Biology subjects

Joca, S.

Publications and source records attributed to Joca, S..

9 recordsLinked to original sources

bioRxiv2026

High-intensity fear engrams extend beyond threat processing to drive cognitive and affective dysfunction

Maladaptive fear memories are a core feature of stress-related disorders and are often accompanied by cognitive and affective disturbances; yet, it remains unclear whether the same neuronal ensembles link maladaptive fear to these behavioural alterations. Here, we show that activity of fear engrams causally contributes to behavioural consequences of intense fear beyond threat processing. Using activity-dependent tagging in the dorsal dentate gyrus (dDG) of mice, we identify neuronal ensembles recruited during high-intensity fear conditioning and show that chemogenetic inhibition of these neurons restores cognitive performance and reduces behavioural despair. These effects are specific to fear-associated ensembles, as inhibition of randomly tagged neurons fails to reproduce them, and depend on persistence of the fear memory, as they are abolished following extinction. Cell-type-specific manipulations revealed that glutamatergic, but not GABAergic, HI-tagged neurons drive fear expression and the associated cognitive and affective alterations, whereas GABAergic neurons exert an opposing influence on fear expression. Consistent with these findings, high-intensity fear was associated with increased reactivation of excitatory fear-tagged neurons and reduced reactivation of GABAergic fear-tagged neurons during behavioural despair. Together, these findings identify high-intensity fear engrams as a causal substrate linking threat-related experiences to cognitive and affective dysfunction and implicate altered excitatory-inhibitory recruitment within a single memory ensemble in the emergence of multi-domain behavioural alterations associated with stress-related disorders.

neuroscience↗

bioRxiv2026

Antidepressants interact with sex steroid receptors and their intracellular signaling components

There is growing interest in understanding how hormonal signaling pathways contribute to the pathophysiology of mood disorders, based on the premise that fluctuations in sex hormones influence mood, a relationship particularly evident in conditions such as premenstrual dysphoric disorder, prenatal depression, postpartum depression, and perimenopausal depression. Estrogen receptor alpha (ER) is predominantly localized in the nucleus, but can also be associated with the cell membrane, thus mediating a broad range of genomic and non-genomic effects through distinct intracellular pathways. By employing a combination of computational simulations and in vitro biochemical and cell-based assays, we systematically evaluated the potential binding and functional interactions of antidepressant compounds with ER. Our results provide compelling evidence that antidepressants may not only affect classical monoaminergic targets but also modulate hormone receptor activity, particularly that of ER. These findings are consistent with the hypothesis that ER plays an important role in mood regulation and highlight it as a potential therapeutic target. Moreover, this work raises the possibility that the clinical efficacy of certain antidepressants may, at least in part, derive from their capacity to influence estrogen receptor-mediated signaling. Significance statementClinical observations suggest a link between female sex hormones and mood, highlighted by the higher prevalence of depression in women and increased vulnerability to depression during hormonal fluctuations. Here, we report that structurally diverse conventional and rapid-acting antidepressants directly interact with estrogen receptor alpha (ER). This interaction is associated with rapid intracellular signaling in cellular models. These findings indicate that, alongside their conventional targets, antidepressants may also engage sex steroid receptor components and signaling. This work broadens our basic understanding of antidepressant pharmacology at the cellular level, offering an additional perspective that may inform future research into the biological mechanisms of mood disorders and suggest a framework for developing targeted therapies for hormone-associated depressive disorders.

pharmacology and toxicology↗

bioRxiv2025

Extracellular vesicles from morphine-exposed prefrontal cortex carry transcriptomic and proteomic signatures of synaptic dysfunction

Extracellular vesicles (EVs) released by neurons and glial cells mediate intercellular communication in the brain and regulate synaptic function, neuronal survival, and neuropathological processes. Although chronic opioid exposure induces widespread neuroadaptations, the contribution of brain-derived EVs (BDEVs) to these processes remains largely unknown. Here, we isolated BDEVs from the prefrontal cortex of rats chronically exposed to morphine and performed integrative transcriptomic and proteomic analyses of their molecular cargo. Total RNA sequencing combined with unbiased proteomics revealed that morphine profoundly reprograms the BDEV transcriptome and proteome, enriching pathways related to synaptic plasticity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and neurodegeneration. Among the most prominent alterations, the synaptic regulator ARC was consistently modulated at the mRNA level, while the ER stress marker HSPA5 was altered at both mRNA and protein levels. Functional assays further demonstrated that BDEVs derived from morphine-treated rats were sufficient to reconfigure transcriptional programs in naive cortical neurons, affecting genes associated with synaptic remodeling and excitability. Collectively, these findings provide the first evidence that chronic opioid exposure reprograms BDEV cargo in a brain region critical for addiction and that these vesicles can propagate transcriptional reorganization to recipient neurons. BDEVs thus emerge as active mediators of morphine-induced neuroadaptations and as potential targets for biomarker discovery and therapeutic intervention in opioid use disorder.

