Biology subjects

Rybalchenko, V.

Publications and source records attributed to Rybalchenko, V..

3 recordsLinked to original sources

bioRxiv2026

Evolutionary rise of a synaptic mechanism for creating and diversifying key reinforcement signals

Most neurons release either excitatory or inhibitory neurotransmitters. However, multiple inputs to the lateral habenula (LHb) co-transmit glutamate and GABA, transmitters with opposing effects on LHb output. Although the LHb has an established role in reinforcement learning, the adaptive significance of glutamate/GABA co-release remains unclear. Using experimentally informed simulations, we show that GABA co-release is sufficient to produce temporal difference (TD)-like transformations of input activity, computations commonly used for reinforcement learning and behavioral optimization. Heterogeneous GABA-to-glutamate ratios, like those found among LHb neurons ex vivo, produce diverse TD-like computations linked to higher-order decision-making. Single-cell RNA-sequencing analysis and machine-learning image analysis further indicate that glutamate/GABA co-release expanded across vertebrate evolution, from fish to mice, rats, and monkeys. Evolutionary expansion of glutamate/GABA co-release may have supported increasingly sophisticated learning and decision-making that contribute to intelligent behavior.

neuroscience↗

bioRxiv2020

FOXP1 negatively regulates intrinsic excitability in D2 striatal projection neurons by promoting inwardly rectifying and leak potassium currents

Heterozygous loss-of-function mutations in the transcription factor FOXP1 are strongly associated with autism. Dopamine receptor 2 expressing (D2) striatal projection neurons (SPNs) in heterozygous Foxp1 (Foxp1+/-) mice have higher intrinsic excitability. To understand the mechanisms underlying this alteration, we examined SPNs with cell-type specific homozygous Foxp1 deletion to study cell-autonomous regulation by Foxp1. As in Foxp1+/- mice, D2 SPNs had increased intrinsic excitability with homozygous Foxp1 deletion. This effect involved postnatal mechanisms. The hyperexcitability was mainly due to down-regulation of two classes of potassium currents: inwardly rectifying (KIR) and leak (KLeak). Single-cell RNA sequencing data from D2 SPNs with Foxp1 deletion indicated the down-regulation of transcripts of candidate ion channels that may underlie these currents: Kcnj2 and Kcnj4 for KIR and Kcnk2 for KLeak. This Foxp1-dependent regulation was neuron-type specific since these same currents and transcripts were either unchanged, or very little changed, in D1 SPNs with cell-specific Foxp1 deletion. Our data are consistent with a model where FOXP1 negatively regulates the excitability of D2 SPNs through KIR and KLeak by transcriptionally activating their corresponding transcripts. This, in turn, provides a novel example of how a transcription factor may regulate multiple genes to impact neuronal electrophysiological function that depends on the integration of multiple current types - and do this in a cell-specific fashion. Our findings provide initial clues to altered neuronal function and possible therapeutic strategies not only for FOXP1-associated autism but also for other autism forms associated with transcription factor dysfunction.

neuroscience↗

bioRxiv2020

An essential role for MEF2C in the cortical response to loss of sleep

Neuronal activity and gene expression in response to the loss of sleep can provide a window into the enigma of sleep function. Sleep loss is associated with brain differential gene expression, an increase in pyramidal cell mEPSC frequency and amplitude, and a characteristic rebound and resolution of slow wave sleep-slow wave activity (SWS-SWA). However, the molecular mechanism(s) mediating the sleep loss response are not well understood. We show that sleep-loss regulates MEF2C phosphorylation, a key mechanism regulating MEF2C transcriptional activity, and that MEF2C function in postnatal excitatory forebrain neurons is required for the biological events in response to sleep loss. These include altered gene expression, the increase and recovery of synaptic strength, and the rebound and resolution of SWS-SWA, which implicate MEF2C as an essential regulator of sleep function. One Sentence SummaryMEF2C is critical to the response to sleep loss.

neuroscience↗