Biology subjects

de Kerchove d'Exaerde, A.

Publications and source records attributed to de Kerchove d'Exaerde, A..

8 recordsLinked to original sources

bioRxiv2024

Direct and indirect striatal projecting neurons exert strategy-dependent effects on decision-making.

The striatum plays a key role in decision-making, with its effects varying with anatomical location and direct and indirect pathway striatal projecting neuron (d- and i-SPN) populations. Using a mouse gambling task with a reinforcement-learning model, we described of individual decision-making profiles as a combination of three archetypal strategies: Optimizers, Risk-averse, Explorers. Such strategies reflected stable differences in the parameters generating decisions (sensitivity to the reward magnitude, to risk or to punishment) derived from a reinforcement-learning model of animal choice. Chemogenetic manipulation showed that dorsomedial striatum (DMS) neurons substantially impact decision-making, while the nucleus accumbens (NAc) and dorsolateral striatum neurons (DLS) have lesser or no effects, respectively. Specifically, DMS dSPNs decrease risk aversion by increasing the perceived value of risky choices, while DMS iSPNs emphasize large gains, affecting decisions depending on decision-making profiles. Hence, we propose that striatal populations from different subregions influence distinct decision-making parameters, leading to profile-dependent choices.

neuroscience↗

bioRxiv2024

Spontaneous activity of striatal projection neurons supports maturation of striatal inputs to substantia nigra dopaminergic neurons

Spontaneous activity of neurons during early ontogenesis is instrumental for stabilization and refinement of developing neuronal connections. The role of spontaneous activity in synaptic development has been described in detail for cortical-like structures. Yet, very little is known about activity-dependent development of long-range inhibitory projections, such as projections from striatum. Here, we show that striatal projection neurons (SPNs) in dorsal striatum are spontaneously active in P4-P14 mice. Spontaneous activity was detected in both direct-pathway SPNs (dSPNs) and indirect-pathway SPNs (iSPNs). Most of the spontaneously active cells were in striosomes - a chemical compartment in striatum defined by expression of {micro}-opioid receptor. Higher excitability of both striosomal dSPNs and iSPNs was related to their intrinsic excitability properties (higher action potential half-width and IV slope). Tonic activation of muscarinic M1 receptor maintains the spontaneous activity of striosomal SPNs, the effect being stronger in iSPNs and weaker in dSPNs. To investigate if the neonatal spontaneous activity is needed for the stabilization of SPN long-range projections, we chemogenetically inhibited striosomal SPNs in neonatal animals and studied the efficiency of striatonigral projections in adult animals. Inhibition of striosomal SPNs by chronic CNO administration to P6-14 pups caused a reduction in the functional GABAergic innervation and in the density of gephyrin puncta in dopaminergic neurons of substantia nigra pars compacta of the adult (P52-79) animals. Chronic administration of CNO later in development (P21-29), on the contrary, resulted in higher mIPSC frequency in dopaminergic cells of the adult animals. Thus, the activity-dependent stabilization of striosomal projections has different developmental phases, and the long-term outcome of perturbations in these processes depends on the developmental period when they occur. Taken together, our results demonstrate that spontaneous activity of SPNs is essential for the maturation and stabilization of striatal efferents.

neuroscience↗

bioRxiv2022

Balance between direct and indirect pathways of the nucleus accumbens controls social behavior in mice

