A recent study published in Cell Metabolism reported a specific cluster of neurons in the ventromedial hypothalamus (VMH) that express preprodynorphin (Pdyn) and can control homeostatic thermogenesis and social interaction-associated hyperthermia. This research identified Pdyn-expressing neurons in the VMH as a novel nucleus that not only responds to cold temperature in the environment and promotes homeostatic thermogenesis, but also modulates social interaction and associated thermogenesis. 

This work was accomplished by the labs of Dr. ZHANG Zhe, Dr. LIANG Zhifeng, and Dr. XU Xiaohong at the Center for Excellence in Brain Science and Intelligence Technology (CEBSIT) of the Chinese Academy of Sciences. 

As endotherms, birds and mammals can maintain their body temperature within a relatively stable range despite changes in environmental temperature. A proper and stable body temperature ensures efficient metabolism, which is important for survival, since a few degrees’ change in body temperature can produce severely debilitating effects. While previous research has identified some neural pathways critical for body temperature homeostasis, the exact cell types that control thermoregulation have remained elusive. 

Early studies of the temperature regulation neural circuit showed that environmental temperature was sensed by thermoreceptors that separated on the skin and this information was transmitted to the hypothalamus through the spinal cord and midbrain. Pituitary adenylate cyclase-activating polypeptide (PACAP)/brain-derived neurotrophic factor (BDNF)-producing neurons in the preoptic area (POA) respond to warm environmental temperatures and mediate the decrease in body temperature.  

Furthermore, activation of adenylate cyclase-activating polypeptide 1 (ADCYAP1)-expressing or pyroglutamylated RFamide peptide (QRFP)-expressing hypothalamic neurons can induce extreme hypothermia, leading to a state of hibernation or torpor.  

Recent studies discovered that the bombesin-like receptor 3 (BRS3)-expressing neurons in the POA are capable of inducing thermogenesis, and the hypothalamus-projecting glutamatergic prefrontal neurons mediate stress-induced hyperthermia. However, the cell types involved in the cold-sensing function outside of the POA were largely unknown. 

In order to systematically screen for brain regions sensitive to environmental temperature, the researchers applied an alternating hot or cold stimulus to head-restrained mice and monitored brain activity using an fMRI scanner. They found that the VMH exhibited the most robust cold-response, blood-oxygen-level-dependent (BOLD) signals (Fig. A). After the analysis of single-cell transcriptome data and fluorescence in situ hybridization, the researchers further discovered that Pdyn-expressing neurons in the VMH could be the candidate population for cold-sensitive neurons. 

The team then used fiber photometry to record the calcium activity of the VMH^Pdyn neurons and verified that these neurons are sensitive to the cold stimulus (Fig. B). Subsequent optogenetic manipulation showed that the activation of these neurons increases body temperature, while inhibition leads to body temperature reduction (Fig. C).  

Using rabies virus-mediated retrograde mono-transsynaptic tracing, investigators found that VMH^Pdyn neurons receive a wide range of inputs from the whole brain, including the dorsal-medial hypothalamus (DMH), the POA, the parabrachial nucleus (PBN), and the periaqueductal gray (PAG). These projections indicate VMH^Pdyn neurons may be involved in mediating other sensory and cognitive information together with information for regulating body temperature. Previous work reported an increase in body temperature in mice during social behavior. Investigators thus recorded the calcium activity of VMH^Pdyn neurons and the change in body temperature simultaneously and observed a concurrent increase in both VMH^Pdyn neuronal activity and body temperature during social interaction. In addition, optogenetic inhibition of VMH^Pdyn neurons suppressed the elevation of body temperature and social interaction (Fig. D), indicating that the activation of VMH^Pdyn neurons could serve the dual function of modulating both social interactions and thermogenesis. 

Researchers showed that VMH^Pdyn neurons are critical to maintaining body temperature in cold environments, thus adding an important piece to the neural circuit for thermoregulation. What’s more, this work discovered the dual function of VMH^Pdyn neurons in coordinating energy metabolism and social behaviors.