the majority of these studies used a region-oriented approach, without considering the neuronal subtype diversity of the nucleus. In the present study, we provide the anatomical and transcriptomic characterization of a subpopulation of PVT neurons molecularly defined by the expression of glucokinase (Gck). Combining a genetically modified mouse model with viral tracing approaches, we mapped both the anterograde and the retrograde projections of Gck-positive neurons of the anterior PVT (GckaPVT ). Our results demonstrated that GckaPVT neurons innervate several nuclei throughout the brain axis. The strongest connections are with forebrain areas associated with reward and stress and with hypothalamic structures involved in energy balance and feeding regulation. Furthermore, transcriptomic analysis of the Gck-expressing neurons revealed that they are enriched in receptors for hypothalamic-derived neuropeptides, adhesion molecules, and obesity and diabetes susceptibility transcription factors. Using retrograde labeling combined with immunohistochemistry and in situ hybridization, we identify that GckaPVT neurons receive direct inputs from well-defined hypothalamic populations, including arginine-vasopressin-, melanin-concentrating hormone-, orexin-, and proopiomelanocortin-expressing neurons. This detailed anatomical and transcriptomic characterization of GckaPVT neurons provides a basis for functional studies of the integration of homeostatic and hedonic aspects of energy homeostasis, and for deciphering the potential role of these neurons in obesity and diabetes development.

Is vagal stimulation or inhibition benefit on the regulation of the stomach brain axis in obesity?

Objective: Possible effects of the vagus inhibition and stimulation on the hypothalamic nuclei, myenteric plexes and the vagus nerve were investigated.Methods: The female rats divided to the inhibition (INH), stimulation (STI) and, sham (SHAM) groups were fed with high fat diet (including 40% of energy from animal fat). After nine weeks, the rats were allowed to recover for 4 weeks in INH group. In STI group, the left vagus nerve stimulated (30 Hz/500 msn/30 sec.) starting 2nd post operative day for 5 minutes during 4 weeks. Healthy female rats used as control (CONT). Then, tissue samples were analyzed by biochemical, histological and stereological methods.Results: The mean number of the neurons in the arcuate nucleus of the INH group was significantly less; but, that is significantly more in the STI group compared to the other groups. The neuronal density of ventromedial nucleus in the STI group was higher; while the density in the INH group was lower than the other groups. In the dorsomedial nucleus, neuron density of the INH group was lower than the other groups. In terms of the myenteric plexus volumes, that of the INH group was lowest. The myelinated axon number in the INH group was significantly highest. The myelin sheath thickness and axon area of the INH group was significantly lower than the other groups.Discussion: The results of the study show that the vagal inhibition is more effective than the vagal stimulation on the weight loss in the obesity.

Hypothalamic aging and hormones.

It is the heterogeneous changes of hypothalamic functions that determine the chronological sequence of aging in mammals. Recently, it was hypothesized by Cai the decrease in slow-wave sleep (SWS) resulting from skin aging as responsible for the degeneration of hypothalamic suprachiasmatic nucleus (SCN). It was soon hypothesized by the European people in television that the increase in body fat as responsible for the degeneration of male preoptic sexually dimorphic nucleus (SDN-POA), via the aromatase converting testosterone to estradiol as proposed by Cohen. It is the hypothalamic paraventricular nucleus (PVN) that remains unchanged in neuron number during aging for psychological stress. In this chapter, it is briefly reviewed more manifestations of hypothalamic related mammalian aging processes, including (1) the aging of ovary by lipid, estradiol and hypothalamus; (2) the aging of muscle, stomach, intestine, thymus, and the later aging of brain, regulated by growth hormone/insulin-like growth factor 1(GH/IGF1); (3) the cardiovascular hypertension from PVN activation, the bone and other peripheral aging by psychological stress, and that of kidney by vasopressin. It is classified these aging processes by the primary regulation from one of the three hypothalamic nuclei, although still necessary to investigate and supplement their secondary regulation by the hypothalamic nuclei in future. It is the hypothalamic structural changes that shift the functional balance among these three hypothalamic systems toward aging.

Projections from the dorsomedial division of the bed nucleus of the stria terminalis to hypothalamic nuclei in the mouse.

As stressful environment is a potent modulator of feeding, we seek in the present work to decipher the neuroanatomical basis for an interplay between stress and feeding behaviors. For this, we combined anterograde and retrograde tracing with immunohistochemical approaches to investigate the patterns of projections between the dorsomedial division of the bed nucleus of the stria terminalis (BNST), well connected to the amygdala, and hypothalamic structures such as the paraventricular (PVH) and dorsomedial (DMH), the arcuate (ARH) nuclei and the lateral hypothalamic areas (LHA) known to control feeding and motivated behaviors. We particularly focused our study on afferences to proopiomelanocortin (POMC), agouti-related peptide (AgRP), melanin-concentrating-hormone (MCH) and orexin (ORX) neurons characteristics of the ARH and the LHA, respectively. We found light to intense innervation of all these hypothalamic nuclei. We particularly showed an innervation of POMC, AgRP, MCH and ORX neurons by the dorsomedial and dorsolateral divisions of the BNST. Therefore, these results lay the foundation for a better understanding of the neuroanatomical basis of the stress-related feeding behaviors.

