Biology subjects

Walle, R.

Publications and source records attributed to Walle, R..

6 recordsLinked to original sources

bioRxiv2025

A role for prefrontal dopamine signaling in control of goal-directed actions

Impairments in behavioral flexibility commonly found across psychiatric disorders have often been attributed to a dysfunction of the medial prefrontal cortex (mPFC), notably in relation with altered dopamine transmission. However, how dopamine transmission shapes neuronal activity in the mPFC to allow adapting to a changing situation remains largely elusive. Here, we show that dopamine dynamics in the mPFC encode the value of instrumental actions, in particular during reversal learning. Such signal shapes the activity of mPFC dopaminoceptive neurons during reversal learning through the recruitment of heteromers formed by dopamine D1 and D2 receptors with NMDA receptors. In accordance, blockade of either D1/NMDA or D2/NMDA heteromers in the mPFC selectively impairs reversal of outcome identities but not learning and expression of initial action-outcome associations. Our findings provide mechanistic evidence for a central role of dopamine in the mPFC to allow updating goal-directed actions.

neuroscience↗

bioRxiv2025

Developmental vitamin A deficiency induces sex-specific reward processing alterations through a dysregulation of the mesolimbic dopamine transmission in mice

Neurodevelopmental psychiatric diseases such as schizophrenia or affective disorders share common symptomatic dimensions, in particular reward processing dysfunctions, associated with dysregulation of dopamine (DA) transmission. Retinoic acid (RA) homeostasis is altered across psychiatric disorders but whether impaired developmental RA signaling impacts the functionality of DA-related reward processing at adulthood remains poorly explored. Herein, we explored in male and female mice how developmental vitamin A deficiency (VAD), as a model of blunted RA signaling, could impact motivational processes through a modulation of mesolimbic DA transmission. Behavioral performances were evaluated using operant conditioning tasks, parallel with investigations of the integrity of DA transmission through biochemical analyses of markers of DA transmission and measures of DA dynamics using DA biosensor coupled with fiber photometry. Finally, chemogenetic manipulation of the mesolimbic DA pathway was used to normalize DA transmission and assess the effect on motivational performance in VAD offspring. Developmental VAD induced sex-specific alterations of reward-related processes at adulthood. Indeed, while female behavioral performances were spared, VAD males exhibited elevated instrumental performance and impulsivity. These behavioral alterations were coherent with reduced DA transporter (DAT) expression and increased DA dynamic in the mesolimbic pathway. Strikingly, chemogenetic inhibition of the mesolimbic DA pathway normalized motivational performance in VAD males. Our results show that developmental RA hyposignaling induces sex-specific reward processing alterations in adulthood through hyperactivity of the mesolimbic DA pathway. Our data support that developmental impairment in RA signaling might be at the core of reward-related symptoms across psychiatric disorders.

neuroscience↗

bioRxiv2022

The addiction-susceptibility TaqIA/Ankyrin repeat and kinase domain containing 1 kinase (ANKK1) controls reward and metabolism through dopamine receptor type 2 (DR2)-expressing neurons

Significant evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the Taq1A polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the Ankyrin repeat and kinase domain containing 1 kinase (ANKK1) near the dopamine D2 dopamine receptor (DR2) gene. Depending on race it affects 30 to 80% of the population and its homozygous expression of the A1 allele correlates with a 30 to 40% reduction of striatal DR2, a typical feature of addiction, over-eating and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior is unknown. Here we used transgenic and viral-mediated strategies to reveal the role of ANKK1 in the regulation of activity and functions of the striatum. We found that Ankk1 is preferentially enriched in striatal DR2 expressing neurons and that Ankk1 loss-of-function in dorsal and ventral striatum leads to alteration in learning, impulsive, and flexible behaviors resembling the endophenotypes described in A1 carriers. We also observed an unsuspected role of ANKK1 in striatal DR2-expressing neurons in the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with versus without the A1 allele. Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for ANKK1 in the regulation of body metabolism.