neuroscience↗

bioRxiv2022

Characterization of a novel gene-environment-based animal model to study resilience and susceptibility to PTSD and co-morbid depression

BACKGROUNDPost-traumatic stress disorder (PTSD) and co-morbid depression are frequently associated with severe symptoms, poor response to treatment and worse prognosis. Due to the absence of a suitable animal model, little is known about the biological basis of the comorbidity, severely limiting the discovery of new and more effective treatment options. The Flinders Sensitive Line rats (FSL) is a well-validated, selectively bred animal model of depression. However, several of its features, such as cognitive deficits and altered hypothalamic-pituitary-adrenal (HPA) axis response, also match symptomatic clusters of PTSD. In parallel, its resistant counterpart, the Flinders Resistant Line (FRL), is extensively used as a simple control. Still, little is known about its performance compared to the original strain, Sprague Dawley (SD), from which the FSL/FRL was originally derived. AIMSCharacterizing the behavioural performance and mechanisms involved in FSL, FRL and SD rats in fear-memory paradigms. METHODSFSL, SD and FRL animals were submitted to tests assessing hippocampal-dependent and fear-related memory. Subsequently, plasticity factors and endocrine responses to stress were analysed to elucidate the molecular basis for the observed behavioural alterations. RESULTSWe found that FRL animals presented intact recognition memory and innate fear responses but could not properly display conditioned responses in the Conditioned Fear Conditioning (CFC) paradigm. FSL animals, despite a poor performance in the Novel Object Recognition task (NOR), showed similar levels of conditioned responses compared to SD, but impairments in extinction learning, a feature highly related to PTSD. The behavioural alterations were accompanied by alterations in plasma corticosterone levels and hippocampal expression of the glucocorticoid receptor and FKBP51. CONCLUSIONFor the first time, we demonstrate an animal model of resilience and vulnerability to PTSD and co-morbid depression. The results suggest that the endophenotypes may be based on aberrant endocrine stress responses in the hippocampus.

neuroscience↗

bioRxiv2021

Fluoxetine acts concomitantly on dorsal and ventral hippocampus to Trk-dependently modulate the extinction of fear memory

BackgroundHippocampus can be divided along its longitudinal axis into dorsal and ventral parts. Both are usually committed to modulate different aspects of behavior and stress response. However, it is not clear whether the hippocampal subregions could differently modulate the effect of antidepressant drugs. Since fluoxetine (FLX) effect on extinction of aversive memory is well known to depend on hippocampal BDNF levels, we hypothesized that the hippocampal subregions might play different roles in fluoxetine efficacy in decreasing fear response. MethodWistar rats were fear-cued conditioned and treated chronically with fluoxetine to enhance their subsequent extinction memory. First, FLX effect on BDNF levels was assessed considering the dorsal (dHC) and ventral (vHC) hippocampus apart. Then, K252a (a functional Trk blocker) was infused either into the dHC or vHC to assay its interaction with FLX treatment over the fear response. Next, BDNF was directly infused into either the dHC or vHC to compare its behavioral effects with FLX. Finally, FLX effect on c-Fos expression was evaluated also considering the dHC and vHC apart, along with subareas of amygdala and medial prefrontal cortex. ResultsChronic FLX treatment increased BDNF in the dHC, whereas BDNF was increased in the vHC after acute treatment only. K252a infused after the extinction protocol into either dHC or vHC was able to prevent FLX effect on fear response. BDNF directly infused into the dHC increased fear response, however its administration into the vHC induced an opposite effect. Besides, a negative correlation between the fear response and c-Fos expression was observed after chronic FLX treatment specifically in the dHC CA3/CA1 and vHC CA1/DG. ConclusionBoth dHC and vHC are important for the Trk-dependent FLX effect on extinction memory, although a discrepancy on the fear response was observed with the direct infusion of BDNF into the dHC or vHC.

