The G Protein-Coupled Serotonin 1A Receptor Augments Protein Kinase Cε-Mediated Neurogenesis in Neonatal Mouse Hippocampus-PKCε-Mediated Signaling in the Early Hippocampus.

The neurotransmitter serotonin (5-HT) plays an important role in mood disorders. It has been demonstrated that 5-HT signaling through 5-HT receptors (5-HT-R) is crucial for early postnatal hippocampal development and later-life behavior. Although this suggests that 5-HT-R signaling regulates early brain development, the mechanistic underpinnings of this process have remained unclear.

Circulatory miR-98-5p levels are deregulated during diabetes and it inhibits proliferation and promotes apoptosis by targeting PPP1R15B in keratinocytes.

Although deregulated circulatory miRNA signatures during diabetes have been identified for some years now, the effects of such miRNAs on several target tissues are not yet thoroughly investigated. The skin that is nourished by components present in the circulation exhibits several notable abnormal features during diabetes. We, therefore, hypothesized that such altered circulatory miRNA levels might be critical in the onset and progression of impaired skin health during diabetes.

Hypothalamic microinflammation: a common basis of metabolic syndrome and aging.

Chronic microinflammation is a hallmark of many aging-related neurodegenerative diseases as well as metabolic syndrome-driven diseases. Recent research indicates that chronic caloric excess can lead to hypothalamic microinflammation, which in turn participates in the development and progression of metabolic syndrome disorders such as obesity, glucose intolerance, and hypertension. Additionally, it was recently shown that increasing age after young adulthood can cause hypothalamic microinflammation independently of nutritional status, mediating a central mechanism of systemic aging.

Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response.

The brain, in particular the hypothalamus, plays a role in regulating glucose homeostasis; however, it remains unclear whether this organ is causally and etiologically involved in the development of diabetes. Here, we found that hypothalamic transforming growth factor-β (TGF-β) production is excessive under conditions of not only obesity but also aging, which are two general etiological factors of type 2 diabetes. Pharmacological and genetic approaches revealed that central TGF-β excess caused hyperglycemia and glucose intolerance independent of a change in body weight.

Control of obesity and glucose intolerance via building neural stem cells in the hypothalamus.

Neural stem cells (NSCs) were recently revealed to exist in the hypothalamus of adult mice. Here, following our observation showing that a partial loss of hypothalamic NSCs caused weight gain and glucose intolerance, we studied if NSCs-based cell therapy could be developed to control these disorders. While hypothalamus-implanted NSCs failed to survive in mice with obesity, NF-κB inhibition induced survival and neurogenesis of these cells, leading to effects in counteracting obesity and glucose intolerance.

Neuroinflammatory basis of metabolic syndrome.

Inflammatory reaction is a fundamental defense mechanism against threat towards normal integrity and physiology. On the other hand, chronic diseases such as obesity, type 2 diabetes, hypertension and atherosclerosis, have been causally linked to chronic, low-grade inflammation in various metabolic tissues. Recent cross-disciplinary research has led to identification of hypothalamic inflammatory changes that are triggered by overnutrition, orchestrated by hypothalamic immune system, and sustained through metabolic syndrome-associated pathophysiology.

A New Horizon: Oxytocin as a Novel Therapeutic Option for Obesity and Diabetes.

The story of oxytocin (OXT) began long ago in evolutionary terms with its recognition as a classical neurohypophyseal hormone important for lactation and uterine contraction. With the recent discovery of its local actions in the brain, its previously-unappreciated diverse functions in regulating social behaviors and metabolic physiology are emerging. In light of metabolic control, OXT has been shown to induce feeding restriction and body weight lowering through acting on brain regulatory regions, in particular the hypothalamus.

Disruption of neurogenesis by hypothalamic inflammation in obesity or aging.

Adult neural stem cells contribute to neurogenesis and plasticity of the brain which is essential for central regulation of systemic homeostasis. Damage to these homeostatic components, depending on locations in the brain, poses threat to impaired neurogenesis, neurodegeneration, cognitive loss and energy imbalance. Recent research has identified brain metabolic inflammation via proinflammatory IκB kinase-β (IKKβ) and its downstream nuclear transcription factor NF-κB pathway as a non-classical linker of metabolic and neurodegenerative disorders.

Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH.

Ageing is a result of gradual and overall functional deteriorations across the body; however, it is unknown whether an individual tissue primarily works to mediate the ageing progress and control lifespan. Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IκB kinase-β (IKK-β), nuclear factor κB (NF-κB) and related microglia-neuron immune crosstalk. Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-β and NF-κB activation.

Clozapine functions through the prefrontal cortex serotonin 1A receptor to heighten neuronal activity via calmodulin kinase II-NMDA receptor interactions.

