QPLOT Neurons-Converging on a Thermoregulatory Preoptic Neuronal Population

Abstract

The preoptic area of the hypothalamus is a homeostatic control center. The heterogeneous neurons in this nucleus function to regulate the sleep/wake cycle, reproduction, thirst and hydration, as well as thermogenesis and other metabolic responses. Several recent studies have analyzed preoptic neuronal populations and demonstrated neuronal subtype-specific roles in suppression of thermogenesis. These studies showed similar thermogenesis responses to chemogenetic modulation, and similar synaptic tracing patterns for neurons that were responsive to cold, to inflammatory stimuli, and to violet light. A reanalysis of single-cell/nucleus RNA-sequencing datasets of the preoptic nucleus indicate that these studies have converged on a common neuronal population that when activated, are sufficient to suppress thermogenesis. Expanding on a previous name for these neurons (Q neurons, which reflect their ability to promote quiescence and expression of Qrfp), we propose a new name: QPLOT neurons, to reflect numerous molecular markers of this population and to capture its broader roles in metabolic regulation. Here, we summarize previous findings on this population and present a unified description of QPLOT neurons, the excitatory preoptic neuronal population that integrate a variety of thermal, metabolic, hormonal and environmental stimuli in order to regulate metabolism and thermogenesis.

Keywords: Leptin receptor; Opn5; PTGER3; QRFP; Tacr3; neuropsin; thermoregulation; torpor.

FIGURE 1

A single molecular identity for QPLOT neurons. (A) Heatmap of excitatory POA neurons from Moffitt et al. (2018) and Hrvatin et al. (2020) Known marker genes for thermoregulatory POA neurons, prostaglandin-associated genes, and temperature-sensitive proteins are indicated in columns. Additionally, the top 8 marker genes for excitatory cluster 13 (e13) from Moffitt et al. (2018) and excitatory cluster 10 (e10) from Hrvatin et al. (2020) are provided as well as marker genes for the indicated cluster representing QPLOT neurons when the datasets are merged. Clusters identified in Torpor-TRAP experiments (Hrvatin et al., 2020 clusters only) are indicated. Data is represented as relative expression of each gene within the cluster, averaged over all neuronal clusters, including inhibitory neurons (shown in Supplementary Figure 1). (B) Uniform manifold projection of 46,621 POA neurons integrated with Seurat v3 (Stuart et al., 2019). Cluster 16, the cluster containing QPLOT neurons, is indicated by the dashed black line. The QPLOT neuron cluster is composed predominantly of e13 from Moffitt et al. (2018) and e10 from Hrvatin et al. (2020) (C) Summary of neuronal populations within the POA that are sufficient to reduce body temperature and thermogenesis (Supplementary Figure 2).

FIGURE 2

Afferent and efferent thermoregulatory signaling for QPLOT neurons. Schematic of connectivity of QPLOT neurons that mediate body temperature regulation. QPLOT neurons are responsive to numerous stimuli that are integrated to produce the appropriate response.