Biology subjects

Iglesias, L. P.

Publications and source records attributed to Iglesias, L. P..

3 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↗

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

Hippocampal TRPV1 channels in the modulation of contextual fear conditioning

Psychiatric disorders have been linked to impairments in fear memory circuitry. Thus, pharmacological approaches that impair aversive memories have been investigated as new treatments. The TRPV1 channel modulates biological processes related to memory consolidation and retrieval. However, TRPV1 seems involved in memories generated by high intense conditioning. Anandamide (AEA), the main endocannabinoid, is an agonist of both, TRPV1 channels and CB1 receptors which are colocalized in several brain structures. Remarkably, AEA has twenty-times more affinity for CB1 than for TRPV1, which may be involved in the intensity-dependent recruitment of this channel. In order to evaluate the role of intensity of the conditioning in the recruitment of TRPV1, the animals were submitted to the contextual fear conditioning (CFC) and conditioned with low, moderate or high intensity. Before the retrieval a TRPV1 blocker was administered into the dorsal hippocampus (dHPC). The levels of AEA were quantified by Mass Spectrometry. The RNA levels of Arc, Zif and Trkb, involved in memory and plasticity, were quantified by PCR. Our results showed that TRPV1 blockers impair the retrieval of memory in animals conditioned with moderate and high intensity but not low ones. As revealed by Mass Spectrometry, this different recruitment among intensities seems to be associated with the levels of AEA released. Moreover, the impairment in freezing induced by blocking TRPV1 was prevented by a subeffective dose of the cannabinoid receptor CB1 antagonist which suggest that TRPV1 blockers act increasing AEA availability in the synaptic cleft to act through CB1 receptors. Despite blocking TRPV1 channels impairs freezing in moderate and high intensities, it increases the RNA levels of Arc, Zif and Trkb only in animals conditioned with the moderate intensity. In accordance, the treatment impairs retrieval in both intensities but only in the moderate intensity is able to prevent the reinstatement. Summarizing, our results suggested that intensity of the conditioning modulates AEA levels which in turns determines if TRPV1 will be recruited at the retrieval and which molecular pathways will be engaged due to TRPV1 blocking.

pharmacology and toxicology↗