Aberrant dopamine release in the prefrontal cortex (PFC) is believed to underlie schizophrenia, but the mechanistic pathway through which a widely used antipsychotic, clozapine (Clz), evokes neurotransmitter-releasing electrical stimulation is unclear. We analyzed Clz-evoked regulation of neuronal activity in the PFC by stimulating axons in layers IV and V and recording the electrical effect in the post-synaptic pyramidal cells of layers II and III. We observed a Clz-evoked increase in population spike (PS), which was mediated by serotonin 1A receptor (5-HT(1A)-R), phospholipase Cβ, and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII).

Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning.

The molecule responsible for the enzyme activity plasma membrane (PM) aminophospholipid translocase (APLT), which catalyzes phosphatidylserine (PS) translocation from the outer to the inner leaflet of the plasma membrane, is unknown in mammals. A Caenorhabditis elegans study has shown that ablation of transbilayer amphipath transporter-1 (TAT-1), which is an ortholog of a mammalian P-type ATPase, Atp8a1, causes PS externalization in the germ cells. We demonstrate here that the hippocampal cells of the dentate gyrus, and Cornu Ammonis (CA1, CA3) in mice lacking Atp8a1 exhibit a dramatic increase in PS externalization.

Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB.

Obesity-related hypertension has become an epidemic health problem and a major risk factor for the development of cardiovascular disease (CVD). Recent research on the pathophysiology of obesity has implicated a role for the hypothalamus in the pathogenesis of this condition. However, it remains unknown whether the often-seen coupling of hypertension with obesity can also be explained by hypothalamic dysfunction, despite the emerging appreciation that many forms of hypertension are neurogenic in origin.

Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress.

Chronic endoplasmic reticulum (ER) stress was recently revealed to affect hypothalamic neuroendocrine pathways that regulate feeding and body weight. However, it remains unexplored whether brain ER stress could use a neural route to rapidly cause the peripheral disorders that underlie the development of type 2 diabetes (T2D) and the metabolic syndrome. Using a pharmacologic model that delivered ER stress inducer thapsigargin into the brain, this study demonstrated that a short-term brain ER stress over 3 d was sufficient to induce glucose intolerance, systemic and hepatic insulin resistance, and blood pressure (BP) increase.

Regulation of protein kinase C isozymes during early postnatal hippocampal development.

During neonatal hippocampal development, serotonin 1A receptor-mediated signaling initially employs PKCepsilon to boost neuronal proliferation and then uses PKCalpha to promote synaptogenesis. Such stage-specific involvement of a PKC isozyme could be determined by its relative expression level. In mouse hippocampi, we detected relatively low levels of alpha, beta, gamma, and delta isozymes at postnatal days 2-6 (P2-6), which was followed by a large increase in their expression.

Curcumin blocks brain tumor formation.

Turmeric, an essential ingredient of culinary preparations of Southeast Asia, contains a major polyphenolic compound, named curcumin or diferuloylmethane, which eliminates cancer cells derived from a variety of peripheral tissues. Although in vitro experiments have addressed its anti-tumor property, no in vivo studies have explored its anti-cancer activity in the brain. Oral delivery of this food component has been less effective because of its low solubility in water.

E6-AP promotes misfolded polyglutamine proteins for proteasomal degradation and suppresses polyglutamine protein aggregation and toxicity.

The accumulation of intracellular protein deposits as inclusion bodies is the common pathological hallmark of most age-related neurodegenerative disorders including polyglutamine diseases. Appearance of aggregates of the misfolded mutant disease proteins suggest that cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular quality control system. Recently, the quality control ubiquitin ligase CHIP has been shown to suppress the polyglutamine protein aggregation and toxicity.

Modulation of gastric mucosal mast cell population: role of vestibulo cerebellar lesion.

Posterior cerebellar lesion induced severe focal inflammatory ulcers at the stomach associated with extensive damage of the surface epithelial cells, leading to focal necrotic ulcers. The ulcer index increased maximally and progressively between day 7 and day 14 after lesion. The total mucosal mast cell and degranulated mucosal mast cell increased maximally on day 7 and progressively declined from day 14 to day 21.

Vestibulo-cerebellar participation in protection of duodenal mucosa: possible role of neurotransmitters.

Vestibulo cerebellar lesion in rats produced a decrease in the intracellular presecreted mucus together with a decrease in the norepinephrine (NE) and serotonin (5HT) content of the duodenal tissue. Whereas vestibulo cerebellar stimulation by rotation produced an increase in the intracellular presecreted mucus and an increase in the NE content of the duodenal tissue but very little increase in 5HT content of the duodenum. The results suggest that the vestibulo cerebellum by modulating the tissue content of the neurotransmitter NE and 5HT has a direct influence in the protective mechanism through the intracellular mucus content.