neuroscience↗

bioRxiv2022

The ventral striatum contributes to energy balance

Accumulating evidence points to dysregulations of common brain systems in eating disorders (ED), the Nucleus Accumbens (NAc) in particular. However, to which extent alterations in NAc activity contribute to ED-like dimensions remains unclear. Using chemogenetic manipulations of dopamine D1 receptor-expressing and D2-expressing neuronal subpopulations of the NAc in male mice, we assessed their respective roles in incentive processes, food intake and the balance between feeding and exercise-mediated energy expenditure. We found that D1-neurons facilitate effort for a food reward but decreased food intake, while D2-neurons have opposite effects. The anorexigenic influence of D1-neurons was accompanied by increased voluntary exercise while the orexigenic effect of D2-neurons was concomitant with decreased running, congruent with D2-neurons being more active than D1-neurons during feeding while it is the opposite during running. Chronic manipulations of each subpopulations had limited effects on energy balance. However, repeated activation of D1-neurons combined with inhibition of D2-neurons biased behavior toward activity-related energy expenditure leading to weight/fat loss, whilst the opposite manipulations favored energy intake and hence weight/fat gain. Strikingly, concomitant activation of D1-neurons and inhibition of D2-neurons precipitated weight loss in anorexia models. These results suggest that dysregulations of NAc dopaminoceptive neurons might be at the core of EDs.

neuroscience↗

bioRxiv2020

Synaptic and supra-synaptic organisation of the dopaminergic projection to the striatum.

Dopamine is a monoamine involved in reward processing and motor control. Volume transmission is thought to be the mechanism by which monoamines modulate effector systems at glutamate and GABA synapses. Hence, dopamine synapses are scarcely described. We applied fluorescence activated synaptosome sorting to explore the features of the dopaminergic synaptome. We provide the proteome of striatal dopaminergic synapses with 57 proteins specifically enriched. Beyond canonical markers of dopamine neurotransmission (Th, Slc6a3/DAT, Slc18a2/VMAT2), we validated 6 proteins belonging to pre- and postsynaptic sides (Cpne7, Apba1/Mint1, Cadps2, Cadm2/SynCAM 2, Stx4 and Mgll). Moreover, dopaminergic varicosities adhere to both a post-synapse with cognate receptors and glutamatergic, GABAergic or cholinergic synapses in structures we named dopaminergic "hub synapses". Markers of presynaptic vesicles and active zone, post-synaptic density and spine apparatus, are significantly increased upon association with dopamine inputs in hubs. Thus neuromodulation frequently operates from hub synapses affecting associated synapses and is not solely dependent on volume transmission. Finally, FASS provides a new framework for the exploration of dopaminergic synapses and more generally for discrete synapse populations ex-vivo. HighlightsO_LIA first proteome of dopaminergic synapses in the striatum C_LIO_LIStriatal dopaminergic synaptosomes display post-synaptic cognate receptors C_LIO_LIDopaminergic projections build hub synapses with excitatory, inhibitory, and cholinergic projections. C_LIO_LICortico-striatal synaptic scaffolds are strengthened upon association in hub synapses. C_LI

neuroscience↗

bioRxiv2019

Detecting GPCR Complexes in Postmortem Human Brain with Proximity Ligation Assay and a Bayesian Classifier

Despite the general controversy regarding the existence and physiological relevance of Class A GPCR dimerization, there is substantial evidence for functional interactions between dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AR). A2AR-D2R complexes have been detected in rodent brains by proximity ligation assay (PLA), but their existence in the human brain is yet to be demonstrated. In this study, we used brightfield PLA, combined with a systematic sampling and a parameter-free naive Bayesian classifier, and demonstrated proximity between D2R and A2AR in the adult human ventral striatum, consistent with their colocalization within complexes and the possible existence of D2R-A2AR heteromers. These methods are applicable to the quantitative analysis of proximity of two proteins and the expression of individual proteins.\n\nMethod SummaryBrightfield proximity ligation assay (PLA) was used to assess the expression of G protein-coupled receptors and their proximity in postmortem adult human brains. A novel automated machine learning method (Bayesian Optimized PLA Signal Sorting) was developed to automatically quantify brightfield PLA data.

neuroscience↗