Biology subjects

Cecchi, C. R.

Publications and source records attributed to Cecchi, C. R..

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↗

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↗

bioRxiv2024

The selective 5-HT2A receptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents

Psychedelic-assisted psychotherapy has over the last decade emerged as a promising treatment strategy for mental health disease, and the therapeutic potential in classical psychedelics such as psilocybin, LSD and 5-MeO-DMT is presently being pursued in a plethora of clinical trials. However, the resurgent interest in the drugs as therapeutics has also prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the results of an elaborate preclinical characterization of one such compound, LPH-5 [(S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT2A receptor (5-HT2AR) and to exhibit pronounced selectivity for this receptor over the related 5-HT2B and 5-HT2C receptors in a range of functional assays. LPH-5 (0.375 - 12.0 mg/kg, i.p.) dose-dependently induced head-twitch responses (HTR) in Sprague Dawley rats, with substantial 5-HT2AR engagement being observed at 0.5-1.0 mg/kg. Acute administration of LPH-5 (1.5 mg/kg, i.p.) induced robust antidepressant-like effects in Flinders Sensitive Line rats and adrenocorticotropic hormone-treated Sprague Dawley rats, and LPH-5 (0.3 and 1.5 mg/kg, i.p.) induced significant effects in a recently developed Wistar Kyoto rat model proposed to reflect the long-term antidepressant-like effects produced by psychedelics in humans. In conclusion, selective 5-HT2AR activation, as mediated here by LPH- 5, seems to hold antidepressant potential, suggesting that this activity component is key for the beneficial effects of classical psychedelics. Hence, we propose that LPH-5 and other 5-HT2AR- selective agonists could hold potential as therapeutics in psychiatric disease as a new generation of psychedelic-derived antidepressant.

neuroscience↗