Biology subjects

Donegan, D.

Publications and source records attributed to Donegan, D..

4 recordsLinked to original sources

bioRxiv2025

Transcutaneous auricular vagus nerve stimulation during movement modulates motor neural circuitry without widespread cortical or autonomic activation

Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising neuromodulatory approach for treating neurological disorders, with growing interest in its potential to support motor rehabilitation. Yet, its mechanisms of action, potentially influenced by behavioral context, remain elusive. This sham-controlled study investigated transient taVNS interactions with movement in healthy adults, focusing on autonomic, neuromodulatory, and motor circuits. During a finger-tapping paradigm, heart rate (HR), galvanic skin response (GSR), pupil diameter, and electroencephalography (EEG) were recorded to probe movement-dependent stimulation effects. This study first identified a novel physiological dissociation: all measures responded to movement, but taVNS did not significantly alter HR, GSR, or general EEG spectral slope; taVNS increased pupil diameter in both conditions, but enhanced sensorimotor EEG spectral slope solely during movement. This context-specific effect on motor systems was further supported by a transcranial magnetic stimulation (TMS) experiment demonstrating increased corticospinal excitability during taVNS. These findings provide mechanistic insights into how taVNS may selectively enhance motor system responsiveness during active states, supporting future exploration of behaviorally paired stimulation protocols for neurorehabilitation.

neuroscience↗

bioRxiv2024

Distinct bandwidths of orexin neuron activity independently encode body movement and metabolic state

Tracking net body movement in real time may enable the brain to estimate ongoing demands and thus better orchestrate muscle tone, energy balance, and arousal. To identify neural populations specializing in tracking net body movement, here we compared self-initiated movement-related activity across genetically-defined subcortical neurons in the mouse brain, including dopaminergic, glutamatergic, noradrenergic, and key peptidergic neurons. We show that hypothalamic orexin/hypocretin-producing neurons (HONs) are exceptionally precise movement-trackers, encoding net body movement across multiple classified behaviors with a high degree of precision, independent of head acceleration. This tracking was so precise, that video analysis of the mouse body movement reliably served as a low-cost biometric for HON population activity. The movement tracking was independent of internal nutritional states, and occurred in a communication bandwidth distinct from HON encoding of blood glucose. At key projection targets, orexin/hypocretin peptide outputs correlated with self-initiated movement in a projection-specific manner, indicating functional heterogeneity in HON outputs. Finally, we found that body movement was not encoded to the same extent in other key neural populations related to arousal or energy. These findings indicate that subcortical orchestrators of arousal and metabolism are finely tuned to encode net body movement, constituting a bridge multiplexing ongoing motor activity with internal energy resources.

neuroscience↗

bioRxiv2022

Arousal neurons that anticipate deviations in blood glucose.

Blood glucose variability shapes human brain performance and diverse clinical outcomes. However, it remains poorly understood how blood glucose fluctuations are decoded by genetically-defined neurons to change brain activity and behavior. Recent breakthroughs in genetics and clinical diagnostics identified hypothalamic hypocretin/orexin neurons (HONs) as core determinants of brain activity and adaptive behavior across mammals. Here we show that low-frequency HON population waves are tuned for transmitting information about minute-to-minute temporal features of blood glucose, thus rapidly converting its variability into brain state of behaving mice. Contrary to current theories envisioning glucose-proportional neural responses, the HONs response tracked blood glucose gradients, thus generating efficient neural adaptations in anticipation of maximal glucose deviations. Resolving this population response at the single cell level with volumetric multiphoton imaging furthermore revealed glucose-excited and glucose-inhibited HONs, distinctly coupled to body movements in the high-frequency domain. Finally, HON-selective opotogenetics and cell ablation demonstrated that HONs are critical for linking glucose to adaptive behavior. These results provide an insight into how behaviorally influential hypothalamic networks interpret blood glucose variability. This may inform future metrics for efficient prediction of glycemic states in health and disease.

neuroscience↗

bioRxiv2021

Vagus nerve stimulation accelerates motor learning through cholinergic modulation

Vagus nerve stimulation (VNS) is a neuromodulation therapy for a broad and rapidly expanding set of neurologic conditions. Classically used to treat epilepsy and depression, VNS has recently received FDA approval for stroke rehabilitation and is under preclinical and clinical investigation for other neurologic indications. Despite benefits across a diverse range of neurological disorders, the mechanism through which VNS influences central nervous system circuitry is not well described, limiting therapeutic optimization. A deeper understanding of the influence of VNS on neural circuits and activity is needed to maximize the use of VNS therapy across a broad range of neurologic conditions. To investigate how VNS can influence the neurons and circuits that underlie behavior, we paired VNS with upper limb movement in mice learning a skilled motor task. We leveraged genetic tools to perform optogenetic circuit dissection, as well as longitudinal in vivo imaging of calcium activity in cortical neurons to understand the effect of VNS on neural function. We found that VNS robustly enhanced motor learning when temporally paired with successful movement outcome, while randomly applied VNS impaired learning. This suggests that temporally-precise VNS may act through augmenting outcome cues, such as reinforcement signals. Within motor cortex, VNS paired with movement outcome selectively modulates the neural population that represents outcome, but not other movement-related neurons, across both acute and behaviorally-relevant timescales. Phasic cholinergic signaling from basal forebrain is required both for VNS-driven improvements in motor learning and the effects on neural activity in M1. These results indicate that VNS enhances motor learning through precisely-timed phasic cholinergic signaling to reinforce outcome, resulting in the recruitment of specific, behaviorally-relevant cortical circuits. A deeper understanding of the mechanisms of VNS on neurons, circuits and behavior provides new opportunities to optimize VNS to treat neurologic conditions.

neuroscience↗