Biology subjects

Meye, F. J.

Publications and source records attributed to Meye, F. J..

7 recordsLinked to original sources

bioRxiv2025

Comparative gene editing reduces dopamine receptor levels across rodent species

Translational challenges in neuroscience originate from species-specific differences that limit the generalizability of experimental findings. Comparative approaches can help distinguish conserved from species-specific mechanisms, but their application has been limited by the lack of molecular tools beyond traditional model organisms, complicating direct comparisons of conserved and divergent mechanisms of neural function. This gap is particularly evident for the dopaminergic system, a key regulator of motivated behaviors across species and the principal pharmacological target for current psychotherapies. Building on our recent development of comparative gene editing, we here present an adeno-associated virus-mediated CRISPR/Cas9 strategy to reduce in vivo dopamine receptors D1 and D2 levels across the rodent phylogeny. Using this approach, we achieved specific reduction of receptor levels in three rodent species (house mouse, prairie vole, and Syrian hamster), which we demonstrate with radioactive ligand binding assays. This toolkit expands the reach of comparative gene editing approaches, enabling functional investigation of the dopaminergic system across rodent species. Thereby, it supports comparative neuroscience by facilitating the identification of conserved versus species-specific neural mechanisms with enhanced translational potential.

neuroscience↗

bioRxiv2024

Distinct ventral tegmental area neuronal ensembles are indispensable for reward-driven approach and stress-driven avoidance behaviors

Assigning valence to stimuli for adaptive behavior is an essential function, involving the ventral tegmental area (VTA). VTA cell types are often defined through neurotransmitters (NT). However, valence function in VTA does not parse along NT-boundaries as, within each NT-class, certain neurons are excited by reward and others by stressors. Here we identify the co-activated mouse VTA neuronal ensembles for reward and stress, and determine their role in adaptive behaviors. We show that stimuli of opposite valence (opioid vs acute social stress) recruit two segregated intermingled small VTA neuronal ensembles. These two ensembles continue to be preferentially engaged by congruent valence stimuli. Stimulation of VTA stress- or reward ensembles is aversive/reinforcing, respectively. Strikingly, external valence stimuli fully require activity of these small discrete VTA ensembles for conferring approach/avoidance outcomes. Overall, our study identifies distinct small VTA ensembles for positive and negative valence coding and shows their indispensability for adaptive behavior.

neuroscience↗

bioRxiv2024

A prefrontal cortex-lateral hypothalamus circuit controls stress-driven food intake

Stress can drive overconsumption of high-fat foods. The medial prefrontal cortex (mPFC) is implicated in such stress-eating, but the underlying circuit mechanisms remain unclear. Here we show that mPFC projections to the lateral hypothalamus (LHA) are required for stress-induced fat intake in male mice. We find that mPFC-LHA stimulation in sated states increases fat intake. Social stress acutely engages mPFC-LHA neurons, and inhibiting this pathway selectively prevents stress-driven excess fat intake. Circuit mapping shows that mPFC neurons innervate GABAergic and glutamatergic LHA (LHAVGLUT2) neurons, but that social stress preferentially engages mPFC-LHAVGLUT2 neurons and causes plasticity at mPFC-LHAVGLUT2 synapses. Specifically, stress weakens mPFC synapses onto LHAVGLUT2 neurons that curtail food intake, while strengthening mPFC synapses onto midbrain-projecting LHAVGLUT2 neurons linked to stress-eating. We show that LHAVGLUT2 neurons are required downstream mPFC targets for transforming stress into heightened fat intake. Overall, we identify the mPFC-LHA as a multi-branched network, indispensable for stress-eating.

neuroscience↗

bioRxiv2024

Reduced GABA transmission onto ventral tegmental area dopamine neurons underlies vulnerability for hyperactivity in a mouse model of Anorexia Nervosa

