Biology subjects

Soria-Gomez, E.

Publications and source records attributed to Soria-Gomez, E..

10 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↗

bioRxiv2026

Astrocytic morphology in the Medial Habenula: sex differences and modulatory factors

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.

neuroscience↗

bioRxiv2025

PKC-dependent MYRF dysregulation links Aβ pathology to oligodendrocyte, myelin and cognitive alterations in Alzheimer's disease

Alzheimers disease (AD) is characterized not only by neuronal loss and synaptic dysfunction but also by emerging evidence of oligodendrocyte and myelin pathology. Amyloid-{beta} (A{beta}), a hallmark of AD, disrupts oligodendrocyte homeostasis through mechanisms that remain poorly understood. Here, we investigated the role of the myelin regulatory factor (MYRF), a transcription factor essential for oligodendrocyte maturation, in AD-related glial dysfunction. Using the 3xTg-AD mouse model, we observed aberrantly induced maturation dynamics and reduced oligodendrocyte lineage cell density at 12 months in the dentate gyrus, accompanied by increased MYRF expression. Interestingly, sustained MYRF overexpression was found to be toxic for oligodendrocytes in vitro. Moreover, in vitro and in vivo experiments further demonstrated that A{beta} exposure elevates MYRF protein levels and enhances its transcriptional activity, pointing to post-translational regulation. Mechanistically, A{beta} impaired GSK3-dependent phosphorylation and Fbxw7-mediated ubiquitination of MYRF, prolonging N-MYRF stability, an effect prevented by PKC inhibition in vitro. Intracerebroventricular infusion of PKC inhibitor Go6983 normalized MYRF levels, restored oligodendrocyte populations and myelin integrity, and improved hippocampal-dependent spatial learning in 3xTg-AD mice, with locomotor activity and anxiety-like behavior remaining unaffected. Together, these findings identify MYRF dysregulation as a mechanistic link between A{beta}/PKC signaling and oligodendrocyte pathology, and highlight PKC inhibition as a potential strategy to restore oligodendroglial function and cognition in AD.

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bioRxiv2025

Locus Coeruleus alpha-Synuclein Overexpression Induces Prodromal Parkinsonian Features in Mice

The locus coeruleus is one of the first brain regions to develop -synuclein pathology during the prodromal phase of Parkinsons Disease, contributing significantly to non-motor symptoms such as cognitive decline, mood alterations or sleep disturbances. However, the precise role of the locus coeruleus in the early stages of the disease remains unclear. To address this, we developed and characterized a novel mouse model based on the PRSx8-driven overexpression of human -synuclein in noradrenergic neurons of the locus coeruleus using an adeno-associated viral vector. Animals were assessed at 1 and 3 months post-injection using an integrated battery of histological, behavioural, neurochemical, and electrophysiological analyses. We observed robust accumulation of phosphorylated -synuclein in the locus coeruleus, along with widespread propagation to projection areas, including the hippocampus, prefrontal cortex, and dorsal raphe. Despite the absence of neuronal loss in the locus coeruleus, we identified reduced noradrenergic axonal integrity and marked decreases in both noradrenaline and serotonin levels, highlighting a disruption of neurochemical balance at an early stage. The electrophysiological data revealed transient alterations in the excitability and intrinsic properties of locus coeruleus neurons in a sex-dependent manner, suggesting that -synuclein pathology induces early functional disruption prior to overt neurodegeneration. Behavioural outcomes demonstrated selective cognitive deficits and mild anxiety-like behaviours, while other non-motor functions remained preserved. Importantly, although several pathological and functional alterations were evident in the initial phases, behavioural impairments were also maintained at later time points, indicating that locus coeruleus-driven pathology exerts long-lasting consequences. Interestingly, female mice exhibited colon shortening, providing evidence of a sex-specific pathological process at the level of the gut-brain axis. We believe that this model accurately replicates key prodromal features of Parkinsons disease, demonstrating that -synuclein-induced pathology in the locus coeruleus leads to functional circuit impairment and cognitive decline. Our findings emphasize the locus coeruleus as a critical site of early vulnerability in Parkinsons Disease and underscore the importance of sex as a biological variable influencing disease progression and therapeutic response.

neuroscience↗

bioRxiv2025

NEUROGLIAL CB1 RECEPTORS CONTROL NAVIGATION STRATEGIES

Navigation and memory functions are essential for survival and are regulated by the hippocampus. These processes are tightly controlled, and one of the key modulators involved is the endocannabinoid system, particularly through the cannabinoid receptor type-1 (CB1). CB1 is widely expressed in various hippocampal cell types. While it is known that CB1 participates in memory processes, its specific roles in different cell types and how these roles may differ between sexes remain unclear. This study investigates how CB1 signaling in the hippocampus, in both, cell-type-specific and sex-dependent manner, contributes to navigation and memory. To this end, we selectively deleted CB1 receptors from neurons, CAMKII-expressing neurons, and astrocytes from the hippocampus of adult male and female mice. We then assessed its effect on a broad range of behaviors, including innate emotional responses, memory, navigation, and other hippocampus-related functions such as nesting. Deletion of CB1 in CAMKII-expressing neurons produced a pronounced effect in males, leading to increased anxiety and impairments in both reference and spatial memory. These mice also showed altered performance in the Barnes maze, relying less on spatial strategies. By contrast, females were less affected by this specific deletion. Interestingly, only deletion of CB1 from astrocytes led to spatial memory impairments in females, which also showed reduced LTP and a decreased reliance on spatial strategies in the Barnes maze. In conclusion, our findings show that neuronal CB1 receptors are critical for the spatial navigation strategy in males, while astrocytic CB1 receptors play a key role in memory processes both in males and females.