The anorexigenic effect of beta-melanocyte-stimulating hormone involves corticotrophin-releasing factor and mesotocin in birds.

Beta-melanocyte-stimulating hormone (ß-MSH), when centrally injected, induces anorexigenic effects in rodents and chickens but its mechanism remains unclear. Thus, the primary goal of this research was to elucidate the hypothalamic mechanism using chickens. Intracerebroventricular injection of 0.3, 1.0 and 3.0 nmol of ß-MSH decreased food intake for 540 min. Expression of hypothalamic mRNAs were affected by ß-MSH injection, including corticotrophin-releasing factor (CRF) and its receptor subtype 1 (CRFR1), mesotocin (MT) and its receptor (MTR), pro-opiomelanocortin, cocaine- and amphetamine-regulated transcript (CART), growth hormone secretagogue receptor (GHSR) and neuropeptide Y (NPY) receptor subtype 5 (NPYR5). Within the arcuate nucleus, expressions of NPY, agouti-related peptide, MT and MTR were increased by ß-MSH injection. ß-MSH-treated chicks had more CRF, CRFR1, CRF receptor subtype 2, GHSR, NPY receptor subtype 1 (NPYR1) and NPYR5 mRNA but lower levels of CART and ghrelin, in the paraventricular nucleus. Greater amounts of mRNA for MTR, GHSR, NPYR1 and NPYR5 and less CRF expression were observed in the ventromedial hypothalamus. In conclusion, central injection of ß-MSH potently reduced food intake and was associated with changes in mRNA expression of some anorexigenic factors in a hypothalamic nucleus-specific manner.

Nucleobindin-2/Nesfatin-1 in the Human Hypothalamus Is Reduced in Obese Subjects and Colocalizes with Oxytocin, Vasopressin, Melanin-Concentrating Hormone, and Cocaine- and Amphetamine-Regulated Transcript.

BACKGROUND/AIMS: Nesfatin-1, processed from nucleobindin-2 (NUCB2), is a potent anorexigenic peptide being expressed in rodent hypothalamic nuclei and involved in the regulation of feeding behavior and body weight in animals. The present study aimed to investigate NUCB2/nesfatin-1 protein expression in the human hypothalamus as well as its correlation with body weight. METHODS: Sections of hypothalamus and adjacent cholinergic basal forebrain nuclei, including the nucleus basalis of Meynert (NBM) and the diagonal band of Broca (DBB), from 25 autopsy cases (17 males, 8 females; 8 lean, 9 overweight, 8 obese) were examined using immunohistochemistry and double immunofluorescence labeling. RESULTS: Prominent NUCB2/nesfatin-1 immunoexpression was detected in supraoptic, paraventricular, and infundibular nuclei, lateral hypothalamic area (LHA)/perifornical region, and NBM/DBB. NUCB2/nesfatin-1 was found to extensively colocalize with (a) oxytocin and vasopressin in paraventricular and supraoptic nuclei, (b) melanin-concentrating hormone in the LHA, and (c) cocaine- and amphetamine-regulated transcript in infundibular and paraventricular nuclei and LHA. Interestingly, in the LHA, NUCB2/nesfatin-1 protein expression was significantly decreased in obese, compared with lean (p < 0.01) and overweight (p < 0.05) subjects. CONCLUSIONS: The findings of the present study are suggestive of a potential role for NUCB2/nesfatin-1 as an integral regulator of food intake and energy homeostasis in the human hypothalamus. In the LHA, an appetite- and reward-related brain area, reduced NUCB2/nesfatin-1 immunoexpression may contribute to dysregulation of homeostatic and/or hedonic feeding behavior and obesity. NUCB2/nesfatin-1 localization in NBM/DBB might imply its participation in the neuronal circuitry controlling cognitive influences on food intake and give impetus towards unraveling additional biological actions of NUCB2/nesfatin-1 in human neuronal networks.

The investigation of the effects of topiramate on the hypothalamic levels of fat mass/obesity-associated protein and neuropeptide Y in obese female rats.

