Description

Depression represents a major global health burden and is frequently associated with an increased risk of comorbid cardiovascular diseases, particularly in women. A key limitation of selective serotonin reuptake inhibitors (SSRIs), the current first-line treatment for major depression, lies in the substantial proportion of patients who fail to respond, as well as in their lack of cardioprotective effects. We hypothesize that the serotonin type 3 receptor (5-HT3R) contributes to this limited therapeutic efficacy through its GABAergic inhibitory actions. Specifically, activation of 5-HT3Rs in the prefrontal cortex may attenuate the amplification of serotonergic signaling and impair hippocampal function. In parallel, 5-HT3R activation in medullary regions may drive vagally mediated cardiac dysfunction and systemic inflammation,
with potential downstream effects on central structures, particularly the hippocampus.
To test this hypothesis, we will evaluate the therapeutic effects of combining an SSRI (fluoxetine) with a 5- HT3 receptor antagonist (ondansetron), compared to fluoxetine alone, in mice exposed to different stress paradigms: males subjected to a pharmacological stress model and females to an emotional stress model. We will assess behavioral and cognitive phenotypes, as well as functional and structural brain alterations.
We will also investigate vagus nerve–mediated cardiac and inflammatory responses. In addition, by combining genetic and pharmacological suppression of the 5-HT3 receptor, we aim to disentangle the specific contributions of receptor populations located in the brainstem/spinal cord and cortex to treatment resistance

Skills required

The ideal candidate should ideqlly have experience in a Master’s program working with animal stress models, be proficient in immunohistochemistry techniques, and have prior experience with small animal surgery. He/she should also be comfortable writing reports and scientific articles.

Bibliography

-Mendez-David, I. et al. A complex relation between levels of adult hippocampal neurogenesis and expression of the immature neuron marker doublecortin. Hippocampus 33, 1075–1093 (2023).
-Vialou, V. et al. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of ΔFosB. J Neurosci 34, 3878–3887 (2014).
-David, D. J. et al. Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of Anxiety/Depression. Neuron 62, 479–493 (2009).
-Brouillard, C., Carrive, P. & Sévoz-Couche, C. Social defeat: Vagal reduction and vulnerability to ventricular arrhythmias. Neurobiol Stress 13, 100245 (2020).

Keywords

depression, cognitive alteration, animal model, treatment resistance, serotonine, autonomic