Biology subjects

Anaclet, C.

Publications and source records attributed to Anaclet, C..

4 recordsLinked to original sources

bioRxiv2025

Enriched experience increases reciprocal synaptic connectivity and coding sparsity in higher-order cortex

The integration of new information during sleep reshapes cortical representations that support categorical knowledge. Auto-associative attractor network theories predict that reciprocal excitatory connections help form stable categorical attractors, but direct evidence is missing. We tested this using ten weeks of enriched experience (ENR) in mice as a model for knowledge accumulation and recorded single-unit activity across hippocampus and neocortex. ENR induced significant remodeling in high- but not low-level neocortex, with a shift from unidirectional to bidirectional excitatory-excitatory connections, suggestive of increased cell assemblies. This was accompanied by increased inhibitory-to-excitatory connections and sparser, more orthogonal population activity during awake rest and slow-wave sleep, particularly in deep layers. Thus, ENR reorganizes cortical circuits into a symmetric, inhibition-balanced network that improves coding efficiency, supporting long-standing attractor network predictions.

neuroscience↗

bioRxiv2025

Chronic chemogenetic slow-wave sleep enhancement in mice.

While epidemiological associations and brief studies of sleep effects in human disease have been conducted, rigorous long-term studies of sleep manipulations in animal models are needed to establish causation and to understand mechanisms. We have previously developed a mouse model of acute slow-wave-sleep (SWS) enhancement using chemogenetic activation of parafacial zone GABAergic neurons (PZGABA) in the parvicellular reticular formation of the pontine brainstem. However, it was unknown if SWS could be enhanced chronically in this model. In the present study, mice expressing the chemogenetic receptor hM3Dq in PZGABA were administered once daily with, sequentially, the chemogenetic ligands, clozapine N-oxide (CNO), deschloroclozapine (DCZ) and compound 21 (C21), and sleep-wake phenotypes were analyzed using electroencephalogram (EEG) and electromyogram (EMG). We found that SWS time is increased for three hours following the administration of the chemogenetic ligand, and at the same magnitude for at least six months. This phenotype is associated with longer SWS episode duration and an increase of slow wave activity (SWA) of similar magnitude throughout the six-month dosing period. Interestingly, following the end of the six-month dosing period, SWA remains increased for at least a week. In control mice, six-month long daily administration of the chemogenetic ligands did not affect SWS quantity or quality. This study validates a mouse model of chronic SWS enhancement that will allow mechanistic investigations into how SWS promotes physiological function and prevents diseases. The approach of a rotating schedule of three chemogenetic ligands may be broadly applicable in chemogenetic studies that require chronic administration.

neuroscience↗

bioRxiv2024

Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of Ca2+ and Mg2+ in the formulation

Oligonucleotide therapeutics (ASOs and siRNAs) have been explored for modulation of gene expression in the central nervous system (CNS), with several drugs approved and many in clinical evaluation. Administration of highly concentrated oligonucleotides to the CNS can induce acute neurotoxicity. We demonstrate that delivery of concentrated oligonucleotides to the CSF in awake mice induces acute toxicity, observable within seconds of injection. Electroencephalography (EEG) and electromyography (EMG) in awake mice demonstrated seizures. Using ion chromatography, we show that siRNAs can tightly bind Ca2+ and Mg2+ up to molar equivalents of the phosphodiester (PO)/phosphorothioate (PS) bonds independently of the structure or phosphorothioate content. Optimization of the formulation by adding high concentrations (above biological levels) of divalent cations (Ca2+ alone, Mg2+ alone, or Ca2+ and Mg2+) prevents seizures with no impact on the distribution or efficacy of the oligonucleotide. The data here establishes the importance of adding Ca2+ and Mg2+ to the formulation for the safety of CNS administration of therapeutic oligonucleotides.

neuroscience↗

bioRxiv2022

A marked enhancement of a BLOC-1 gene, pallidin, associated with somnolent mouse models deficient in histamine transmission

Histamine (HA) and orexin (Ox, or hypocretin) neurons act distinctly and synergistically in wake control. A double knock out mouse genotype lacking both HA and Ox shows all sleep disorders of human narcolepsy. We identified in this mouse brain a sharp upregulation of a BLOC-1 gene, pallidin that is associated with dramatic changes in the balance of cholinergic and aminergic systems in mice and an enhanced sleep in drosophila. This study demonstrates potential sleep disorders-associated compensatory mechanisms with pallid as a novel biomarker.

neuroscience↗