Biology subjects

Mecdad, Y.

Publications and source records attributed to Mecdad, Y..

3 recordsLinked to original sources

bioRxiv2026

In vitro programming and pseudounipolarization of human iPSC-derived sensory neurons

Ectopic expression of NGN1, BRN3A and ISLET1 (NBI) from a safe harbor locus in induced pluripotent stem cells (iPSCs) yielded robust differentiation into functional sensory neurons (iNBI-SNs) within seven days. Single nucleus transcriptomics identified peripheral sensory neuron profiles of nociceptors and mechanoreceptors. Electrophysiological studies showed that more than 98 % of iNBI-SNs display TTX-resistant sodium currents and that they establish functional connections to excitatory CNS neurons. iNBI-SNs derived from patients with inherited erythromelalgia, a pain disorder associated with gain-of-function mutations in the Nav1.7 sodium channel showed pathologically increased firing rates which could be partially rescued with a Nav1.7 inhibitor. Notably, iNBI-SNs acquire a characteristic pseudounipolar morphology upon co-culture with embryonic rodent DRG cells. Taken together, NBI-based forward programming of iPSCs represents a robust approach for the generation of human sensory neurons suitable for developmental, disease- and therapy-related studies.

neuroscience↗

bioRxiv2025

Loss of noradrenergic Fkbp5 disrupts social behavior and norepinephrine dynamics in the basolateral amygdala

Social dysfunction is common in depression and varies with stress exposure and genetic risk. The current study identifies a cell-type specific role for Fkbp5, a glucocorticoid receptor co-chaperone, in noradrenergic neurons engaged during social stress. Acute social stress upregulated Fkbp5 in the locus coeruleus (LC), whereas repeated exposure attenuated this effect. Noradrenergic Fkbp5 deletion (Fkbp5Nat) increased pro-social behavior exclusively in male mice. In the basolateral amygdala (BLA), social interaction reduced norepinephrine (NE) turnover in wild-type but not Fkbp5Nat mice. Consistently, proteomics revealed mitochondrial/energy and synapse-related remodeling in BLA neurons. Miniscope imaging showed that behavior-locked NE transients in BLA were selectively blunted in Fkbp5Nat mice during interaction with outbred CD1 conspecifics, while same-strain C57BL/6N encounters preserved NE dynamics. Together, this study indicates that Fkbp5 tunes LC-BLA output to social salience in a sex- and context-dependent manner, suggesting a circuit-specific route to normalize social salience without broadly suppressing noradrenergic function.

neuroscience↗

bioRxiv2024

Spermidine alleviates depression via control of the stress response

Depression is a stress-associated disorder, and it represents a major global health issue. Its pathophysiology is complex and remains insufficiently understood, with current medications often showing limited efficacy and undesirable side effects. Here, we identify imbalanced polyamine levels and dysregulated autophagy as key components of the acute stress response in humans, and as hallmarks of chronic stress and depressive disorders. Moreover, conventional antidepressant pharmacotherapy increases endogenous plasma concentrations of the polyamine spermidine exclusively in patients who respond to the treatment, suggesting a link between spermidine and successful outcomes. In a clinical trial, involving drug-naive depressed individuals, three weeks of spermidine supplementation increased autophagy and alleviated symptoms of depression. Behavioral and mechanistic findings of spermidine supplementation were validated in various mouse stress and depression models. In summary, spermidine supplementation mitigates polyamine dysregulation and stimulates autophagy under pathological stress conditions, offering a novel and well-tolerated treatment approach for stress-related depressive disorders.

neuroscience↗