A Whole-Brain Connectivity Map of VTA and SNc Glutamatergic and GABAergic Neurons in Mice

The glutamatergic and GABAergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) mediated diverse brain functions. However, their whole-brain neural connectivity has not been comprehensively mapped. Here we used the virus tracers to characterize the whole-brain inputs and outputs of glutamatergic and GABAergic neurons in VTA and SNc. We found that these neurons received similar inputs from upstream brain regions, but some quantitative differences were also observed. Neocortex and dorsal striatum provided a greater share of input to VTA glutamatergic neurons. Periaqueductal gray and lateral hypothalamic area preferentially innervated VTA GABAergic neurons. Specifically, superior colliculus provided the largest input to SNc glutamatergic neurons. Compared to input patterns, the output patterns of glutamatergic and GABAergic neurons in the VTA and SNc showed significant preference to different brain regions. Our results laid the anatomical foundation for understanding the functions of cell-type-specific neurons in VTA and SNc.

Ontogeny of the Projections From the Dorsomedial Division of the Anterior Bed Nucleus of the Stria Terminalis to Hypothalamic Nuclei

The bed nucleus of the stria terminalis (BNST) is a telencephalic structure well-connected to hypothalamic regions known to control goal-oriented behaviors such as feeding. In particular, we showed that the dorsomedial division of the anterior BNST innervate neurons of the paraventricular (PVH), dorsomedial (DMH), and arcuate (ARH) hypothalamic nuclei as well as the lateral hypothalamic area (LHA). While the anatomy of these projections has been characterized in mice, their ontogeny has not been studied. In this study, we used the DiI-based tract tracing approach to study the development of BNST projections innervating several hypothalamic areas including the PVH, DMH, ARH, and LHA. These results indicate that projections from the dorsomedial division of the anterior BNST to hypothalamic nuclei are immature at birth and substantially reach the PVH, DMH, and the LHA at P10. In the ARH, only sparse fibers are observed at P10, but their density increased markedly between P12 and P14. Collectively, these findings provide new insight into the ontogeny of hypothalamic circuits, and highlight the importance of considering the developmental context as a direct modulator in their proper formation.

Compulsive Eating in a Rat Model of Binge Eating Disorder Under Conditioned Fear and Exploration of Neural Mechanisms With c-fos mRNA Expression

Compulsive eating is the most obstinate feature of binge eating disorder. In this study, we observed the compulsive eating in our stress-induced binge-like eating rat model using a conflicting test, where sucrose and an aversively conditioned stimulus were presented at the same time. In this conflicting situation, the binge-like eating prone rats (BEPs), compared to the binge-like eating resistant rats (BERs), showed persistent high sucrose intake and inhibited fear response, respectively, indicating a deficit in palatability devaluation and stronger anxiolytic response to sucrose in the BEPs. We further analyzed the neuronal activation with c-fos mRNA in situ hybridization. Surprisingly, the sucrose access under conditioned fear did not inhibit the activity of amygdala; instead, it activated the central amygdala. In the BEPs, sucrose reduced the response of the paraventricular hypothalamic nucleus (PVN), while enhancing activities in the lateral hypothalamic area (LHA) to the CS. The resistance to devaluating the palatable food in the BEPs could be a result of persistent Acb response to sucrose intake and attenuated recruitment of the medial prefrontal cortex (mPFC). We interpret this finding as that the reward system of the BEPs overcame the homeostasis system and the stress-responding system.

The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam or etoricoxib (10 mg/kg for both) and, 30 minutes later, treated with icv CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ~0.4°C from 10 min post-infusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ~70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ~50% in both); all these changes were all completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg; icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways, and that the activation of COX-2 is required for the development of this response.

