This review details the manner in which the central nervous system regulates metabolic homeostasis in normal weight and obese rodents and humans. It includes a review of the homeostatic contributions of neurons located in the hypothalamus, the midbrain and limbic structures, the pons and the medullary area postrema, nucleus tractus solitarius, and vagus nucleus, and details how these brain regions respond to circulating levels of orexigenic hormones, such as ghrelin, and anorexigenic hormones, such as glucagon-like peptide 1 and leptin. It provides an insight as to how high intensity exercise may improve homeostatic control in overweight and obese subjects. Finally, it provides suggestions as to how further progress can be made in controlling the current pandemic of obesity and diabetes.

Retrograde tract tracing combined with immunohistochemical techniques were used to identify the origin of orexin A-immunoreactive (OrA-ir) fibers in the rat medulla. One to 5 days following injection of the fluorescent dye Fluorogold into the dorsal medulla, labeled neurons were found in the lateral half of the lateral hypothalamus, paraventricular, perifornical, dorsomedial, dorsal and posterior hypothalamic nuclei. Labeling the same sections with OrA antisera revealed a concentration of OrA-ir neurons in the perifornical and dorsomedial regions of the tuberal hypothalamus. A maximum of 10% of Fluorogold-labeled hypothalamic neurons were OrA-ir and 15% of OrA-ir hypothalamic neurons contained Fluorogold. Our results demonstrate that a fraction of OrA-ir neurons in the tuberal hypothalamus project to areas of the medulla that are involved in autonomic functions.

Insulin-like 6 immunoreactivity (irINSL6) was detected in Leydig cells of the mouse testis. In the brain, labeled somata were detected mainly in the caudal hypothalamus and midbrain. Double labeling the brainstem sections revealed that irINSL6 somata were 5-hydroxytryptamine (5-HT) positive. The presence of irINSL6 in discrete populations of hypothalamic and brainstem neurons and in Leydig cells of the testis suggests a diverse biological function of this novel peptide.

Metastin, the gene product of metastasis suppressor gene KiSS-1, is the endogenous ligand for the G-protein-coupled receptor GPR54 (or AXOR12, or OT7T175). The expression of KiSS-1 gene and peptide and the distribution of metastin were studied in the rat central nervous system by reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical methods. KiSS-1 gene and peptide expression was higher in the hypothalamus than in the brainstem and spinal cord. In the brain, metastin-like immunoreactivity (irMT) was found mainly in three groups of cells: dorsomedial hypothalamic nucleus, nucleus of the solitary tract, and caudal ventrolateral medulla. Immunoreactive fibers of varying density were noted in bed nucleus of stria terminalis, septal nuclei, nucleus accumbens, caudate putamen, diagonal band, amygdala, hypothalamus, zona incerta, thalamus, periaqueductal gray, raphe nuclei, lateral parabrachial nucleus, locus coeruleus, spinal trigeminal tract, rostral ventrolateral medulla, and medullary reticular nucleus. Preabsorption of the antiserum with metastin peptide fragment (45-54)-NH2 (1 μg/ml) resulted in no staining in any of the sections. The biological activity of metastin was assessed by monitoring intracellular calcium [Ca2+]i in cultured hippocampal neurons, which are known to express GPR54. Metastin increased [Ca 2+]i in a population of cultured hippocampal neurons. The results show that metastin is biologically active in rat central neurons, and its anatomical distribution suggests a possible role in nociception and autonomic and neuroendocrine functions.

The two recently isolated hypothalamic peptides orexin A and orexin B, also known as hypocretin 1 and 2, are reported to be important signaling molecules in feeding and sleep/wakefulness. Orexin-containing neurons in the lateral hypothalamus project to numerous areas of the rat brain and spinal cord including the intermediolateral cell column (IML) of the thoracolumbar spinal cord. An in vivo and in vitro study was undertaken to evaluate the hypothesis that orexins, acting on sympathetic preganglionic neurons (SPNs) in the rat spinal cord, increase sympathetic outflow. First, orexin A (0.3, 1, and 10 nmol) by intrathecal injection increased mean arterial pressure (MAP) and heart rate (HR) by an average of 5, 18, and 30 mmHg and 10, 42, and 85 beats/min in urethane-anesthetized rats. Intrathecal injection of saline had no significant effects. Orexin B (3 nmol) by intrathecal administration increased MAP and HR by an average of 11 mmHg and 40 beats/min. The pressor effects of orexin A were attenuated by prior intrathecal. injection of orexin A antibodies (1:500 dilution) but not by normal serum albumin. Intravenous administration of the α1-adrenergic receptor antagonist prazosin (0.5 mg/kg) or the β-adrenergic receptor antagonist propranolol (0.5 mg/kg) markedly diminished, respectively, the orexin A-induced increase of MAP and HR. Second, whole cell patch recordings were made from antidromically identified SPNs of spinal cord slices from 12- to 16-day-old rats. Superfusion of orexin A or orexin B (100 or 300 nM) excited 12 of 17 SPNs, as evidenced by a membrane depolarization and/or increase of neuronal discharges. Orexin A- or B-induced depolarizations persisted in TTX (0.5 μM)-containing Krebs solution, indicating that the peptide acted directly on SPNs. Results from our in vivo and in vitro studies together with the previous observation of the presence of orexin A-immunoreactive fibers in the IML suggest that orexins, when released within the IML, augment sympathetic outflow by acting directly on SPNs.

