Leptin-mediated suppression of food intake by conserved Glp1r-expressing neurons prevents obesity

The adipose-derived hormone leptin acts via its receptor (LepRb) in the brain to control energy balance. A previously unidentified population of GABAergic hypothalamic LepRb neurons plays key roles in the restraint of food intake and body weight by leptin. To identify markers for candidate populations of LepRb neurons in an unbiased manner, we performed single-nucleus RNA-sequencing of enriched mouse hypothalamic LepRb cells, as well as with total hypothalamic cells from multiple mammalian species. In addition to identifying known LepRb neuron types, this analysis identified several previously unrecognized populations of hypothalamic LepRb neurons. Many of these populations display strong conservation across species, including GABAergic Glp1r-expressing LepRb (LepRbGlp1r) neurons that express more Lepr and respond more robustly to exogenous leptin than other LepRb populations. Ablating LepRb from these cells provoked hyperphagic obesity without impairing energy expenditure. Conversely, reactivating LepRb in Glp1r-expressing cells decreased food intake and body weight in otherwise LepRb-null mice. Furthermore, LepRb reactivation in GABA neurons improved energy balance in LepRb-null mice, and this effect required the expression of LepRb in GABAergic Glp1r-expressing neurons. Thus, the conserved GABAergic LepRbGlp1r neuron population plays crucial roles in the control of food intake and body weight by leptin.

Controlling Alzheimer’s Disease Through the Deep Brain Stimulation to Thalamic Relay Cells

Experimental and clinical studies have shown that the technique of deep brain stimulation (DBS) plays a potential role in the regulation of Alzheimer’s disease (AD), yet it still desires for ongoing studies including clinical trials, theoretical approach and action mechanism. In this work, we develop a modified thalamo-cortico-thalamic (TCT) model associated with AD to explore the therapeutic effects of DBS on AD from the perspective of neurocomputation. First, the neuropathological state of AD resulting from synapse loss is mimicked by decreasing the synaptic connectivity strength from the Inter-Neurons (IN) neuron population to the Thalamic Relay Cells (TRC) neuron population. Under such AD condition, a specific deep brain stimulation voltage is then implanted into the neural nucleus of TRC in this TCT model. The symptom of AD is found significantly relieved by means of power spectrum analysis and nonlinear dynamical analysis. Furthermore, the therapeutic effects of DBS on AD are systematically examined in different parameter space of DBS. The results demonstrate that the controlling effect of DBS on AD can be efficient by appropriately tuning the key parameters of DBS including amplitude A, period P and duration D. This work highlights the critical role of thalamus stimulation for brain disease, and provides a theoretical basis for future experimental and clinical studies in treating AD.

Spinal neurons innervating multiple local and distant motor pools

Motor neurons control muscle contractions, and their recruitment by premotor circuits is tuned to produce accurate motor behaviours. To understand how these circuits coordinate movement across and between joints, it is necessary to understand whether spinal neurons pre-synaptic to motor pools, project to more than one motor neuron population. Here, we used modified rabies virus tracing in mice to investigate premotor INs projecting to synergist flexor or extensor motor neurons, as well as those projecting to antagonist pairs of muscles controlling the ankle joint. We show that similar proportions of premotor neurons diverge to agonist and antagonist motor pools. Divergent premotor neurons were seen throughout the spinal cord, with decreasing numbers but increasing proportion with distance from the hindlimb enlargement. In the cervical cord, divergent long descending propriospinal neurons were found in contralateral lamina VIII, had large somata, were excitatory, projected to both lumbar and cervical motoneurons, and were at least in part of the V0 class. We conclude that distributed spinal premotor neurons coordinate activity across multiple motor pools and that there are spinal neurons mediating co-contraction of antagonist muscles.

Orexin neuron activity in mating mice - a pilot study

Mating behaviours affect hypothalamic orexin/hypocretin neurons and vice versa. However, activity of orexin neurons has not been recorded during mating before. We report an anecdotal dataset of freely-moving miniature microscope recordings of orexin neuron activity during mating behaviours, as well as an oral sexual encounter previously undocumented in mice. Across the orexin neuron population in the male, firing rates were maximally diverse during ejaculation, similarly diverse though weaker during intromission, and inverse to this during anterior thrusting. In the female mouse, orexin neurons tended to decrease firing during intromission after a transient increase. We provide this brief dataset for re-use, to enable further studies of these rare behaviours with challenging surgical preparations.

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

Post-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission. We have recently demonstrated projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) can regulate dopamine neuron activity in the ventral tegmental area (VTA). Specifically, inactivation of the PVT leads to a reversal of aberrant dopamine system function and psychosis-like behavior. The PVT receives dense innervation from orexin containing neurons, therefore, targeting orexin receptors may be a novel approach to restore dopamine neuron activity and alleviate PTSD-associated psychosis. In this study, we induced stress-related pathophysiology in male Sprague Dawley rats using an inescapable foot-shock procedure. We observed a significant increase in VTA dopamine neuron population activity, deficits in sensorimotor gating, and hyperresponsivity to psychomotor stimulants. Administration of selective orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) antagonists (SB334867 and EMPA, respectively) or the FDA-approved, dual-orexin receptor antagonist, Suvorexant, were found to reverse stress-induced increases in dopamine neuron population activity. However, only Suvorexant and SB334867 were able to reverse deficits in behavioral corelates of psychosis. These results suggest that the orexin system may be a novel pharmacological target for the treatment of comorbid psychosis related to PTSD.

Mice hypomorphic for Pitx3 define a minimal dopamine neuron population sufficient for entraining behavior and metabolism to scheduled feeding

SummaryPitx3ak mice lack a functioning retina and nearly all dopamine neurons of the substantia nigra (SN). del Rio-Marten et al (2019) reported that entrainment of circadian rhythms to daily light-dark and feeding schedules is absent in these mice. With food limited to 12h/day, food anticipatory circadian rhythms failed to emerge, and metabolic rhythms failed to synchronize with locomotor and feeding rhythms. The authors propose that retinal innervation of the suprachiasmatic nucleus clock is required for development of cyclic metabolic homeostasis, but methodological issues limit interpretation of the results. Using standardized feeding schedules and procedures for distinguishing free-running from entrained circadian rhythms, we confirm that behavioral and metabolic rhythms in Pitx3ak mice do not entrain to LD cycles, but we find no desynchrony between these rhythms nor a deficit in entrainment to daily feeding schedules. SN dopamine neurons surviving in Pitx3ak mice may define a mininum population sufficient for food entrainment.

A closed-loop optogenetic screen for neurons controlling feeding in Drosophila

Feeding is an essential part of animal life that is impacted greatly by the sense of taste. Although the characterization of taste-detection at the periphery is extensive, higher-order taste and feeding circuits are still being elucidated. Here, we use an automated closed-loop optogenetic activation screen for novel taste and feeding neurons in Drosophila melanogaster. Out of 122 Janelia FlyLight Project GAL4 lines preselected based on expression pattern, we identify six lines that acutely promote feeding and 35 lines that inhibit it. As proof of principle, we follow up on the R70C07-GAL4 neuron population, which strongly inhibits feeding. Using split-GAL4 lines to isolate subsets of the R70C07-GAL4 population, we find both appetitive and aversive neurons. We also show that R70C07-GAL4 labels a population of putative second-order taste interneurons that contact both sweet and bitter sensory neurons. These results serve as a resource for further functional dissection of fly feeding circuits.