Biology subjects

Cathala, A.

Publications and source records attributed to Cathala, A..

4 recordsLinked to original sources

bioRxiv2025

Ketamine strengthens synaptic inputs to the dorsal raphe to boost serotonergic activity: pivotal for rapid antidepressant-like effects

Ketamine at subanaesthetic dose is known as a fast-acting antidepressant (AD), able to facilitate synaptic plasticity in the medial prefrontal cortex (mPFC) or the hippocampus. However, its influence on the serotonergic (5-HT) system is more confusing as it loses its behavioral effects in 5-HT-depleted animals, but does not modify 5-HT neuron function. We hypothesized that this discrepancy was due to the different temporal scales chosen in the related studies. We performed electrophysiological recordings of 5-HT neurons in the dorsal raphe nucleus (DRN) and microdialysis measurements of 5-HT release in the ventral hippocampus of male Sprague-Dawley rats. Experiments were designed to collect the results over a long duration, i.e. 4-5 hours after the injection. Levels of the pro-neuroplastic factors PSD-95 and Synapsin-1 in the DRN were also assessed, as was cell proliferation in the dentate gyrus (DG). 5-HT neuron mean firing rate was unmodified within the 2 h that followed ketamine (10 mg/kg, i.p.), but strongly (90%) increased in the 2-5 h time bin, an effect abolished by lesioning the mPFC or administering the mTOR inhibitor Torin-2. A similar kinetics was found for hippocampal 5-HT release. Synapsin-1 and PSD-95 mRNA transcriptions were enhanced at 2 h, and PSD-95 protein levels appeared to peak at 24 h. Finally, DG mitogenesis was enhanced 48 h post-injection, an augmentation suppressed in 5-HT-depleted animals. Low-dose ketamine provokes a "neuroplastic wave" originating in the mPFC and emerging in the hippocampus, a transfer in which the 5-HT system appears to act as an integrative hub of plasticity. SIGNIFICANCE STATEMENTThis study helps reconcile two theories, often opposed to explain antidepressant (AD) action: the "serotonergic hypothesis" proposing that AD efficacy primarily results from an increase of serotonin, and the "neuroplastic theory" whereby only significant changes in brain connectivity can explain mood improvement. Here we show that ketamine, a drug exerting AD effects much faster than classical molecules do, augments synaptic strength onto serotonergic neurons, which subsequently triggers an elevation of serotonin. In turn, this enhanced serotonergic neurotransmission leads to the production of new neurons in the hippocampus, therefore reshaping the circuitry of this brain area. The serotonergic system appears to transfer the neuroplastic changes induced by ketamine across the brain, thus behaving like an integrative hub for its AD action.

neuroscience↗

bioRxiv2025

Stress-induced plasminogen activator inhibitor-1 (PAI-1) as a blood biomarker and brain risk factor for PTSD

Post-traumatic stress disorder (PTSD) is a severe stress-related psychiatric condition triggered by traumatic life-threatening events, characterized notably by an altered memory profile. Although clinically well-documented, no specific biomarker exists. This translational study identifies plasminogen activator inhibitor-1 (PAI-1) as a brain risk factor for PTSD, thereby supporting its potential as a blood-derived biomarker. Mice with genetically ablated PAI-1 were protected from developing a PTSD-like memory profile. Conversely, mice exhibiting PTSD-like cognitive impairment showed increased blood PAI-1 levels, correlating with their profile severity. In the brain, PAI-1 levels were specifically increased in the dorsal hippocampus, a key region for cognitive functions and in the etiology of PTSD. Finally, a longitudinal study of soldiers revealed that those developing PTSD symptoms exhibit rising blood PAI-1 levels over a 12-month period. Its significant association with various indicators of PTSD-related psychological distress attests to PAI-1s potential as a blood biomarker and brain therapeutic target for PTSD.

neuroscience↗

bioRxiv2025

Pregnenolone and AEF0117 block cannabinoid-induced hyperlocomotion through GSK3β signaling at striatopallidal neurons

Administration of {Delta}9-tetrahydrocannabinol (THC), the main psychoactive component of the plant Cannabis sativa, can induce psychotic symptomatology in humans and a large spectrum of acute psychotic-like behaviors in mice, including hyperlocomotion observed at low dose of THC (0.3 mg/kg). The cellular and molecular substrates of this effect have not been fully identified yet. Here we demonstrate that THC-induced hyperlocomotion depends on plasma membrane CB1R, which regulate the {beta}-arrestin 1/Akt/GSK3{beta} signaling pathway in D2R-positive neurons of the dorsal striatum forming the striatopallidal pathway of the basal ganglia. Pregnenolone (PREG) and its clinically developed analog, AEF0117, which are signaling specific inhibitors of CB1R (CB1-SSi), prevented GSK3{beta}-dependent psychomotor stimulation induced by THC. Overall, this work highlights a novel intracellular mechanism of CB1R, thereby revealing a neuronal pathway underlying an important but still underexplored effect of THC and cannabis consumption, which could help the development of innovative therapeutic concepts against psychotic conditions.

neuroscience↗

bioRxiv2024

Midbrain dopamine D2R regulates the salience of threat-related events

Salience attributed to stimuli predicting rewarding or aversive outcomes is critical for adaptive behavior. Dopamine (DA)-neurons play a central role in this process by modulating responses to both rewarding and aversive cues. DA-neurons are tightly and readily modulated by DA D2 autoreceptors (autoD2Rs), but their role in regulating responses to aversive stimuli remains unclear. In this study, we investigated the role of autoD2R in regulating the activity of VTA DA-neurons in response to salient aversive stimuli. Using Drd2Slc6a3 mice, in which Drd2 is selectively deleted in DA-neurons, we observed enhanced excitatory and inhibitory responses of VTA DA-neurons to aversive stimuli, suggesting that autoD2R acts as a critical regulatory brake. Importantly, this modulation occurred independently of either the pacemaker activity of DA-neurons or their coupling to the non-selective sodium leak channel NALCN. Behaviorally, Drd2Slc6a3 male mice showed enhanced discrimination between threat-predicting and non-predicting cues that persisted during extinction learning, highlighting a sex-biased role of autoD2R in threat processing. Our results provide new mechanistic insights through which autoD2R influence behavioral responses to aversive stimuli, with implications for understanding neuropsychiatric disorders characterized by maladaptive threat processing.

neuroscience↗