The nucleus of the solitary tract (NTS) receives viscerosensory information from the vagus nerve to regulate diverse homeostatic reflex functions. The NTS projects to a wide network of other brain regions, including the paraventricular nucleus of the hypothalamus (PVN). Here we examined the synaptic characteristics of primary afferent pathways to PVN-projecting NTS neurons in rat brainstem slices. Expression of the Transient Receptor Potential Vanilloid receptor (TRPV1+ ) distinguishes C-fiber afferents within the solitary tract (ST) from A-fibers (TRPV1-). We used resiniferatoxin (RTX), a TRPV1 agonist, to differentiate the two. The variability in the latency (jitter) of evoked excitatory postsynaptic currents (ST-EPSCs) distinguished monosynaptic from polysynaptic ST-EPSCs. Rhodamine injected into PVN was retrogradely transported to identify PVN-projecting NTS neurons within brainstem slices. Graded shocks to the ST elicited all-or-none EPSCs in rhodamine-positive NTS neurons with latencies that had either low jitter (<200 µs – monosynaptic), high jitter (>200 µs - polysynaptic inputs) or both. RTX blocked ST-evoked TRPV1 + EPSCs whether mono- or polysynaptic. Most PVN-projecting NTS neurons (17/21 neurons) had at least one input polysynaptically connected to the ST. Compared to unlabeled NTS neurons, PVN-projecting NTS neurons were more likely to receive indirect inputs and be higher order. Surprisingly, sEPSC rates for PVN-projecting neurons were double that of unlabeled NTS neurons. The ST synaptic responses for PVN-projecting NTS neurons were either all TRPV1+ or all TRPV1-, including neurons that received both direct and indirect inputs. Overall, PVN-projecting NTS neurons received direct and indirect vagal afferent information with strict segregation regarding TRPV1 expression.

No description available.

Glucocorticoids bind with high affinity to intracellular receptors located in high density within discrete regions of the rodent and primate brain. The binding of [3H]corticosterone was compared in the brains of male vs female rats. The number and affinity of cytosol receptors in the hippocampus and hypothalamus were examined in vitro. The cytosolic binding capacity of the hippocampus is greater in the female than in the male. This difference in binding capacity is not dependent on the presence of gonadal steroids: the effect of gonadectomy was not significant for either sex. The difference is not due to transcortin since the binding capacity of [3H]dexamethasone is also greater in the female hippocampus. Receptor affinity in the female hippocampus is half that of the male value. In the hypothalamus, the dimorphism is in the opposite direction: the number of [3H]corticosterone cytosolic binding sites was found to be greater in the male. The male hypothalamus also showed a greater affinity for [3H]corticosterone than did the female. Ovariectomy increased the number of binding sites in the female hypothalamus. In vivo nuclear uptake of a tracer dose of [3H]corticosterone was determined in animals having intact gonads. The percent of tissue [3H]corticosterone present in cell nuclei from 4 brain regions, including the hippocampus and hypothalamus, was calculated per unit DNA. The concentrations of [3H]corticosterone in nuclei relative to tissue homogenates were higher in females than males for the 4 brain regions, but not for the pituitary or liver. The data are interpreted as suggesting that glucocorticoid secretion under basal conditions and during stress may differentially effect specific brain structures in male vs female rats.

No description available.

There are two distinct communication systems in the brain, term wiring and volume transmission (Agnati et al., 2010). Volume transmission refers to a way of communication lacking any wire-like channel connecting the source of signal and its target. This way of signaling is the focus of the current thesis. Portal systems are one aspect of volume transmission in which they provide a pathway for diffusible signaling between bodily fluids (blood and cerebrospinal fluid) and the nervous system. A portal system entails two capillary beds linked by connecting veins. This connection allows signals from one capillary bed to be transported to a target in high concentrations without being diluted in the systemic circulation (Dorland, 2020). For the past decades, the only identified portal system in the brain is pituitary portal system (Popa, 1930; Popa & Fielding, 1933). Here, hypothalamic neurosecretions are released into the fenestrated capillaries of median eminence, a circumventricular organ, and transported to the capillaries of anterior pituitary via portal veins. The median eminence, due to its location on the surface of the ventricle and its contact to the cerebrospinal fluid, is categorized as a circumventricular organ. According to the classification (Oldfield & McKinley, 2015), there are three sensory circumventricular organs in the brain, all are characterized by fenestrated capillaries allowing contact between brain parenchyma and blood. For this reason, the circumventricular organs are known as “windows to the brain” (Gross et al., 1987). Whether other circumventricular organs also form portal systems is unknown. This thesis examines whether sensory circumventricular organs, specifically the organum vascular organ of the lamina terminals, the subfornical organ and the area postrema, bear portal systems. Although there have been prior studies of the vascularity of these CVOs in many species (reviewed in Duvernoy and Risold (2007)), the tissue preparation methods available limited the possibility of tracking small vessels over relatively large volumes in these structures. In the present work, to preserve the blood vessel structure, brain clearing and light sheet microscopy were combined to acquire volumetric images of the regions containing the circumventricular organs. In vivo two-photon microscopy was used to study the blood flow of the sensory circumventricular organs and the adjacent neuropil. The results indicate that organum vasculosum of the lamina terminalis is connected to the brain’s clock located in the suprachiasmatic nucleus by portal vessels. The direction of blood flow is from the suprachiasmatic nucleus to the organum vasculosum of the lamina terminalis, and speed of blood flow is faster during the night compared to the day. Volumetric imaging of the suprachiasmatic nucleus also shows portal veins emerging from the rostral shell region of this nucleus. Also, the subfornical organ connects to the septofimbrial nucleus and the triangular nucleus of the septum via portal veins. The arrangement of the vasculature of the area postrema differs from the other sensory CVOs: the AP and the nucleus of the solitary tract share a common capillary bed directly joining the vasculature of these morphologically distinct nuclei. In summary, there are multiple portal systems connecting the circumventricular organs. These newly discovered portal systems represent new pathways for diffusible signaling, bridging the systemic circulation, cerebrospinal fluid, circumventricular organs and the portal veins connected regions.