Biology subjects

Oya, M.

Publications and source records attributed to Oya, M..

4 recordsLinked to original sources

bioRxiv2025

Ventral tegmental area dopamine controls timing variability

Precision defines successful behavior, yet the brain mechanisms promoting precision are unclear. Here, we dissect dopaminergic circuits controlling precision along a single behavioral dimension - the timing of action. We use an interval timing paradigm that requires participants to indicate their estimate of an interval of several seconds with a motor response. We find that humans with Parkinsons disease (PD) had increased timing variability that predicted PD-related cognitive deficits and executive dysfunction. Surprisingly, lesioning ventral tegmental area (VTA) dopamine neurons increased temporal variability. Further, GCaMP6s fiber photometry demonstrated that VTA dopamine neuron activity is strongly modulated at the start of temporal intervals, and that this trial start-related activity predicted temporal variability. Finally, we found that stimulation of VTA dopamine neurons improved timing by decreasing temporal variability in both intact and dopamine-depleted animals. Our data establish a model of cognitive symptoms of human PD and provide insight into the neuronal control of temporal variability, which impacts a wide range of executive functions.

neuroscience↗

bioRxiv2025

Glycolysis-enhancing alpha 1-adrenergic antagonists are neuroprotective in Alzheimers disease

Terazosin (TZ) is an 1-adrenergic receptor antagonist that enhances glycolysis by activating the enzyme phosphoglycerate kinase 1 (PGK1). Epidemiological data suggest that TZ may be neuroprotective in Parkinsons disease and in dementia with Lewy bodies and that glycolysis-enhancing drugs might be protective in other neurodegenerative diseases involving protein aggregation, such as Alzheimers disease (AD). We investigated TZ in AD and report four main results. First, we found that TZ increased ATP levels in a Saccharomyces cerevisiae mutant with impaired energy homeostasis and reduced the aggregation of the AD-associated protein, amyloid beta (A{beta}) 42. Second, in an AD transgenic mouse model (5xFAD) we found that TZ attenuated amyloid pathology in the hippocampus and rescued cognitive impairments in spatial memory and interval timing behavioral assays. Third, using the Alzheimers Disease Neuroimaging Initiative (ADNI) database, we found that AD patients newly started on TZ or related glycolysis-enhancing drugs had a slower progression of both cognitive dysfunction and neuroimaging biomarkers, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), a measure of brain metabolism. Finally, in a large human administrative dataset, we found that patients taking TZ or related glycolysis-enhancing drugs had a lower hazard of being diagnosed with AD compared to those taking tamsulosin or 5-alpha reductase inhibitors. These data further implicate metabolism in neurodegenerative diseases and suggest that glycolysis-enhancing drugs may be neuroprotective in AD.

neuroscience↗

bioRxiv2024

Melanocortin system activates carotid body arterial chemoreceptors in hypertension

BackgroundThe bodys internal milieu is controlled by a system of interoceptors coupled to motor outflows that drive compensatory adaptive responses. These include the arterial chemoreceptors, best known for sensing arterial oxygen. In cardiometabolic diseases, such as essential hypertension, the carotid bodies (CB) exhibit heightened reflex sensitivity and tonic activity without an apparent stimulus. The mechanisms behind CB sensitization in these conditions are not well understood. MethodsGuided by functional genomics, a range of functional assays is used to interrogate downstream intracellular and interorgan signalling pathways involved in arterial chemosensory function. ResultsHere, we report the presence of the Melanocortin 4 receptor (MC4R) in the mammalian CB and show its elevated expression in experimental hypertension. We demonstrate that melanocortin agonists activate arterial chemosensory cells, modulating CB chemosensory afferent drive to influence both resting and chemoreflex-evoked sympathetic and ventilatory activity. Transcriptional analysis of hypertensive CB implicates the activation of the Mash1 (Ascl1) regulatory network in driving elevated Mc4r expression. ConclusionsCollectively, our data indicate a primarily pathophysiological role of melanocortin signalling in arterial chemosensation, contributing to excess sympathetic activity in cardiometabolic disease.

neuroscience↗

bioRxiv2021

Experience-related remapping of temporal encoding by striatal ensembles.

Temporal control of action is key for a broad range of behaviors and is disrupted in human diseases such as Parkinsons disease and schizophrenia. A brain structure that is critical for temporal control is the dorsal striatum. Experience and learning can influence dorsal striatal neuronal activity, but it is unknown how these neurons change with experience in contexts which require precise temporal control of movement. We investigated this question by recording from medium-spiny neurons (MSNs) in the dorsal striatum of mice as they gained experience controlling their actions in time. We leveraged an interval timing task optimized for mice which required them to "switch" response ports after enough time had passed without receiving a reward. We report three main results. First, we found that time-related ramping activity and response-related activity increased with more experience. Second, temporal decoding by MSN ensembles improved with experience and was predominantly driven by time-related ramping activity. Finally, we found that some MSNs had differential modulation on error trials. These findings enhance our understanding of dorsal striatal temporal processing by demonstrating how MSN ensembles can evolve with experience. Our results can be linked to temporal habituation and illuminate striatal flexibility during interval timing, which may be relevant for human disease.

neuroscience↗