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.

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Modulate the Anesthetic Potency of Isoflurane in Mice

The lateral hypothalamic area (LHA) plays a pivotal role in regulating consciousness transition, in which orexinergic neurons, GABAergic neurons, and melanin-concentrating hormone neurons are involved. Glutamatergic neurons have a large population in the LHA, but their anesthesia-related effect has not been explored. Here, we found that genetic ablation of LHA glutamatergic neurons shortened the induction time and prolonged the recovery time of isoflurane anesthesia in mice. In contrast, chemogenetic activation of LHA glutamatergic neurons increased the time to anesthesia and decreased the time to recovery. Optogenetic activation of LHA glutamatergic neurons during the maintenance of anesthesia reduced the burst suppression pattern of the electroencephalogram (EEG) and shifted EEG features to an arousal pattern. Photostimulation of LHA glutamatergic projections to the lateral habenula (LHb) also facilitated the emergence from anesthesia and the transition of anesthesia depth to a lighter level. Collectively, LHA glutamatergic neurons and their projections to the LHb regulate anesthetic potency and EEG features.

Migraine and orexin

Migraine is diagnosed in approximately 15% of the population in the developed countries. This disease affects not only patient’s well-being, but also economy and social sphere. Despite this significant impact, little is known on the genetic causes of migraine. Several migraine symptoms, including tiredness, yawning, drowsiness, and the desire to eat certain foods, give an idea of migraine connection to orexin system. This system includes orexines – peptides, predominantly synthesized in the lateral hypothalamic area and involved in wake and sleep cycle and many other neurological functions; and their two receptors HCRTR1 and HCRTR2. Here we summarize known data on orexin system polymorphisms and changes in peptide concentration in patients with migraine.

κ-Opioid Signaling in the Lateral Hypothalamic Area Modulates Nicotine-Induced Negative Energy Balance

Several studies have reported that nicotine, the main bioactive component of tobacco, exerts a marked negative energy balance. Apart from its anorectic action, nicotine also modulates energy expenditure, by regulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. These effects are mainly controlled at the central level by modulation of hypothalamic neuropeptide systems and energy sensors, such as AMP-activated protein kinase (AMPK). In this study, we aimed to investigate the kappa opioid receptor (κOR)/dynorphin signaling in the modulation of nicotine’s effects on energy balance. We found that body weight loss after nicotine treatment is associated with a down-regulation of the κOR endogenous ligand dynorphin precursor and with a marked reduction in κOR signaling and the p70 S6 kinase/ribosomal protein S6 (S6K/rpS6) pathway in the lateral hypothalamic area (LHA). The inhibition of these pathways by nicotine was completely blunted in κOR deficient mice, after central pharmacological blockade of κOR, and in rodents where κOR was genetically knocked down specifically in the LHA. Moreover, κOR-mediated nicotine effects on body weight do not depend on orexin. These data unravel a new central regulatory pathway modulating nicotine’s effects on energy balance.

Specific pattern of melanin-concentrating hormone (MCH) neuron degeneration in Alzheimer’s disease and possible clinical implications

ABSTRACTStudy ObjectivesThe lateral hypothalamic area (LHA) is one of the key regions orchestrating sleep and wake control. It is the site of wake-promoting orexinergic and sleep-promoting melanin-concentrating hormone (MCH) neurons, which share a close anatomical and functional relation. The aim of the study was to investigate the degeneration of MCH neurons in Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP), and relate the new findings to our previously reported pattern of degeneration of wake-promoting orexinergic neuronsMethodsPost-mortem human brain tissue of subjects with AD, PSP and controls was examined using unbiased stereology. Double immunohistochemistry with MCH- and tau-antibodies on formalin-fixed, celloidin embedded tissue was performed.ResultsThere was no difference in the total number of MCH neurons between AD, PSP and controls, but a significant loss of non-MCH neurons in AD patients (p=0.019). The proportion of MCH neurons was significantly higher in AD (p=0.0047). No such a difference was found in PSP. In PSP, but not AD, the proportion of tau+ MCH neurons was lower than the proportion of tau+ non-MCH neurons (p=0.002). When comparing AD to PSP, the proportion of tau+MCH neurons was higher in AD (p<0.001).ConclusionsMCH neurons are more vulnerable to AD than PSP pathology. High burden of tau-inclusions, but comparably milder loss of MCH neurons in AD, together with previously reported orexinergic neuronal loss may lead to a hyperexcitability of the MCH system in AD, contributing to wake-sleep disorders in AD. Further experimental research is needed to understand why MCH neurons are more resistant to tau-toxicity compared to orexinergic neurons.STATEMENT OF SIGNIFICANCEThis is the first study to investigate the involvement of melanin-concentrating hormone (MCH) neurons in patients with Alzheimer’s disease and progressive supranuclear palsy. MCH neurons are key regulators of sleep and metabolic functions, and one of the major neuronal populations of the lateral hypothalamic area (LHA), but still underexplored in humans. Uncovering the pathology of this neuronal population in neurodegenerative disorders will improve our understanding of the complex neurobiology of the LHA and the interaction between MCH and orexinergic neurons. This new knowledge may open new strategies for treatment interventions. Further, this study represents a fundament for future research on MCH neurons and the LHA in tauopathies.