Brain-wide mapping of neuronal architecture controlling torpor

Abstract

Endotherms can survive low temperatures and food shortage by actively entering a hypometabolic state known as torpor. Although the decrease in metabolic rate and body temperature during torpor is controlled by the brain, the underlying neural circuits remain largely unknown. In this study, we identify the neural circuits involved in torpor regulation by combining whole-brain mapping of torpor-activated neurons, cell type-specific manipulation of neural activity, and viral tracing-based circuit mapping. We found that Trpm2-positive neurons in the preoptic area and Vgat-positive neurons in the dorsal medial hypothalamus are activated during torpor. Genetic silencing shows the activity of either cell type is necessary to enter the torpor state. Finally, we show that these cells receive projections from the arcuate and suprachiasmatic nucleus and send projections to brain regions involved in thermoregulation. Our results demonstrate an essential role of hypothalamic neurons in the regulation of body temperature and metabolic rate during torpor and identify critical nodes of the torpor-regulatory network.

Nutrient Abundance Signals the Changing of the Seasons by Phosphorylating PER2

“…We turned to an acute fasting paradigm in standard, 12:12 LD cycles to isolate molecular effects from differences in circadian phase that are inherent to PER2 mutant animals during seasonal entrainment. During fasting, mice enter a transient period of inactivity and energy conservation termed 'torpor' that is regulated by hypothalamic nuclei 22,23 and the circadian clock 24 . Signals that activate CK1δ, such as insulin and gastrin, are low during fasting 25,26 , suggesting that PER2-S662 is hypo-phosphorylated in this condition.…”

“…In addition, the pancreatic b-cell rhythmically regulates lipolysis by circadian insulin secretion 48 . Centrally, hypothalamic nuclei that regulate circadian rhythms, diurnal behaviors, and metabolism 22,23,49 are obvious candidates. Within the SCN, it may be intriguing to interrogate distinct sub-populations as the NMS-and VIP-expressing neurons regulate neurotransmitter plasticity in response to seasonal light cues 50 .…”

An arginine-rich nuclear localization signal (ArgiNLS) strategy for streamlined image segmentation of single-cells

“…Notably, they have democratized experimental access to spatially integrated intact whole-brain anatomy, at the resolution of single-cells and within computationally feasible datasets that are compatible with brain atlas mapping. For example, in combination with genetic fluorescent labeling, these techniques have facilitated the mapping of cellular activity [4][5][6][7][8][9][10][11][12][13][14][15][16] , cell-type distributions [17][18][19][20] , and endogenous genetic 21 and connectivity patterns 22 . However, while significant hardware-based advancements have been made in microscopy systems 2,23,24 , and numerous software-based image analysis tools are readily available 5,13,14,[25][26][27][28][29] , there has been a relative lack of genetic tool development that maximizes single-cell detection and quantification through the optimization of fluorescent signal.…”