neuroscience↗

bioRxiv2025

A phenomenological interpretation of multiple bursting patterns in Lateral Habenula neurons

The Lateral Habenula (LHb) is a small brain structure specialized in encoding aversive signals. Bursting activity in the LHb has been consistently linked to mood regulation, with increased bursting activity proposed to promote depressive behaviors. Bursting is a complex dynamic process that has been extensively studied and modeled in other neuronal contexts. However, at the LHb this type of activity has typically been described only as transient periods of high frequency firing. Here, to provide a deeper understanding of LHb bursting, we analyzed this activity from the perspective of dynamical systems. Ex vivo, LHb neurons display a variety of bursting patterns, characterized at one extreme by a dominating square-wave type and in other by parabolic type, plus transitional forms referred to as triangular bursting. Notably, these bursting patterns, which reflect different LHb output modes, can occur within the same neuron, suggesting that they may correspond to distinct dynamic states of the same LHb neuron. To capture these complex behaviors, we propose an idealized multiple-timescale dynamical model. This model successfully reproduces the three main bursting patterns observed in experimental data. Furthermore, we identify a special point in the parameter space, termed the saddle-node homoclinic bifurcation, which acts as an organizing center demarcating the boundary between the two primary bursting patterns and around which the third pattern appear. Our model suggests that LHb bursting activity is structured around distinct dynamic states with potentially diverse and unexplored impacts on mood regulation. By providing new insights into the dynamic principles underlying LHb bursting, this framework may advance our understanding of its biological significance.

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bioRxiv2023

Autoimmune inflammation triggers aberrant astrocytic calcium signaling to impair synaptic plasticity

Cortical pathology involving inflammatory and neurodegenerative mechanisms is a hallmark of multiple sclerosis (MS) and a correlate of disease progression and cognitive decline. Astrocytes play a pivotal role in MS initiation and progression but astrocyte-neuronal network alterations contributing to gray matter pathology remain undefined. Here we measured astrocytic calcium in the experimental autoimmune encephalomyelitis (EAE) model of MS using fiber photometry in freely behaving mice and two-photon imaging ex vivo. We identified the emergence of spontaneously hyperactive cortical astrocytes displaying calcium transients of increased duration as well as dysfunctional responses to cannabinoid, glutamate and purinoreceptor agonists during acute EAE disease. Deficits in astrocyte calcium responses are associated to abnormal signaling by Gi and Gq protein coupled receptors in the inflamed cortex and are partially mirrored in cells activated with pro-inflammatory factors both in vitro and ex vivo thus suggesting cell-autonomous effects of the cortical neuroinflammatory environment. Finally, we show that deregulated astrocyte calcium activity is associated to an enhancement of glutamatergic gliotransmission and a shift of astrocyte-mediated short-term and long-term plasticity mechanisms towards synaptic potentiation. Overall our data identities astrocyte-neuronal network dysfunction as key pathological feature of the inflammatory gray matter that may contribute to MS symptomatology and clinical progression.

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bioRxiv2020

A new mutant mouse model lacking mitochondrial-associated CB1 receptor

The idea that the effects of drugs largely depend on subcellular target location is emerging as a novel predictive factor of their beneficial or adverse outcomes. G protein-coupled type-1 cannabinoid receptors (CB1) are regulators of several brain functions as well as the main targets of cannabinoid-based medicines. Besides their classical location at plasma membranes, CB1 receptors are present at different locations within cells, including in association to mitochondrial membranes (mtCB1). Here we report the generation and characterization of a mutant mouse line, which lack mtCB1 receptors.

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bioRxiv2019

Specific hippocampal interneurons shape consolidation of recognition memory

A complex array of different inhibitory interneurons tightly controls hippocampal activity, but how such diversity specifically impacts on memory processes is scantly known. We found that a small subclass of type-1 cannabinoid receptor (CB1)-expressing hippocampal interneurons determines episodic-like memory consolidation by linking dopamine D1 receptor signaling to GABAergic transmission. Mice lacking CB1 in D1-positive cells (D1-CB1-KO) displayed impaired long-term, but not short-term, object recognition memory. Re-expression of CB1 in hippocampal, but not striatal, D1-positive cells rescued this memory impairment. Learning induced a facilitation of in vivo hippocampal long-term potentiation (LTP), which was abolished in mutant mice. Chemogenetic and pharmacological experiments revealed that both CB1-mediated memory and associated LTP facilitation involves the local control of GABAergic inhibition in a D1-dependent manner. This study reveals that CB1-/D1-expressing interneurons shape hippocampal circuits to sustain recognition memory, thereby identifying a mechanism linking the diversity of hippocampal interneurons to specific behavioral and cognitive outcomes.

neuroscience↗

bioRxiv2019

Top-down control of water intake by the endocannabinoid system

Water intake is regulated by neocortical top-down circuits, but their identity and the cellular mechanisms involved are scantly known. Here, we show that endogenous activation of type-1 cannabinoid receptors (CB1) promotes water intake and that endocannabinoid modulation of excitatory projections from the anterior cingulate cortex to the basolateral amygdala is sufficient to guarantee physiological drinking. These data reveal a new circuit involved in the homeostatic control of water intake.

neuroscience↗