Hypothalamic adult neurogenesis provides the basis for renewal of neurons involved in the regulation of whole-body energy status. In addition to hormones, cytokines and growth factors, components of the diet, particularly fatty acids, have been shown to stimulate hypothalamic neurogenesis; however, the mechanisms behind this action are unknown. Here, we hypothesized that GPR40 (FFAR1), the receptor for medium and long chain unsaturated fatty acids, could mediate at least part of the neurogenic activity in the hypothalamus. We show that a GPR40 ligand increased hypothalamic cell proliferation and survival in adult mice. In postnatal generated neurospheres, acting in synergy with brain-derived neurotrophic factor (BDNF) and interleukin 6, GPR40 activation increased the expression of doublecortin during the early differentiation phase and of the mature neuronal marker, microtubule-associated protein 2 (MAP2), during the late differentiation phase. In Neuro-2a proliferative cell-line GPR40 activation increased BDNF expression and p38 activation. The chemical inhibition of p38 abolished GPR40 effect in inducing neurogenesis markers in neurospheres, whereas BDNF immunoneutralization inhibited GPR40-induced cell proliferation in the hypothalamus of adult mice. Thus, GPR40 acts through p38 and BDNF to induce hypothalamic neurogenesis. This study provides mechanistic advance in the understating of how a fatty acid receptor regulates adult hypothalamic neurogenesis. Neurons of the mediobasal hypothalamus play central roles in the homeostatic control of food intake and energy expenditure 1,2. They are responsive to hormones, neural signals, and nutrients that indicate the energy stores in the body; as long as orexigenic and anorexigenic responses are preserved, body mass stability is sustained over time 3-5. However, a number of environmental and genetic factors can affect the function and viability of hypothalamic neurons, changes that result in abnormal regulation of body mass 6-9. In aging and obesity, hypothalamic neurons are damaged by inflammation; they undergo abnormal function and eventually apoptosis 10-15. This phenomenon generates an imbalance in neuronal orexigenic and anorexigenic subpopulations and further contributes to the progression of increased adiposity and metabolic complications 10-15. If neuronal loss is prevented by modifications in the diet or inhibition of hypothalamic inflammation, whole body energy homeostasis is restored 8,15. However, upon long-lasting exposure to the damaging effects of obesity and aging, neuronal loss may be reverted only by the generation of new neurons 16,17. Physiological adult hypothalamic neurogenesis occurs at a much lower rate than neurogenesis in the subventricular and subgranular zones, the most important anatomical sources of newborn neurons in adulthood 18. Nevertheless, under certain types of stimuli, hypothalamic neurogenesis can increase substantially and impact whole body energy homeostasis 9,12,17. This phenomenon occurs for stimuli provided by growth factors,...

Under high-fat feeding, the hypothalamus atypically undergoes pro-inflammatory signaling activation. Recent data from transcriptomic analysis of microglia from rodents and humans has allowed the identification of several microglial subpopulations throughout the brain. Numerous studies have clarified the roles of these cells in hypothalamic inflammation, but how each microglial subset plays its functions upon inflammatory stimuli remains unexplored. Fortunately, these data unveiling microglial heterogeneity have triggered the development of novel experimental models for studying the roles and characteristics of each microglial subtype. In this review, we explore microglial heterogeneity in the hypothalamus and their crosstalk with astrocytes under high fat diet–induced inflammation. We present novel currently available ex vivo and in vivo experimental models that can be useful when designing a new research project in this field of study. Last, we examine the transcriptomic data already published to identify how the hypothalamic microglial signature changes upon short-term and prolonged high-fat feeding.

Glutamic acid is the main excitatory neurotransmitter acting both in the brain and in peripheral tissues. Abnormal distribution of glutamic acid receptors occurs in skin hyperproliferative conditions such as psoriasis and skin regeneration; however, the biological function of glutamic acid in the skin remains unclear. Using ex vivo, in vivo and in silico approaches, we showed that exogenous glutamic acid promotes hair growth and keratinocyte proliferation. Topical application of glutamic acid decreased the expression of genes related to apoptosis in the skin, whereas glutamic acid increased cell viability and proliferation in human keratinocyte cultures. In addition, we identified the keratinocyte glutamic acid excitotoxic concentration, providing evidence for the existence of a novel skin signalling pathway mediated by a neurotransmitter that controls keratinocyte and hair follicle proliferation. Thus, glutamic acid emerges as a component of the peripheral nervous system that acts to control cell growth in the skin. These results raise the perspective of the pharmacological and nutritional use of glutamic acid to treat skin diseases.