neuroscience↗

bioRxiv2018

Dual mechanism of TRKB activation by anandamide through CB1 and TRPV1 receptors

Backgroundadministration of anandamide (AEA) or 2-arachidonoylglycerol (2AG) induces CB1 coupling and activation of TRKB receptors, regulating the neuronal migration and maturation in the developing cortex. However, at higher concentrations AEA also engages vanilloid receptor - TRPV1, usually with opposed consequences on behavior. Methods and ResultsUsing primary cell cultures from the cortex of rat embryos (E18) we determined the effects of AEA on phosphorylated TRKB (pTRK). We observed that AEA (at 100 and 200nM) induced a significant increase in pTRK levels. Such effect of AEA at 100nM was blocked by pretreatment with the CB1 antagonist AM251 (200nM) and, at the higher concentration of 200nM by the TRPV1 antagonist capsazepine (200nM), but mildly attenuated by AM251. Interestingly, the effect of AEA or capsaicin (a TRPV1 agonist, also at 200nM) on pTRK was blocked by TRKB.Fc (a soluble form of TRKB able to bind BDNF) or capsazepine, suggesting a mechanism dependent on BDNF release. Using the marble-burying test (MBT) in mice, we observed that the local administration of ACEA (a CB1 agonist) into the prelimbic region of prefrontal cortex (PL-PFC) was sufficient to reduce the burying behavior, while capsaicin or BDNF exerted the opposite effect, increasing the number of buried marbles. In addition, both ACEA and capsaicin effects were blocked by previous administration of k252a (an antagonist of TRK receptors) into PL-PFC. The effect of systemically injected CB1 agonist WIN55,212-2 was blocked by previous administration of k252a. We also observed a partial colocalization of CB1 /TRPV1 /TRKB in the PL-PFC, and the localization of TRPV1 in CaMK2+ cells. Conclusiontaken together, our data indicate that anandamide engages a coordinated activation of TRKB, via CB1 and TRPV1. Thus, acting upon CB1 and TRPV1, AEA could regulate the TRKB-dependent plasticity in both pre- and postsynaptic compartments.

neuroscience↗

bioRxiv2018

Refinement of anesthetic choice in procedures preceding psychopharmacological studies

RationalePrevious studies indicated that some general anesthetics induce long-term antidepressant and/or anxiolytic-like effects. This raises the concern about the use of anesthesia in surgeries that precede psycopharmacological tests, since it may be a potential bias on results depending on the experimental design used.\n\nObjectivesTo evaluate whether commonly used general anesthetics in surgeries preceding psychopharmacological tests would affect rat behavior in tests predictive of antidepressant or anxiolytic-like effects. We also evaluated whether prior anesthesia would interfere in the detection of the antidepressant-like effect of imipramine or the anxiolytic-like effect of diazepam.\n\nMethodsWe tested if a single exposure to subanesthetic or anesthetic doses of 2,2,2-tribromoethanol, chloral hydrate, thiopental or isoflurane would change rats behavior in the forced swimming test (FST) or in the elevated plus-maze (EPM) test, at 2 hours or 7 days after administration.\n\nResultsPrevious anesthesia with the aforementioned anesthetics did not change rat behavior in FST per se nor it changed the antidepressant-like effect induced by imipramine treatment. Rats previously anesthetized with tribromoethanol or chloral hydrate exhibited, respectively, anxiogenic-like or anxiolytic-like behavior in the EPM. Prior anesthesia with thiopental or isoflurane did not produce any per se effect in rat behavior in the EPM nor disturbed the anxiolytic-like effect of diazepam.\n\nConclusionOur results suggest that, in our experimental conditions, tribromoethanol and chloral hydrate are improper anesthetics for surgeries that precede behavioral tests related to anxiety. Isoflurane or thiopental may be suitable for anesthesia before evaluation in animal models predictive of antidepressant or anxiolytic-like effect.

neuroscience↗

bioRxiv2017

Elastase-2 knockout mice display anxiogenic- and antidepressant-like phenotype: putative role for BDNF metabolism in prefrontal cortex

Several pieces of evidence indicate that elastase-2 (ELA2; chymotrypsin-like ELA2) is an alternative pathway to the generation of angiotensin II (ANG II). Elastase-2 knockout mice (ELA2KO) exhibit alterations in the arterial blood pressure and heart rate. However, there is no data on the behavioral consequences of ELA2 deletion. In this study we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety- and depression-like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimeter test indicated a decrease in total activity and confirmed the increase in repetitive behavior. The spatial memory was tested by repeated exposure to the actimeter in a 24h interval. Both ELA2KO and WT exhibited decreased activity compared to the first exposure, without any distinction between the genotypes. However, when submitted to the cued fear conditioning, ELA2KO displayed lower levels of freezing behavior in the extinction session when compared to WT, but no difference was observed during the conditioning phase. Increased levels of BDNF were found in the prefrontal cortex but not in the hippocampus of ELA2KO mice compared to WT. Finally, in silico analysis indicates that ELA2 is putatively able to cleave BDNF, and incubation of the purified enzyme with BDNF led to the degradation of the later. Our data suggested an anxiogenic- and antidepressant-like phenotype of ELA2KO, possibly associated with increased levels of BDNF in the prefrontal cortex.

animal behavior and cognition↗

bioRxiv2016

TrkB signaling underlies the rapid antidepressant effects of isoflurane

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3{beta} (GSK3{beta}). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.

neuroscience↗