Namihira, M. | Search bioRxiv

bioRxiv2025

Repetitive Neuronal Activation Regulates Cellular Maturation State via Nuclear Reprogramming

Neural stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS), are highly effective clinical interventions for a broad spectrum of psychiatric disorders, including depression and schizophrenia. However, their mechanism of action at the cellular level remains poorly understood. Here, we modelled ECT with repeated optogenetic neuronal stimulation in the mouse dentate gyrus, and observed ECT-like behavioral effects, including decreased depression-like behavior and increased locomotor activity. At the cellular level, we found dematuration to a long-term stable state, persisting for more than one month, defined by changes in nuclear structure, gene expression patterns resembling the G2/M phase of the cell cycle, and altered neural coding of navigational information. Moreover, knockout of the G2/M master regulator Cyclin B rescued some of behavioral and cellular effects. These findings demonstrate that ECT-like brain stimulation triggers plasticity of the cellular state, revealing a form of stimulus-regulated nuclear reprogramming with potential clinical utility.

neuroscience↗

bioRxiv2021

Protein lactylation induced by neural excitation

Lactate is known to have diverse roles in the brain at the molecular and behavioral levels under both physiological and pathophysiological conditions, such as learning and memory and regulation of mood. Recently, a novel post-translational modification called lysine lactylation has been found in histone H3 of mouse macrophages, and the lactylation levels paralleled the intracellular lactate levels1. However, it is unknown whether lysine lactylation occurs in brain cells, and if it does, whether lactylation is induced by the stimuli that accompany changes in lactate levels. Herein, we reveal that lysine lactylation in brain cells is regulated by systemic changes in lactate levels, neural excitation, and behaviorally relevant stimuli. Lysine lactylation levels were increased by lactate treatment and by high-potassium-induced depolarization in cultured primary neurons; these increases were attenuated by pharmacological inhibition of monocarboxylate transporter 2 and lactate dehydrogenase, respectively, suggesting that both cell-autonomous and non-cell-autonomous neuronal mechanisms are involved in overall lysine lactylation. In vivo, electroconvulsive stimulation increased lysine lactylation levels in the prefrontal cortices of mice, and its levels were positively correlated with the expression levels of the neuronal activity marker c-Fos on an individual cell basis. In the social defeat stress model of depression in which brain lactate levels increase, lactylation levels were increased in the prefrontal cortices of the defeated mice, which was accompanied by increased c-Fos expression, decreased social behaviors, and increased anxiety-like behaviors, suggesting that stress-induced neuronal excitation may induce lysine lactylation, thereby affecting mood-related behaviors. Further, we identified 63 candidate lysine-lactylated proteins in the mouse cortex and found that lactylation levels in histone H1 increased in response to defeat stress. This study may open up an avenue for exploration of a novel role of neuronal activity-induced lactate mediated by protein lactylation in the brain.

neuroscience↗