Currently, experimental animals are widely used in biological and medical research. However, the scientific community has raised several bioethical concerns, such as the number of animals required to achieve reproducible and statistically relevant results. These concerns involve aspects related to pain, discomfort, and unwanted animal loss. Retrospectively, we compare two different approaches for anesthesia dosage: a mobile app for dose calculation and a standard dose calculation. A total of 939 C57BL/6J and Swiss mice were analyzed. We collected data on intraoperative and anesthesia-related mortality as described in electronic or physical handwritten records. Our results showed that the mobile app approach significantly reduces anesthetic-related deaths upon using doses of ketamine and xylazine. The results suggest that anesthesia-related mortality can be minimized even more using information technology approaches, helping to solve an old but transversal challenge for researchers working with experimental mice. The mobile app is a free and open code which could be implemented worldwide as an essential requirement for all anesthetic procedures in mice using xylazine and ketamine combination. As an open code app, the Labinsane initiative could also represent the starting point to unify and validate other anesthetic procedures in different species and strains.

Abstract-Cardiac tissue is densely innervated by sensory neurons that are believed to play important modulatory roles in cardiac functions. In this study, pretreatment of neonate rats with capsaicin was performed. In adult rats, cardiomyocyte size and amount of fibrous tissue in left ventricles as well as in vitro coronary flow were evaluated. The chronotropic and inotropic responses to ␤-adrenoceptor agonists (norepinephrine and isoproterenol), muscarinic agonists (carbachol and pilocarpine), and calcitonin gene-related peptide (CGRP) were also investigated with the use of the isolated right atria preparation. Capsaicin pretreatment significantly (PϽ0.05) reduced both basal coronary flow (18% reduction) and cardiomyocyte size (34% reduction) without affecting the amount of fibrous tissues in the left ventricles. The positive inotropic and chronotropic effects in response to norepinephrine in the isolated rat heart did not significantly differ between control and capsaicin-treated rats. Similarly, the positive chronotropic effects in response to norepinephrine, isoproterenol, and CGRP as well as the negative chronotropic responses to carbachol and pilocarpine in the isolated right atria were not affected by capsaicin pretreatment. Our data are consistent with the suggestion that reductions of both basal coronary flow and cardiomyocyte size seen in hearts from capsaicin-pretreated rats may be consequences of CGRP depletion. The cardiomyocyte size reduction produced by capsaicin treatment may be related to a modulatory role of CGRP as a growth factor. Key Words: capsaicin Ⅲ receptors, muscarinic Ⅲ receptors, adrenergic, beta Ⅲ neuropeptides Ⅲ peptides S ensory fibers have been associated with the control of smooth muscle tone, autonomic ganglia transmission, immunologic processes, tissue growth, 1 and heart functions. 2-5 A number of substances, including the peptides substance P and calcitonin gene-related peptide (CGRP), are released by the sensory nerve endings. 1,6 Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a highly selective neurotoxin that, on systemic administration, causes CGRP and substance P depletion from sensory neurons 7-9 and thus has largely been used to study the involvement of sensory fibers in different pathophysiological functions. 10 In the heart, capsaicin increases contractile force and spontaneous heart rate 3 as well as evokes coronary vasodilation through CGRP release. 11,12 Previous studies reported the presence of CGRP in the heart, predominantly in the right atria, followed by the left atria and right and left ventricles, 3,13 where it causes concentration-dependent and long-lasting positive inotropic and chronotropic effects in several species, 9,14 -17 including humans. 18 Although CGRP has also been described as a potent hypertrophic factor for cardiomyocytes, 19 no study has been performed to investigate the effect of CGRP depletion on cardiomyocyte size. The existence of interactions of sympathetic and parasympathetic nerves with sensory fibers in in vitro 20,21 and in vivo 22...