Biology subjects

Grajales-Reyes, J. G.

Publications and source records attributed to Grajales-Reyes, J. G..

3 recordsLinked to original sources

bioRxiv2025

Identification of a Thermogenic Target in the Dorsal Raphe Nucleus for Weight Management

Obesity emerges from a complex interplay of factors, including imbalanced interoception, genetic predisposition, and environmental cues, ultimately disrupting body weight homeostasis1. While much research has concentrated on strategies to suppress appetite for sustained weight loss, insufficient attention has been given to counterregulatory mechanisms that promote energy expenditure. Here, we show that chronic inhibition of GABAergic neurons in the Dorsal Raphe Nucleus (DRNVGAT) reduces body weight in diet-induced obese (DIO) mice. In this study, molecular profiling and in-situ hybridization in rodent and human brains revealed that the constitutively activated orphan receptor GPR6 is selectively enriched in DRNVGAT neurons. We next developed and administered a potent and highly selective GPR6 inverse agonist, which significantly reduced weight gain in DIO mice by stimulating brown adipose tissue thermogenesis without affecting appetite. Altogether, this study transitions from transcriptomic profiling, high-throughput drug screening and metabolic phenotyping to successfully identify a novel candidate to treat obesity.

neuroscience↗

bioRxiv2018

Cell type-specific modulation of sensory and affective components of itch in the periaqueductal gray

Itch is a distinct aversive sensation that elicits a strong urge to scratch. Despite recent advances in our understanding of the peripheral basis of itch, we know very little regarding how central neural circuits modulate acute and chronic itch processing. Here we establish the causal contributions of defined periaqueductal gray (PAG) neuronal populations in itch modulation. Chemogenetic manipulations demonstrate bidirectional modulation of scratching by neurons in the PAG. Fiber photometry studies show that activity of GABAergic and glutamatergic neurons in the PAG is modulated in an opposing manner during chloroquine-evoked scratching. Furthermore, activation of PAG GABAergic neurons or inhibition of glutamatergic neurons resulted in attenuation of scratching in both acute and chronic pruritis. Surprisingly, PAG GABAergic neurons, but not glutamatergic neurons, seem to encode the aversive component of itch. Thus, the PAG represents a neuromodulatory hub that regulates both the sensory and affective aspects of acute and chronic itch.

neuroscience↗

bioRxiv2017

Optogenetic silencing of primary afferents reduces evoked and ongoing bladder pain

Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) suffer from chronic pain that severely affects quality of life. Although the underlying pathophysiology is not well understood, inhibition of bladder sensory afferents temporarily relieves pain. Here, we explored the possibility that optogenetic inhibition of bladder sensory afferents could be used to modulate bladder pain. Specifically, we chose to study the role of Nav1.8+ sensory afferents before and after induction of a mouse model of bladder pain. The light-activated inhibitory proton pump Archaerhodopsin (Arch) was expressed under control of the Nav1.8+ promoter to selectively silence these neurons. Optically silencing Nav1.8+ afferents significantly blunted the evoked visceromotor response to bladder distension and led to small but significant changes in bladder function. To study of the role of these fibers in freely behaving mice, we developed a fully implantable, flexible, wirelessly powered optoelectronic system for the long-term manipulation of bladder afferent expressed opsins. We found that optogenetic inhibition of Nav1.8+ fibers reduced both ongoing pain and evoked cutaneous hypersensitivity in the context of cystitis, but had no effect in uninjured, naive mice. These results suggest that selective optogenetic silencing of bladder afferents may represent a potential future therapeutic strategy for the treatment of bladder pain.

neuroscience↗