Biology subjects

Luscher, C.

Publications and source records attributed to Luscher, C..

5 recordsLinked to original sources

bioRxiv2026

Microbiopsy of living mouse brain for longitudinal molecular profiling

MOTIVATIONLongitudinal molecular studies of the mouse brain are limited by the need for terminal tissue collection. This prevents analysis of preexisting molecular states and their evolution within the same individual. We developed a stereotactic microbiopsy technique that enables minimally invasive sampling of defined brain regions in vivo. The method preserves survival while yielding material suitable for RNA and nuclei isolation. It provides a practical solution for linking baseline molecular states to subsequent behavioural, pharmacological, or disease-related outcomes. SUMMARYThis study presents a stereotactic microbiopsy technique for sampling defined brain regions in living mice, enabling transcriptomic and epigenomic analyses without sacrificing the animal. The method will allow pre-intervention tissue collection, making it possible to separate preexisting molecular differences from experience- or treatment-induced changes. We show that microbiopsies yield sufficient, high-quality RNA and chromatin for sequencing, with minimal tissue damage that largely resolves over time. The procedure uses standard stereotactic equipment and achieves reproducible spatial precision when the syringe is stabilised. This approach provides a practical framework for within-subject molecular comparisons, reducing animal use and enabling longitudinal profiling of the living mouse brain. It establishes a foundation for investigating how baseline molecular states influence later physiological or behavioural outcomes.

neuroscience↗

bioRxiv2026

Optogenetically Evoked Accumbal Dopamine Transients Are Sufficient to Drive Locomotor Sensitization and Cross-Sensitization to Cocaine

Repeated exposure to psychostimulants produces locomotor sensitization, a durable behavioral adaptation thought to reflect enhanced incentive salience driven by mesolimbic dopamine. However, the causal contribution of dopamine transients themselves, independent of drug pharmacology, remains elusive. Here we show that repeated optogenetic activation of ventral tegmental area (VTA) dopamine neurons is sufficient to induce persistent locomotor sensitization. Across successive stimulation sessions, mice exhibited a progressive escalation of locomotor activity that persisted for at least ten days after the last stimulation. Sensitization generalized beyond laser-on epochs, elevating baseline locomotion throughout the session. Importantly, mice previously exposed to optogenetic dopamine neuron stimulation displayed an enhanced locomotor response to a subsequent cocaine challenge, demonstrating cross-sensitization between optogenetic and pharmacological reinforcers. These findings establish phasic dopamine neuron activation as a sufficient driver of locomotor sensitization and reveal shared neural substrates underlying dopamine-dependent behavioral plasticity induced by optogenetic and drug reinforcers.

animal behavior and cognition↗

bioRxiv2025

Dissecting the Crosstalk Between Dopaminergic and Serotonergic Systems in the Striatum

Dopamine (DA) and serotonin (5-HT) are neuromodulators in reward processing, decision- making, and motivated behavior. While often viewed as opposing or complementary systems, how DA and 5-HT release integrate in the striatum remains elusive. Using optogenetics, fiber photometry, and slice electrophysiology, we found that ventral tegmental area (VTA) DA neuron stimulation increased DA release without affecting 5-HT release. Dorsal raphe nucleus (DRN) 5-HT neuron activation, on the other hand, induced serotonin release and a transient increase in DA in the NAc, likely via glutamate co-release onto VTA DA neurons during the initial stimulation phase. These findings indicate that DA and 5-HT operate largely independently in the striatum, with selective circuit-dependent interactions. This work refines our understanding of DA-5HT interactions and provides a foundation for future research into their roles in motivated behaviors and neuropsychiatric disorders.

neuroscience↗

bioRxiv2025

Distinct modes of dopamine modulation on striatopallidal synaptic transmission

Dopamine (DA) affects voluntary movement by modulating basal ganglia function. In the classical model, DA depletion leads to overactivity of the indirect pathway and excessively inhibits the thalamus, resulting in hypokinesia. The contribution of DA on striatopallidal synapses, an initial hub in the indirect pathway connecting the striatum to the external globus pallidus (GPe), remains poorly understood because of the sparse DA innervation. Here, we combine optogenetic projection targeting, whole cell patch clamp recordings in acute brain slices from mice, and computational modeling to overcome this limitation. We show that DA activates D2R receptors (D2Rs) and D4 receptors (D4Rs) differentially in distinct GPe subregions. In a pinwheel-like fashion, dorsolateral and ventromedial GPe expresses high levels of D2Rs, which exert presynaptic inhibition, while in dorsomedial and ventrolateral GPe D4Rs cause postsynaptic inhibition. DA depletion by 6-OHDA (6-hydroxydopamine) reverses the region- specific effect of DA, shifting it in the opposite direction and contributing to hypokinesia. These findings reveal the mechanism by which the different modality information conveyed spatially through the indirect pathway is differentially modulated by DA at striatopallidal synapses.

neuroscience↗

bioRxiv2017

Periaqueductal Efferents To Dopamine And GABA Neurons Of The VTA

Neurons in the periaqueductal gray (PAG) modulate threat responses and nociception. Activity in the ventral tegmental area (VTA) on the other hand can cause reinforcement and aversion. While in many situations these behaviors are related, the anatomical substrate of a crosstalk between the PAG and VTA remains poorly understood. Here we describe the anatomical and electrophysiological organization of the VTA-projecting PAG neurons. Using rabies-based, cell type-specific retrograde tracing, we observed that PAG to VTA projection neurons are evenly distributed along the rostro-caudal axis of the PAG, but concentrated in its posterior and ventrolateral segments. Optogenetic projection targeting demonstrated that the PAG-to-VTA pathway is predominantly excitatory and targets similar proportions of Ih-expressing VTA DA and GABA neurons. Taken together, these results set the framework for functional analysis of the interplay between PAG and VTA in the regulation of reward and aversion.

neuroscience↗