Glucose is the essential energy source for the brain, whose deficit, triggered by energy deprivation or therapeutic agents, can be fatal. Increased appetite is the key behavioral defense against hypoglycemia; however, the central pathways involved are not well understood. Here, we describe a glucoprivic feeding pathway by tyrosine hydroxylase (TH)-expressing neurons from nucleus of solitary tract (NTS), which project densely to the hypothalamus and elicit feeding through bidirectional adrenergic modulation of agouti-related peptide (AgRP)-and proopiomelanocortin (POMC)-expressing neurons. Acute chemogenetic inhibition of arcuate nucleus (ARC)-projecting NTS TH neurons or their target, AgRP neurons, impaired glucoprivic feeding induced by 2-Deoxy-D-glucose (2DG) injection. Neuroanatomical tracing results suggested that ARC-projecting orexigenic NTS TH neurons are largely distinct from neighboring catecholamine neurons projecting to parabrachial nucleus (PBN) that promotes satiety. Collectively, we describe a circuit organization in which an ascending pathway from brainstem stimulates appetite through key hunger neurons in the hypothalamus in response to hypoglycemia.

Background: Melanin-concentrating hormone (MCH)-expressing neurons have been implicated in regulation of energy homeostasis and reward, yet the role of their electrical activity in short-term appetite and reward modulation has not been fully understood. Objectives: We investigated short-term behavioral and physiological effects of MCH neuron activity manipulations. Methods: We used optogenetic and chemogenetic approaches in Pmch-cre transgenic mice to acutely stimulate/inhibit MCH neuronal activity while probing feeding, locomotor activity, anxiety-like behaviors, glucose homeostasis, and reward. Results: MCH neuron activity is neither required nor sufficient for short-term appetite unless stimulation is temporally paired with consumption. MCH neuronal activation does not affect short-term locomotor activity, but inhibition improves glucose tolerance and is mildly anxiolytic. Finally, using two different operant tasks, we showed that activation of MCH neurons alone is sufficient to induce reward. Conclusions: Our results confirm diverse behavioral/physiological functions of MCH neurons and suggest a direct role in reward function.

Oligodendrocyte precursor cells (OPCs) represent the most abundant group of proliferating cells in the adult central nervous system. OPCs serve as progenitors for oligodendrocyte (OLs) throughout the life, and contribute to developmental and adaptive myelination, and myelin repair during diseased state. OPCs make synaptic and extra-synaptic contacts with axons, and detect and respond to neuronal activity. How OPCs translate the information relayed by the neuronal activity into Ca2+ signals, which in turn influence their fate and survival, is less understood. We developed novel transgenic mouse lines expressing a cytosolic and membrane anchored variants of genetically encoded Ca2+ sensors (GCaMP6f or mGCaMP6s) in OPCs, performed 2-photon microscopy in the somatosensory cortex of the awake behaving mice, and simultaneously monitored intracellular Ca2+ signals and their cell-fate progression. We found Ca2+ signals in OPCs mainly occur within processes and confine to micrometer-size segments called Ca2+ microdomains. Microdomain Ca2+ signals enhanced in OPCs when mice engage in exploratory behavior. OPCs exhibit distinct Ca2+ signals while they proliferate to maintain their precursor pool or differentiate to generate new OL. When mice engaged in exploratory behavior, the cortical projections of noradrenergic neurons in locus coeruleus showed increased firing rate and norepinephrine release. Norepinephrine activated all three subtypes of alpha1 adrenergic receptor expressed by OPCs and evoked intracellular Ca2+ increase in OPCs. A chemogenetic activation of noradrenergic neurons, promoted differentiation of cortical OPCs into OL, and at the same time suppressed OPC proliferation rate. Hence, we uncovered that various cell types of oligodendrocyte lineage exhibits unique signatures of Ca2+ activity, which these cells might integrate for making their fate decisions, and norepinephrine signaling can be a potent regulator of OPC fate.

Several forms of chronic pain do not respond to the conventional analgesics, such as opioids, but can be treated with antidepressants, such as serotonin and noradrenalin reuptake inhibitors (SNRIs). Recent studies indicate that noradrenalin signalling is a key target for SNRI-induced analgesia in neuropathic pain. SNRIs inhibit chronic pain by blocking reuptake of noradrenalin and subsequent activation of adrenergic receptors on neurons in the dorsal horn of the spinal cord. However, in the nervous system, various subtypes of adrenergic receptors are highly expressed by astrocytes and microglial cells. Activation of these receptors on astrocytes engages complex intracellular signalling pathways and prevents inflammatory changes of microglia, which in turn can affect neuronal activity. Hence, SNRIs-induced modulations of the glial cell physiology can impact neural circuit functions and pain perception. In this review, we summarize our current knowledge on the impact of SNRIs on glial cells and in modulating chronic pain in experimental animal models.