Biology subjects

Polotsky, V. Y.

Publications and source records attributed to Polotsky, V. Y..

3 recordsLinked to original sources

bioRxiv2026

Leptin alleviates obesity hypoventilation via serotonergic pathways

RationaleThere is no effective pharmacotherapy for obesity hypoventilation syndrome (OHS). Intranasal leptin augments the hypercapnic ventilatory response (HCVR), attenuates upper airway obstruction, and increases ventilation during sleep in diet-induced obese (DIO) mice. Respiratory effects of leptin can be attenuated by serotonergic antagonists. ObjectivesTo establish if serotonergic innervation of the hypoglossal motoneurons (XII MN) mediates effects of leptin on OHS. MethodsWe examined effects of intranasal leptin on the HCVR, sleep architecture, arousal latency, flow limited (obstructed) and non-flow limited breathing, genioglossus muscle (GG) activity and metabolic rate across sleep/wake states in the presence and absence of serotonergic neurons innervating XII MN in DIO Sert-flp mice expressing FlpO recombinase in the serotonergic neurons. These mice were transfected into the XII MN with retrograde adeno-associated virus carrying either FlpO-dependent caspase or control yellow fluorescent protein (YFP). Measurements and Main ResultsControl YFP virus was densely localized to the serotonergic neurons of the medullary raphe (MR), but not the dorsal raphe (DR), and these neurons were ablated by caspase. Leptin enhanced the HCVR, increased arousal latency in males, but not in females, and these effects were abolished by caspase. Neither leptin nor caspase affected sleep architecture or metabolic rate. Leptin increased GG activity awake and during NREM sleep, attenuated pharyngeal obstruction and increased minute ventilation in NREM and REM sleep. All effects of leptin were abolished by the FlpO-dependent caspase. ConclusionsLeptin treats OHS by stimulating MR serotonergic neurons, which project to XII MN and stimulate pharyngeal muscles during sleep.

physiology↗

bioRxiv2026

Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression

BackgroundThe primary cause of death associated with opioids is opioid-induced respiratory depression (OIRD). Naloxone is used to reverse OIRD, but this drug is a competitive antagonist of {micro}-opioid receptor (MOR) and reverses analgesia, which limits its therapeutic use. Alternative non-opioid receptor antagonist-based approaches to OIRD treatment and prevention are needed. The aim of this study was to evaluate if setmelanotide (SET) is capable of reversing OIRD in a mouse model. MethodsC57BL/6J male and female mice and Sprague-Dawley rats were given IP morphine or fentanyl and then treated 15 min later with either SET or vehicle VEH (IP) in a random order. Breathing was recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. ResultsIn mice with OIRD, SET induced a 3-fold reduction of the apnea index, and decreased apnea duration as compared to the VEH treatment. SET increased respiratory rate and did not affect opioid-induced analgesia. Photostimulation of MC4R+ ChR2-expressing fibers in the parafacial region of MC4R-Cre mice elicited short-latency excitatory postsynaptic current in rostral ventral respiratory group (rVRG) pre-motoneurons projecting to the phrenic nucleus in the C3-C4 ventral horns of the spinal cord. Fentanyl inhibited the activity of rVRG neurons and SET reversed this effect. ConclusionsSET effectively treated OIRD by increasing respiratory rate and inducing a significant decrease in the number of apneas without decreasing analgesia.

physiology↗

bioRxiv2025

Oxytocin Receptor Expression and Activation in Parasympathetic Brainstem Cardiac Vagal Neurons

Autonomic imbalance, particularly reduced activity from brainstem parasympathetic cardiac vagal neurons (CVNs) is a major characteristic of many cardiorespiratory diseases. Therapeutic approaches to selectively increase CVN activity have been limited by lack of identified selective translational targets. Recent work has shown that there is an important excitatory synaptic pathway from oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVN) to brainstem CVNs, and that OXT could provide a key selective excitation of CVNs. In clinical studies, intranasal OXT increases parasympathetic cardiac activity, autonomic balance, and reduces obstructive event durations and oxygen desaturations in obstructive sleep apnea patients. However, the mechanisms by which activation of hypothalamic OXT neurons, or intranasal OXT, increases brainstem parasympathetic cardiac activity is poorly understood. CVNs are located in two cholinergic brainstem nuclei: the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMNX). In this study we characterize the co-localization of OXT receptors in CVNs (OXTR), as well as non-CVN cholinergic neurons, located in the NA and DMNX nuclei. Selective chemogenetic excitation of OXTR+ CVNs was performed by expressing DREADDs with a combination of Cre and flp dependent viruses. We found that OXT receptors are highly expressed in CVNs in the DMNX and OXT increases DMNX CVN activity, but the receptors and responses are absent in CVNs in the NA. Selective chemogenetic activation of OXTR+ CVNs in the DMNX evoked a rapid and sustained bradycardia.

neuroscience↗