Biology subjects

Fuller, P. M.

Publications and source records attributed to Fuller, P. M..

3 recordsLinked to original sources

bioRxiv2025

Molecular Logic of Cell Diversity and Circuit Connectivity in the REM Sleep Hub

The complexity of the brain arises from the diversity of its circuits and the molecular heterogeneity of the cells that compose them. A mechanistic understanding therefore requires mapping cellular identity and connectivity at single-cell resolution. Here we define the cellular taxonomy of the murine sublaterodorsal tegmental nucleus (SLD), a critical hub for REM sleep, using single-nucleus RNA sequencing. We identified all major brain cell classes, with oligodendrocytes as the most abundant, and resolved seventeen transcriptionally distinct neuronal groups defined by neurotransmitters, neuromodulators, and neuropeptides, each with unique molecular signatures. Projection-specific analysis further revealed that glutamatergic subpopulations targeting the ventrolateral periaqueductal gray (vlPAG) and ventral medulla are molecularly distinct, marked by characteristic receptor motifs. Strikingly, we provide the first direct evidence that SLDGLUT neurons innervate the vlPAG. This newly uncovered SLDGLUT[->]vlPAG pathway represents a previously unrecognized circuit node for REM sleep regulation, with the potential to act as a REM-OFF population suppressing it. Together, these findings establish a transcriptionally resolved atlas of the SLD, reveal the molecular logic of its circuit connectivity, and nominate candidate molecular actuators of REM sleep control, opening new avenues for dissecting how brainstem circuits orchestrate REM state and its transitions.

neuroscience↗

bioRxiv2025

Suprachiasmatic Neuromedin-S Neurons Regulate Arousal

Mammalian circadian rhythms, which orchestrate the daily temporal structure of biological processes, including the sleep-wake cycle, are primarily regulated by the circadian clock in the hypothalamic suprachiasmatic nucleus (SCN). The SCN clock is also implicated in providing an arousal signal, particularly during the wake-maintenance zone (WMZ) of our biological day, essential for sustaining normal levels of wakefulness in the presence of mounting sleep pressure. Here we identify a role for SCN Neuromedin-S (SCNNMS) neurons in regulating the level of arousal, especially during the WMZ. We used chemogenetic and optogenetic methods to activate SCNNMS neurons in vivo, which potently drove wakefulness. Fiber photometry confirmed the wake-active profile of SCNNM neurons. Genetically ablating SCNNMS neurons disrupted the sleep-wake cycle, reducing wakefulness during the dark period and abolished the circadian rhythm of body temperature. SCNNMS neurons target the dorsomedial hypothalamic nucleus (DMH), and photostimulation of their terminals within the DMH rapidly produces arousal from sleep. Pre-synaptic inputs to SCNNMS neurons were also identified, including regions known to influence SCN clock regulation. Unexpectedly, we discovered strong input from the preoptic area (POA), which itself receives substantial inhibitory input from the DMH, forming a possible arousal-promoting circuit (SCN->DMH->POA->SCN). Finally, we analyzed the transcriptional profile of SCNNMS neurons via single-nuclei RNA-Seq, revealing three distinct subtypes. Our findings link molecularly-defined SCN neurons to sleep-wake patterns, body temperature rhythms, and arousal control. Significance StatementOur studys findings provide a cellular and neurobiological understanding of how Neuromedin-S (NMS)-containing SCN neurons contribute to regulating circadian rhythms, sleep-wake patterns, body temperature, and arousal control in mammals. This research illuminates the circuit, cellular, and synaptic mechanisms through which SCN neurons regulate daily cycles of wakefulness and sleep, with implications for understanding and potentially manipulating these processes in health and disease.

neuroscience↗

bioRxiv2021

Depleting Hypothalamic Somatostatinergic Neurons Recapitulates Diabetic Phenotypes in Brain, Bone Marrow, Adipose, and Retina

Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunologic pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. The present data show that leptin receptor deficient (db/db) mice exhibit reduced hypothalamic somatostatinergic cells, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus (AAV) delivery of diphtheria toxin (DTA) driven by an SST-cre system to deplete these cells in SSTcre/gfp mice (SST-DTA). SST-DTA mice exhibit enhanced hypothalamic c-fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed hematopoiesis, generating excess granulocyte-monocyte precursors and increased pro-inflammatory (CCR2hi) monocytes. Visceral adipose tissue from DTA-treated animals was resistant to catecholamine induced lipolysis. Finally, SST-DTA mice exhibited a "diabetic retinopathy like" phenotype: reduced visual function by optokinetic response and electroretinogram, as well as increased percentages of retinal monocytes. Importantly, hyperglycemia was not observed in SST-DTA mice. Thus, the isolated reduction in hypothalamic somatostatinergic neurons was able to recapitulate several hallmark features of type 2 diabetes in disease relevant tissues.

neuroscience↗