Anorexia nervosa (AN) has the highest mortality among psychiatric diseases. Hyperactivity is a persistent symptom, which is difficult to control for patients and a major barrier to recovery as it interferes with weight gain. Alteration of mesolimbic dopamine transmission has been hypothesized as a critical factor for the development and maintenance of the disease and for hyperactivity. At what level the changes in dopamine occur in anorexic states and whether local mesolimbic neurocircuit plasticity is causally involved remains unclear. Especially the role of local GABA control over dopamine neurons, a powerful regulator of the dopamine system, in an AN context is unknown. We hypothesize that combining caloric restriction with exercise, such as in the activity-based anorexia (ABA) model, alters dopamine transmission via GABA disinhibition that, in turn, facilitates the expression of maladaptive behaviors such as hyperactivity. Therefore, we characterized the impact of the ABA model on plasticity of the dopamine reward system. In ex-vivo brain slices of mice exposed to this model, ventral tegmental area dopamine (VTADA) neurons displayed a higher firing frequency compared to control mice supporting that the midbrain dopamine system undergoes plasticity. This coincided with reduced GABAergic transmission on VTADA neurons. This reduction was at least in part attributable to local VTA GABA (VTAGABA) neurons. Indeed, VTAGABA neurons were less excitable, displayed a lower firing frequency and a lower probability of release onto VTADA neurons. Restoring the excitability of VTAGABA neurons via chemogenetic activation rescued mice from starvation, by decreasing running wheel activity. In summary, we found that the anorexic state leads to dysregulation of VTAGABA transmission on VTADA neurons that reinforces maladaptive behaviors such as excessive exercise. We uncovered a new mechanism linked to the disturbed dopamine system in ABA-exposed animals, identifying a hitherto unknown role of decreased local GABAergic control over VTA dopamine neuron output.

neuroscience↗

bioRxiv2023

Neuropeptide Y neurons of the locus coeruleus inhibit noradrenergic system activity to reduce anxiety

Abstract / SummaryAdaptive responses to challenging environments depend on optimal function of the locus coeruleus (LC), the brains main source of noradrenaline and primary mediator of the initial stress response. Built-in systems that exert regulatory control over the LC are largely unidentified. A good candidate system is neuropeptide Y (NPY), which is traditionally linked to anxiety-relief. Currently, the endogenous source of NPY to the LC, and how NPY-expressing neurons modulate the noradrenergic system to regulate anxiety remain unclear. We here identify, in mice, a novel NPY-expressing neuronal population (peri-LCNPY) neighboring LC noradrenergic neurons that locally innervates the pericoerulean space. Moreover, we demonstrate that stress engages peri-LCNPY neurons, increasing their excitability. Mimicking peri-LCNPY neuronal activation using ex vivo chemogenetics suppresses LC noradrenergic neuron activity, via an NPY Y1 receptor-mediated mechanism. Furthermore, in vivo chemogenetic stimulation of peri-LCNPY neurons results in Y1R-dependent anxiety-relief. Conversely, inhibiting peri-LCNPY neurons increases anxiety-like behaviors. Together, we establish a causal role for peri-LCNPY-mediated neuromodulation of the LC in the regulation of anxiety, providing novel insights in the endogenous mechanisms underlying adaptive responses to adversity.

neuroscience↗

bioRxiv2022

GelMap: Intrinsic calibration and deformation mapping for expansion microscopy

Expansion microscopy (ExM) is a powerful technique to overcome the diffraction limit of light microscopy by physically expanding biological specimen in three dimensions. Nonetheless, using ExM for quantitative or diagnostic applications requires robust quality control methods to precisely determine expansion factors and to map deformations due to anisotropic expansion. Here we present GelMap, a flexible workflow to introduce a fluorescent grid into pre-expanded hydrogels that scales with expansion and reports deformations. We demonstrate that GelMap can be used to precisely determine the local expansion factor and to correct for deformations without the use of cellular reference structures or pre-expansion ground truth images. Moreover, we show that GelMap aids sample navigation for correlative uses of expansion microscopy. Finally, we show that GelMap is compatible with expansion of tissue and can be readily implemented as a quality control step into existing ExM workflows.

cell biology↗

bioRxiv2022

Molecular Signatures and Cellular Diversity During Mouse Habenula Development

The habenula plays a key role in various motivated and pathological behaviors and is composed of molecularly distinct neuron subtypes. Despite progress in identifying mature habenula neuron subtypes, how these subtypes develop and organize into functional brain circuits remains largely unknown. Here we performed single-cell transcriptional profiling of mouse habenular neurons at critical developmental stages instructed by detailed three-dimensional anatomical data. Our data reveal cellular and molecular trajectories during embryonic and postnatal development leading to different habenular subtypes. Further, based on this analysis our work establishes the distinctive functional properties and projection target of a previously uncharacterized subtype of Cartpt+ habenula neurons. Finally, we show how comparison of single-cell transcriptional profiles and GWAS data links specific developing habenular subtypes to psychiatric disease. Together, our study begins to dissect the mechanisms underlying habenula neuron subtype-specific development and creates a framework for further interrogation of habenular development in normal and disease states.

developmental biology↗