OBJECTIVE: The aim of the present study is to investigate the effects of topiramate on the fat mass/obesity-associated protein (FTO) and on the neuropeptide Y (NPY) level in the hypothalamus depending on the recently increased prevalence of obesity. METHOD: In this study, twenty-four female rats were divided into four equal groups: Non-obese control, obese control, non-obese topiramate, and obese topiramate. Obese groups were fed with a 40% high-fat diet. At the end of the 9th week, the drug treatment started and the subjects were treated with topiramate once a day for 6 weeks. All animals underwent cardiac perfusion under high-dose anesthesia on the 15th week. Tissues were analyzed using biochemical, histological, and stereological methods. RESULTS: In terms of neuron number in the arcuate nucleus area, a significant difference was observed among all groups (P < 0.01). The neuron number of the non-obese topiramate group was found to be significantly higher than that of the non-obese control group (P < 0.01). In the examination of the ventromedial nucleus of the entire group, it was observed that the neuron number of the non-obese control group was significantly lower than those of the other groups (P < 0.01). A significant increase in the NPY levels of the obese groups compared to the groups treated with topiramate was observed. Furthermore, the amount of the FTO protein increased in obese rats, while FTO and NPY levels decreased in the groups treated with topiramate. DISCUSSION: In conclusion, the mechanism of the effect of topiramate to create a state of obesity is thought to involve the decrease in the levels of NPY and FTO.

Differential expression of appetite-regulating genes in avian models of anorexia and obesity.

Chickens from lines that have been selected for low (LWS) or high (HWS) juvenile body weight for more than 57 generations provide a unique model by which to research appetite regulation. The LWS display different severities of anorexia, whereas all HWS become obese. In the present study, we measured mRNA abundance of various factors in appetite-associated nuclei in the hypothalamus. The lateral hypothalamus (LHA), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH), dorsomedial nucleus (DMN) and arcuate nucleus (ARC) were collected from 5 day-old chicks that were fasted for 180 minutes or provided with continuous access to food. Fasting increased neuropeptide Y receptor subtype 1 (NPYR1) mRNA in the LHA and c-Fos in the VMH, at the same time as decreasing c-Fos in the LHA, neuropeptide Y receptor subtype 5 and ghrelin in the PVN, and neuropeptide Y receptor subtype 2 in the ARC. Fasting increased melanocortin receptor subtype 3 (MC3R) expression in the DMN and NPY in the ARC of LWS but not HWS chicks. Expression of NPY was greater in LWS than HWS in the DMN. neuropeptide Y receptor subtype 5 mRNA was greater in LWS than HWS in the LHA, PVN and ARC. Expression of orexin was greater in LWS than HWS in the LHA. There was greater expression of NPYR1, melanocortin receptor subtype 4 and cocaine- and amphetamine-regulated transcript in HWS than LWS and mesotocin in LWS than HWS in the PVN. In the ARC, agouti-related peptide and MC3R were greater in LWS than HWS and, in the VMH, orexin receptor 2 and leptin receptor were greater in LWS than HWS. Greater mesotocin in the PVN, orexin in the LHA and ORXR2 in the VMH of LWS may contribute to their increased sympathetic tone and anorexic phenotype. The results of the present study also suggest that an increased hypothalamic anorexigenic tone in the LWS over-rides orexigenic factors such as NPY and AgRP that were more highly expressed in LWS than HWS in several nuclei.

Stereotaxic atlas of the goat brain for an accurate approach to the hypothalamic nuclei.

While the external acoustic meatus of mice, rats and cats are at right angles to the side of the head, they are angled forward in ruminants. Because of this, the coordinates of stereotaxic atlases created using the same methods as for small animals were not suitable for practical use and made it very difficult to place electrodes in hypothalamic nuclei. The aim of this study was to produce a highly accurate stereotaxic atlas for goats that enables precise placement of electrodes in the hypothalamic nuclei. A method of fixing the head in place so as to maintain the basis cranii interna in a horizontal position was established allowing right angled three dimensional axes to be superimposed in the brains of Japanese Saanen goats. This research attempted to establish a new landmark alternative to the external acoustic meatus. The new landmark is the extremitas posterior clivus presphenoidale (EPCP) at the base of cranial bone. This landmark can easily be visualized through lateral radiography. This enabled the AP (anterior-posterior) and H (height) coordinates of the position to be fixed at 30 and 5, respectively. The A30 and H5 coordinates of the serial frontal, sagittal, and horizontal stereotaxic atlases in the present experiment were set to coincide with the position of the EPCP. In order to clarify whether the deviation of the stereotaxic brain coordinates due to inconsistent immobilization the goat's head was eliminated, the AP and H coordinates of the extremitas anterior fossa hypophysialis and the extremitas posterior fossa hypophysialis were measured using the corrected axes. In the three dimensional stereotaxic atlas created using the new landmark, it became possible to approach the hypothalamic nuclei of goats accurately. This method significantly differentiates the stereotaxic atlas from its predecessors.