Biology subjects

Calovi, S.

Publications and source records attributed to Calovi, S..

3 recordsLinked to original sources

bioRxiv2026

Sex-Dependent Modulation of Emotional and Cognitive Processes by Prefrontal CB1 Receptors

The medial Prefrontal Cortex (mPFC) participates in emotional regulation, decision-making and behavioural flexibility. Cannabinoid receptor 1 (CB1) is widely expressed in the mPFC, particularly in GABAergic neurons, where it modulates synaptic transmission, contributing to the mPFC excitation-inhibition balance. Alteration of GABAergic activity and CB1 levels is indeed part of the pathophysiology of many psychiatric disorders, including depression, anxiety, and schizophrenia. Interestingly, both CB1 and mood disorders display important sex differences. In this work, we study the role of CB1 receptors in prefrontal GABAergic interneurons in emotional and cognitive processes in a sex-dependent manner. To achieve this objective, we deleted CB1 from all mPFC neurons and the GABAergic population in adult CB1-flox male and female mice, and GABAergic neuronal activity was assessed via calcium imaging with fiber photometry. Global CB1 deletion in mPFC neurons, specifically in GABAergic cells, altered emotional but not cognitive processes, with opposite patterns. This impairment was sex- and task-dependent. While pan-neuronal CB1 deletion had an anxiolytic effect on females, GABAergic CB1 deletion had the same effect on male mice, linked to increased GABAergic neuronal activity. By contrast, fear conditioning was primarily affected in males with neuronal CB1 depletion and in females with receptor deletion in inhibitory neurons. GABAergic CB1 deletion potentiates females freezing response during acquisition and recall 24 hours later, and is associated with decreased inhibitory neuronal activity during the tone-shock association. In conclusion, mPFC GABAergic CB1 deletion is associated with an anxiolytic phenotype but also heightened responses to conditioned cues in a sex-dependent manner.

neuroscience↗

bioRxiv2025

Internalization of exogenous myelin by oligodendroglia promotes lineage progression

Oligodendrocytes, traditionally recognized for their role in central nervous system myelination, have emerged during the last decades as key participants maintaining brain homoeostasis in response to metabolic demands and stress. In addition, injury to myelin prompts a regenerative response that leads to the formation of new myelin sheaths. However, the signals regulating effective remyelination by oligodendrocytes are still not completely understood. Here, we report that oligodendrocytes can internalize exogenous myelin both in vitro and in vivo, which leads to an increase in their proliferation and differentiation when their functions are not compromised. RNA sequencing reveals that myelin debris alters oligodendrocyte transcriptional profile, suppressing immune-related pathways and de novo cholesterol and fatty acid biosynthesis, while inducing lipid droplet formation to store and process internalized myelin particles. As a result, progression of the oligodendroglial lineage is enhanced in primary cell cultures, as shown by increased viability, proliferation and differentiation. Oligodendrocytes also acquire a more differentiated phenotype, with larger cell areas, a more complex morphology and myelination of synthetic nanofibers. Stereotaxic injection of fluorescent myelin into mouse cortex shows internalization by microglia and, to a lesser extent, by oligodendroglia. Notably, in the zebrafish model, ventricular injections of myelin also increase the number of ventral oligodendrocytes in the spinal cord, further supporting that myelin can promote lineage progression. These findings challenge the classical view that myelin debris intrinsically inhibits oligodendrocyte proliferation, suggesting instead that oligodendrocytes can use myelin to support self-renewal and maturation, acting as a trophic factor in the absence of pathological cues. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/665370v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@b15463org.highwire.dtl.DTLVardef@1b7090org.highwire.dtl.DTLVardef@17b148forg.highwire.dtl.DTLVardef@182d7d1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Monocarboxylate transporter 2 is required for the maintenance of myelin and axonal integrity by oligodendrocytes

Neurodegenerative pathologies including multiple sclerosis (MS) are consistently associated with energy deficit in the central nervous system (CNS). This might directly impact myelinating oligodendrocytes as these are particularly vulnerable to metabolic insults. Importantly, oligodendroglial dysfunction and myelin alterations occur in most, if not all neurodegenerative diseases, and are associated with axonal pathology/loss. Thus, elucidating metabolic mechanisms required for oligodendroglial myelin maintenance and axonal support might be crucial to identify therapeutic targets to achieve neuroprotection. While monocarboxylates are important energy fuels for the CNS, their role in myelinating oligodendrocyte function remains unclear. Here we show that, just like neurons, myelinating oligodendrocytes express high affinity monocarboxylate transporter 2 (MCT2) both in mice and humans, which is downregulated in progressive MS. While deletion of MCT2 in mouse oligodendrocytes did not affect the survival of these cells, it resulted in downregulation of lipid synthesis-associated enzymes and failure of myelin maintenance. Moreover, axonal upregulation of lactate dehydrogenase A concomitant with axonal damage was observed but could be alleviated by ketogenic diet. We conclude that oligodendroglial MCT2 is required for myelin maintenance and axonal support, which becomes altered in progressive MS, but may be compensated for by specific metabolic therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/632306v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@2b7b22org.highwire.dtl.DTLVardef@a111fdorg.highwire.dtl.DTLVardef@a410f5org.highwire.dtl.DTLVardef@1556e2f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