Publications

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

• Authors: Ceprian M, Egaña-Huguet J, Godoy L, Godoy A, Aranguren-Alberdi A, Ospital P, Reyes-Velasquez P, Calovi S, Santos-Martin JA, Piriz J, Ramos-Miguel A, Mato S, Soria-Gomez E

• Publication date: 2026 July 27

• Abstract: 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.

• © The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

• Authors: Cathaysa Rodriguez-Cedrés, Lucia Sangroniz-Beltrán, Nahia López, Naroe Delgado-Martin, Goiane Andueza-Peral, Paula Múgica-Susaeta, Eva Ducourneau, Paula Ospital, Sandra Beriain, María Ceprian, Jon Egaña-Huguet, Joaquin Piriz, Guillaume Ferreira, Susana Mato, and Edgar Soria-Gómez.

• Publication date: 2026 July 2.

• Abstract: The medial habenula (MHb) is an epithalamic structure involved in aversive processing and emotional regulation, notable for its marked cellular heterogeneity and high astrocyte density. This cellular composition suggests that astrocytes may play an important role in MHb structure and plasticity, potentially contributing to the regulation of emotional states. The aim of this study is to characterize sex-dependent astrocytic morphology in the MHb and determine how it is modulated by peripheral alterations and direct central manipulations. A high-fat diet (HFD) was used as a model of metabolic stress, and systemic lipopolysaccharide (LPS) administration was used to induce a peripheral inflammatory challenge. At the central level, a chemogenetic approach using Gi-DREADDs under the GFAP promoter allowed selective modulation of astrocytic intracellular signalling independently of peripheral influences. Preliminary results indicate sex-dependent morphological differences in MHb astrocytes across all these experimental conditions, supporting the idea that MHb astrocytes are sensitive to both peripheral and central disturbances and may represent a key cellular substrate linking body-brain interactions with emotional regulation.

• © The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

• Authors: Jone Razquin 1 2 3 4, Laura De Las Heras-García 1 3 5, Andrea Vaquero-Rodríguez 2 3, Sara Fernández-Roqueñí 1 5, Gloria González-Aseguinolaza 6, Edgar Soria-Gómez 2 7 8, Jérôme Baufreton 5, Harkaitz Bengoetxea 2 3, Leticia Abecia 9, Jorge E Ortega 1 10 11, Naiara Ortuzar 2 3, Cristina Miguélez 12 13

• Publication date: 2026 Jun 8

• Abstract: The locus coeruleus is among the earliest brain regions affected by α-synuclein pathology in prodromal Parkinson's disease, contributing to non-motor symptoms, yet its early pathogenic role remains unclear. We developed a mouse model in which human α-synuclein was selectively overexpressed in noradrenergic locus coeruleus neurons using PRSx8-driven adeno-associated viral vector. Mice were analysed at 1 and 3 months post-injection using histological, behavioural, neurochemical and electrophysiological approaches. Monomeric α-synuclein was localized in the locus coeruleus cell bodies and distributed throughout noradrenergic neuronal projections, while phosphorylated α-synuclein was predominantly confined to the locus coeruleus somata. We also observed reduced noradrenergic axonal density and early decreases in noradrenaline and serotonin levels without neuron loss. In contrast, the dopaminergic system remained unchanged. Electrophysiological recordings revealed transient, sex-dependent alterations in neuronal excitability. At the behavioural level, mice exhibited cognitive deficits and altered innate-emotional behaviour persisting over time. Sex-specific analyses revealed shortening of the colon in females, in the absence of detectable morphological alterations, α-synuclein deposition, or systemic inflammation. This model recapitulates some of the key non-motor Parkinson's disease features, highlighting the locus coeruleus as a potential target for early intervention.

• © 2026. The Author(s).

• Authors: Ines Ibañez-Tallon, Susanna Molas, Christophe D. Proulx, Joaquin Piriz, Edgar Soria-Gómez.

• Publication date: 2026 April 16.

• Abstract: In this review, we synthesize key findings from the 2025 Spanish Society for Neuroscience (SENC) symposium "Understanding Habenulae Function in Emotional Behavior" and propose that the brain possesses a "disappointment circuit" that complements the classic dopaminergic reward system. The "disappointment dilemma" in financial investing-avoiding risk to prevent short-term disappointment, only to later experience greater long-term disappointment when safe choices underperform-illustrates how immediate and delayed negative outcomes can be traded off over time. We argue that this dilemma parallels partially specialized roles of the lateral habenula (LHb), which signals immediate disappointments as acute negative prediction errors, and the medial habenula (MHb), which shapes longer-lasting negative expectations or mood through the accumulation of disappointing experiences over time. We propose that LHb outputs implement fast, trial-by-trial adjustments in coping strategies via RMTg- and VTA-projecting pathways, whereas MHb-IPN circuits gradually reshape threat valuation, withdrawal states, and mood across repeated disappointing or stressful experiences. We discuss how LHb and MHb circuits contribute to short- and long-term disappointment by integrating information on stress resilience, aversive learning, threat and fear responses, drug-related behaviors, and mood adaptation from specific cell types and receptors that modulate fear, addiction, and motivation to circuit-level mechanisms underlying aversive learning and emotional responses.

• © 2026 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.