Gabra5LHA Mediate Astrocytic GABA-induced Obesity via Decreasing Energy Expenditure

The lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (Gabra5LHA) polysynaptically project to brown and white adipose tissues in the periphery. Gabra5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Gene silencing of Gabra5 in LHA decreases weight gain, whereas chemogenetic inhibition of LHA suppresses energy expenditure and increases weight gain. In DIO mouse model, Gabra5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Administration of a MAOB inhibitor, KDS2010 reduces weight gain significantly without affecting food intake, which is recapitulated by gene-silencing of astrocytic MAOB in LHA. We propose that firing of Gabra5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

Whole Brain Mapping of Neurons Innervating Extraorbital Lacrimal Glands in Mice and Rats of Both Genders

The extraorbital lacrimal glands (ELGs) secret tears to maintain a homeostatic environment for ocular surfaces, and pheromones to mediate social interactions. Although its distinct gender-related differences in mice and rats have been identified, its comprehensive histology together with whole-brain neuronal network remain largely unknown. The primary objective of the present study was to investigate whether sex-specific differences take place in histological and physiological perspectives. Morphological and histological data were obtained via magnetic resonance imaging (MRI), hematoxylin-eosin (HE) staining in mice and rats of both genders. The innervating network was visualized by a pseudorabies virus (PRV) mediated retrograde trans-multi-synaptic tracing system for adult C57BL6/J mice of both genders. In terms of ELGs' anatomy, mice and rats across genders both have 7 main lobes, with one exception observed in female rats which have only 5 lobes. Both female rats and mice generally have relatively smaller shape size, absolute weight, and cell size than males. Our viral tracing revealed a similar trend of innervating patterns antero-posteriorly, but significant gender differences were also observed in the hypothalamus (HY), olfactory areas (OLF), and striatum (STR). Brain regions including piriform area (Pir), post-piriform transition area (TR), central amygdalar nucleus (CEA), medial amygdalar nucleus (MEA), lateral hypothalamic area (LHA), parasubthalamic nucleus (PSTN), pontin reticular nucleus (caudal part) (PRNc), and parabrachial nucleus, (PB) were commonly labeled. In addition, chemical isotope labeling-assisted liquid chromatography-mass spectrometry (CIL-LC-MS) and nuclear magnetic resonance spectroscopy (NMR spectroscopy) were performed to reveal the fatty acids and metabolism of the ELGs, reflecting the relationship between pheromone secretion and brain network. Overall, our results revealed basic properties and the input neural networks for ELGs in both genders of mice, providing a structural basis to analyze the diverse functions of ELGs.

Hypersexuality as a Manifestation of Various Disorders

The article deals with hypersexuality, which can be a manifestation of a wide variety of disorders. These include: consequences of a psychotrauma; premature psychosexual development; borderline personality disorder; submaniac and maniac states in bipolar affective disorder and schizoaffective type of the course of schizophrenia; disinhibition of libido, rough and naked eroticism in the initial stage of schizophrenia; consequence of advanced emotional volitional disorders in simple-type schizophrenia; temporal lobe epilepsy; dementia; mental retardation (oligophrenias); various organic brain lesions (resulting from neuroinfections, injuries, vascular damages, neoplasms) [the temporal and frontal lobes of the brain are indicated as regulators of libido]; consequence of disorders in the hypothalamic area and limbic system. It is reported that a correlation exists between development of hypersexuality and damages in certain cerebral areas in patients with non-traumatic brain damage. It is pointed out that hypersexuality may result from maldevelopment of the right hippocampus, anti-NMDA receptor encephalitis, in patients with disseminated sclerosis, Huntington’s disease, Kluver-Bucy syndrome as well as be caused by various hormonal disorders and consequences of premenstrual changes and effect of virilizing hormones during the childhood or intrauterine period. Numerous clinical illustrations of cases with hypersexuality, caused by various disorders, are given. The author holds the opinion that it is necessary to divide hypersexuality at least into two categories: true hypersexuality and sexual disinhibition, when with the normal or even reduced level of libido manifestation the hypersexual behaviour results from absence or insufficiency of inhibitory mechanisms (for example, in dementia).

Identification of a discrete neuronal circuit that relays insulin signaling into the brain to regulate glucose homeostasis

26RFa (QRFP) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localized in the hypothalamus. In the present study, we have investigated whether the 26RFa neurons may be involved in the hypothalamic regulation of glucose homeostasis. Our data indicate that 26RFa, i.c.v. injected, induces a robust antihyperglycemic effect associated with an increase of insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26RFa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26RFa in the lateral hypothalamic area and the ventromedial hypothalamic nucleus also express the insulin receptor and that insulin induces the expression of 26RFa in these neurons. Concurrently, we show that the central antihyperglycemic effect of insulin is abolished in presence of a 26RFa receptor (GPR103) antagonist as well as in mice deficient for 26RFa. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. To conclude, in the present study we have identified a novel actor of the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system and we provide the evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.