Biology subjects

Pigulevskiy, I.

Publications and source records attributed to Pigulevskiy, I..

4 recordsLinked to original sources

bioRxiv2026

Expanding Hippocampal Ensembles through LINE-1 RNA Downregulation Enhances Cognition

Episodic memories are encoded through the activation of small overlapping neuronal ensembles, a coding principle that ensures efficient encoding and high memory capacity. While cellular excitability is known to drive the allocation of select hippocampal neurons into these ensembles, the underlying molecular mechanisms remain elusive. Here, an epigenetic-functional analysis of hippocampal dentate granule cells revealed robust nuclear expression of RNA from autonomous LINE-1 retrotransposons, with significantly lower LINE-1 RNA levels in environmentally activated neurons compared to non-activated counterparts. Knockdown of LINE-1 RNA in the dentate gyrus increased action potential firing capacity and expanded the number of environmentally activated cells, indicating that LINE-1 expression is inversely correlated with ensemble eligibility. LINE-1 RNA knockdown enhanced spatial working memory at the expense of pattern separation, a trade-off consistent with expanded dentate gyrus ensembles and diminished sparse coding. Together, these findings demonstrate that nuclear LINE-1 RNA was co-opted during evolution to control ensemble eligibility in dentate granule cells, a novel postmitotic neuronal function for LINE-1 RNA that restricts ensemble size to preserve sparse coding and support pattern separation.

neuroscience↗

bioRxiv2023

Rapid nongenomic estrogen signaling controls alcohol drinking behavior

Ovarian-derived estrogen is a key modulator of numerous physiological processes via genomic and nongenomic mechanisms, including signaling non-canonically at membrane-associated estrogen receptors in the brain to rapidly regulate neuronal function. However, the mechanisms mediating estrogen regulation of behaviors such as alcohol consumption remain unclear. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen levels, but a causal role for estrogen signaling in driving alcohol drinking in gonadally-intact animals has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance behavior when circulating estrogen was high during the proestrus phase of the estrous cycle than when it was low, contributing to sex differences in these behaviors. The pro-drinking, but not anxiolytic, effect of high endogenous estrogen state occurred via rapid estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis, which promoted synaptic excitation of corticotropin-releasing factor neurons and facilitated their activity during alcohol drinking behavior. This study is the first to demonstrate a rapid, nongenomic signaling mechanism for ovarian-derived estrogen signaling in the brain controlling behavior in gonadally intact females, and it establishes a causal role for estrogen in an intact hormonal context for driving alcohol consumption that contributes to known sex differences in this behavior.

neuroscience↗

bioRxiv2020

Coordinated postnatal maturation of striatal cholinergic interneurons and dopamine release dynamics in mice.

Dynamic changes in motor abilities and motivated behaviors occur during the juvenile and adolescent periods. The striatum is a subcortical nucleus critical for action selection, motor learning and reward processing. Its tonically active cholinergic interneuron (ChI) is an integral regulator of the synaptic activity of other striatal neurons, as well as afferent axonal projections of midbrain dopamine neurons. Thalamic and dopaminergic inputs initiate pauses in ChI firing following salient sensory cues that are extended for several hundred milliseconds by intrinsic regenerative currents. Here, we characterize the electrophysiological and morphological features of ChIs during mouse postnatal development. We demonstrate that ChI spontaneous activity increases with age while the duration of the pause in firing induced by depolarizing inputs decreases during postnatal development. Maturation of ChI activity is driven by two distinct physiological changes: decreased amplitude of the afterhypolarization between P14 and P18 and and increased Ih conductance between the late postnatal period and adulthood. Finally, we uncover postnatal changes in dopamine release properties that are mediated by cholinergic signalling. At P10, striatal dopamine release is diminished compared to the adult, but our data show efficient summation of dopamine relase evoked by multiple grouped stimuli that subsides by P28. Blockade of nictonic acetylcholine receptors enhances release summation in mice older than P28 but has little effect at P10. These data demonstrate a physiological maturation of ChI activity and indicate a reciprocal interaction between the postnatal maturation of striatal ChI and dopamine neurotransmission. Significance StatementMotor skills and motivated behavior regimes develop rapidly during the postnatal period. The functional development of the striatal cholinergic interneuron (ChI), which contributes to these behaviors in adulthood, remains unexplored. In this study, we tracked the ontogeny of spontaneous ChI activity and cellular morphology, as well as the developmental trajectory of ion conductances characteristic to this population. We further report a developmental link between ChI activity and dopamine release, revealing a change in the frequency-dependence of dopamine release during the early postnatal period that is mediated by cholinergic signaling. This study provides evidence that striatal microcircuits are dynamic during the postnatal period and that they undergo coordinated maturation.

neuroscience↗

bioRxiv2019

mTOR suppresses macroautophagy during postnatal development of the striatum.

Macroautophagy (hereafter referred to as autophagy) plays a critical role in neuronal function related to development and degeneration. Here, we investigated whether autophagy is developmentally regulated in the striatum, a brain region implicated in neurodevelopmental disease. We demonstrate that autophagic flux is suppressed during striatal postnatal development, reaching adult levels around postnatal day 28 (P28). We also find that mTOR signaling, a key regulator of autophagy, increases during the same developmental period. We further show that mTOR signaling is responsible for suppressing autophagy, via regulation of Beclin-1 and VPS34 activity. These results demonstrate that neurons coopt metabolic signaling cascades to developmentally regulate autophagy and establish mTOR as a central node in the regulation of neuronal autophagy.

neuroscience↗