Biology subjects

Leste-Lasserre, T.

Publications and source records attributed to Leste-Lasserre, T..

6 recordsLinked to original sources

bioRxiv2026

A Female-Specific Microglial Redox Program Gates Susceptibility to Obesity

Chronic consumption of energy-dense, high-fat foods persistently exposes hypothalamic circuits that govern body weight to nutrient excess, progressively altering their activity and thereby promoting obesity. Microglia, the brain resident immune cells, sense circulating lipids, but how their intracellular metabolic programs adapt to chronic dietary excess, and how this contributes to obesity risk, is unclear. Here, we reveal a sex-dependent control of calorie overload by hypothalamic microglial cells. In females, but not males, microglia engage a protective metabolic program with increased antioxidant capacity and mitochondrial network remodeling, conferring resistance to early weight gain. Over time, activation of mTORC1 signaling in microglia disrupts mitochondrial functions and dismantles this transient resilience, culminating in weight gain. These findings identify microglial mTORC1 as a sex-specific switch between resilience and vulnerability to obesity and position microglial metabolism as a tractable target for sex-informed weight control.

neuroscience↗

bioRxiv2026

Blade-dependent molecular identity and neurogenic potential in the adult dentate gyrus

The dentate gyrus (DG) is a key hippocampal gateway for cognition and emotion and a major site of adult neurogenesis, yet its organization along the transverse (suprapyramidal- infrapyramidal) axis remains poorly understood. Here, by integrating bulk RNA sequencing of microdissected mouse DG blades with spatial transcriptomics and single-nucleus RNA sequencing, we define the suprapyramidal and infrapyramidal blades (SB and IB) as distinct molecular compartments characterized by anterior-posterior-dependent gene expression programs. Functionally, the SB exhibits enhanced neurogenic activity, particularly in the anterior DG, including increased progenitor proliferation and neuronal differentiation, whereas the IB contains a larger pool of quiescent neural stem cells. Together, these findings reveal molecular and functional specialization along both transverse and longitudinal axes of the DG and provide a framework for interrogating hippocampal subregional organization in health and disease.

neuroscience↗

bioRxiv2026

Ventromedial striatal GABAergic interneurons sex-dependently gate cost-benefit choices between food and exercise

Healthy energy balance relies on an equilibrated trade-off between the respective drives for food and exercise. However, the motivation circuitry underlying the choice between these two rewards remains unknown. Here, we developed a neuroeconomic model wherein mice living in operant chambers needed to choose between standard food and wheel running under increasing effort demands. Reward seeking resistance to increasing costs was then quantified using feeding and exercise essential values (EVs). Through conditional genetics and viral approaches, we show that cannabinoid type-1 receptors (CB1Rs) located on GABAergic neurons gate in necessary and sufficient manners exercise EV, exercise preference over feeding and exercise duration per rewarded sequence. Further, we report that these GABAergic neurons are located in the ventromedial striatum in males, but not females. CB1R deletion from medium spiny neurons did not impact exercise motivation, revealing an unforeseen role for ventromedial striatal GABAergic interneurons in effort-based decision-making between food and exercise.

neuroscience↗

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↗

bioRxiv2020

The atypical Rho GTPase Rnd2 is critical for dentate granule neuron development and anxiety-like behavior during adult but not neonatal neurogenesis

Despite the central role of Rho GTPases in neuronal development, their functions in adult hippocampal neurogenesis remain poorly explored. Here, by using a retrovirus-based loss-of-function approach in vivo, we show that the atypical Rho GTPase Rnd2 is crucial for the survival, positioning, somatodendritic morphogenesis and functional maturation of adult-born dentate granule neurons. Interestingly, most of these functions are specific to granule neurons generated during adulthood since the deletion of Rnd2 in neonatally-born granule neurons only affects dendritogenesis. In addition, suppression of Rnd2 in adult-born dentate granule neurons increases anxiety-like behaviour whereas its deletion in pups has no such effect, a finding supporting the adult neurogenesis hypothesis of anxiety disorders. Thus, our results provide mechanistic insight into the differential regulation of hippocampal neurogenesis during development and adulthood, and establishes a causal relationship between Rnd2 expression and anxiety.

neuroscience↗

bioRxiv2019

Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in non-human primates

AO_SCPLOWBSTRACTC_SCPLOWDopaminergic neuronal cell death, associated with intracellular -synuclein (-syn)-rich protein aggregates (termed Lewy bodies), is a well-established characteristic of Parkinsons disease. Much evidence, accumulated from multiple experimental models has suggested that -syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct -syn pathogenic structures derived from PD patients. Unexpectedly, our results show that, in non-human primates, a small amount of singular -syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD as multiple causes can induce similar outcome regarding dopaminergic neurodegeneration.

neuroscience↗