Thermoregulation

The secretion of cortisol in humans and corticosterone (Cort) in rodents follows a daily rhythm which is important in readying the individual for the daily active cycle and is impaired in chronic depression.  This rhythm is orchestrated by the suprachiasmatic nucleus (SCN) which governs the activity of neurons in the paraventricular nucleus of the hypothalamus that produce the corticotropin-releasing hormone (PVH^CRH neurons). The dorsomedial nucleus of the hypothalamus (DMH) serves as a crucial intermediary, being innervated by the SCN both directly and via relays in the subparaventricular zone, and projecting axons to the PVH, thereby exerting influence over the cortisol/corticosterone rhythm. However, the role and synaptic mechanisms by which DMH neurons regulate the daily rhythm of Cort secretion has not been explored. We found that either ablating or acutely inhibiting the DMH glutamatergic (DMH^Vglut2) neurons resulted in a 40-70% reduction in the daily peak of Cort. Deletion of the Vglut2 gene within the DMH produced a similar effect, highlighting the indispensable role of glutamatergic signaling. Chemogenetic stimulation of DMH^Vglut2 neurons led to an increase of Cort levels, and optogenetic activation of their terminals in the PVH in hypothalamic slices directly activated PVH^CRH neurons through glutamate release (the DMH^Vglut2 → PVH^CRH pathway). Similarly, ablating, inhibiting, or disrupting GABA transmission by DMH GABAergic (DMH^Vgat) neurons diminished the circadian peak of Cort, particularly under constant darkness conditions. Chemogenetic stimulation of DMH^Vgat neurons increased Cort, although with a lower magnitude compared to DMH^Vglut2 neuron stimulation, suggesting a role in disinhibiting PVH^CRH neurons. Supporting this hypothesis, we found that rostral DMH^Vgat neurons project directly to GABAergic neurons in the caudal ventral part of the PVH and adjacent peri-PVH area (cvPVH), which directly inhibit PVH^CRH neurons, and that activating the DMH^Vgat terminals in the cvPVH in brain slices reduced GABAergic afferent input onto the PVH^CRH neurons. Finally, ablation of cvPVH^Vgat neurons resulted in increased Cort release at the onset of the active phase, affirming the pivotal role of the DMH^Vgat → cvPVH^Vgat → PVH^CRH pathway in Cort secretion. In summary, our study delineates two parallel pathways transmitting temporal information to PVH^CRH neurons, collectively orchestrating the daily surge in Cort in anticipation of the active phase. These findings are crucial to understand the neural circuits regulating Cort secretion, shedding light on the mechanisms governing this physiological process and the coordinated interplay between SCN, DMH, and PVH.

AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles from male mice during three distinct hunger states of satiety, fasting-induced hunger, and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 18 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Measures of IRF3 activation in vitro and in vivo reveal an increase in IRF3 nuclear occupancy following leptin administration. Finally, gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons. Thus, our findings identify IRF3 as a key mediator of the acute hunger-suppressing effects of leptin in AgRP neurons.

"Many species use a temporary decrease in body temperature and metabolic rate (torpor) as a strategy to survive food scarcity in a cool environment. Torpor is caused by preoptic neurons that express a variety of peptides and receptors1–7 , but no single genetic marker has been found for this population. Here we report that expression of the prostaglandin EP3 receptor (EP3R) marks a unique population of median preoptic nucleus (MnPO) neurons that are required for both torpor and lipopolysaccharideinduced fever8 . The MnPO-EP3R neurons produce persistent fever responses when inhibited and prolonged hypothermic responses when activated either chemogenetically or optogenetically, even for brief periods of time. The mechanism for these prolonged responses appears to involve increases in intracellular levels of cAMP and calcium that may persist for many minutes up to hours beyond the termination of a stimulus. These properties endow the population of MnPO-EP3R neurons with the ability to act as a two-way switch for the hypothermic and hyperthermic responses that are required for survival."

A population of excitatory neurons has been found to have a key role in controlling body temperature in rodents. The discovery adds to a body of work that is raising questions about long-standing models of thermoregulation. 

Fever is a common phenomenon during infection or inflammatory conditions. This stereotypic rise in body temperature (Tb) in response to inflammatory stimuli is a result of autonomic responses triggered by prostaglandin E2 action on EP3 receptors expressed by neurons in the median preoptic nucleus (MnPO^EP3R neurons). To investigate the identity of MnPO^EP3R neurons, we first used in situ hybridization to show coexpression of EP3R and the VGluT2 transporter in MnPO neurons. Retrograde tracing showed extensive direct projections from MnPO^VGluT2 but few from MnPO^Vgat neurons to a key site for fever production, the raphe pallidus. Ablation of MnPO^VGluT2 but not MnPO^Vgat neurons abolished fever responses but not changes in Tb induced by behavioral stress or thermal challenges. Finally, we crossed EP3R conditional knock-out mice with either VGluT2-IRES-cre or Vgat-IRES-cre mice and used both male and female mice to confirm that the neurons that express EP3R and mediate fever are glutamatergic, not GABAergic. This finding will require rethinking current concepts concerning the central thermoregulatory pathways based on the MnPO^EP3R neurons being GABAergic.

There has been an explosion recently in our understanding of the neuronal populations in the preoptic area involved in thermoregulation of mice. Recent studies have identified several genetically specified populations of neurons predominantly in the median preoptic nucleus (MnPO) but spreading caudolaterally into the preoptic area that regulate body temperature. These include warm-responsive neurons that express the peptides PACAP, BDNF, or QRFP; and receptors for temperature, leptin, estrogen, or prostaglandin E2 (PGE2). These neurons are predominantly glutamatergic and driving them opto- or chemogenetically can cause profound hypothermia, and in some cases, periods of torpor or a hibernation-like state. Conversely, fever response is likely to depend upon inhibiting the activity of these neurons through the PGE2 receptor EP3. Another cell group, the Brs3-expressing MnPO neurons, are apparently cold-responsive and cause increases in body temperature. MnPO^QRFP neurons cause hypothermia via activation of their terminals in the region of the dorsomedial nucleus of the hypothalamus (DMH). As the MnPO^QRFP neurons are essentially glutamatergic, and the DMH largely uses glutamatergic projections to the raphe pallidus to increase body temperature, this model suggests the existence of local inhibitory interneurons in the DMH region between the MnPO^QRFP glutamatergic neurons that cause hypothermia and the DMH glutamatergic neurons that cause hyperthermia. The new genetically targeted studies in mice provide a way to identify the precise neuronal circuitry that is responsible for our physiological observations in this species, and will suggest critical experiments that can be undertaken to compare these with the thermoregulatory circuitry in other species.