BackgroundDeficient social interactions are a hallmark of major neuropsychiatric disorders, and cumulating evidence point to altered social reward and motivation as key underlying mechanisms in these pathologies. In the present study, we aimed at assessing the role of the two striatal projecting neuronal (SPN) populations bearing either D1R or D2R dopamine receptors (D1R- and D2R-SPNs), in modulating social behavior and other behaviors often altered in neuropsychiatric disorders. MethodsWe selectively ablated D1R- and D2R-SPNs using an inducible diphtheria toxin receptor (DTR)-mediated cell targeting strategy and assessed social behavior as well as repetitive/perseverative behavior, motor function and anxiety levels. We tested the effects of optogenetic stimulation of D2R-SPNs in the Nucleus Accumbens (NAc) and pharmacological compounds repressing D2R-SPN. ResultsTargeted deletion of D1R-SPNs in the NAc blunted social behavior in mice, facilitated skill motor learning and increased anxiety levels. These behaviors were normalized by pharmacological inhibition of D2R-SPN, which also repressed transcription in the efferent nucleus, the ventral pallidum (VP). In contrast, ablation of D1R-SPNs in the dorsal striatum had no impact on social behavior, impaired motor skill learning, and decreased anxiety levels. Deletion of D2R-SPNs in the NAc also produced motor stereotypies but facilitated social behavior and impaired skill motor learning. We mimicked excessive D2R-SPN activity by optically stimulating D2R-SPNs in the NAc and evidenced a severe deficit in social interaction that was prevented by D2R-SPN pharmacological inhibition. ConclusionsRepressing D2R-SPN activity may represent a promising therapeutic strategy to relieve social deficit in neuropsychiatric disorders.

neuroscience↗

bioRxiv2022

Histone H2A monoubiquitination in the thalamus regulates cocaine effects and addiction risk

The individual risk of developing drug addiction is highly determined by the epigenetic landscape1,2. Chromatin remodeling regulates drug-induced transcriptional and behavioral effects and the consequent development of addictive behaviors2,3. Several chromatin modifications in the ventral tegmental area and nucleus accumbens, including histone H3 methylation, H3 and H4 acetylation, have been implicated in drug addiction. Still, the contribution of other histones and their post-translational modifications (PTMs), such as monoubiquitination is unclear4-8. In the course of investigating the underlying mechanisms associated with melanoma-associated antigen D1 (Maged1)9, a scaffold protein involved in drug addiction9, we found that H2A monoubiquitination in the paraventricular thalamus (PVT) plays a major role in cocaine-adaptive behaviors and cocaine-evoked transcriptional repression. Mice undergoing chronic cocaine administration showed a significant increased monoubiquitination of H2A. Furthermore, we showed that this histone PTM is controlled, in the PVT, by Maged1, along with one of its partner, the deubiquitinase USP710. Accordingly, Maged1 specific inactivation in thalamic vGluT2 neurons, or USP7 inhibition, blocked cocaine-evoked H2A monoubiquitination and abolished cocaine locomotor sensitization. Finally, we identified genetic variations of MAGED1 and USP7 associated with modified transition to cocaine addiction and cocaine-induced aggressive behavior in human subjects. These findings identified a new epigenetic modification in a non-canonical reward pathway of the brain and a potent marker of epigenetic risk factor for drug addiction in human.

neuroscience↗

bioRxiv2022

Complementary coding of behaviors in striatal pathways supports a dual selection-suppression function

The basal ganglia are known to control actions and modulate movements. Neuronal activity in the two efferent pathways of the dorsal striatum, a major input to the basal ganglia, is critical for appropriate behavioral control. Previous evidence has led to divergent conclusions on the respective engagement of both pathways during actions. We used calcium imaging to evaluate how neurons in the direct and indirect pathways in the dorsal striatum encode behaviors during self-paced spontaneous explorations in an open field. We observed that the two striatal pathways exhibit distinct tuning properties during spontaneous behaviors. We applied supervised learning algorithms and found that direct pathway neurons encode behaviors through their activation, whereas indirect pathway neurons exhibit behavior-specific silencing. These properties remain stable for weeks. Our findings highlight a complementary encoding of behaviors in the two striatal pathways that supports an updated model, reconciling previous conflicting conclusions on motor encoding in the striatum.

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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↗

bioRxiv2022

Unexpected inhibition of motor function by dopamine activation of D1/D2 co-expressing striatal neurons.

The central function of the striatum and its dopaminergic (DA) afferents in motor control and the integration of cognitive and emotional processes is commonly explained by the two striatal efferent pathways characterized by striatal projection neurons (SPNs) expressing DA D1 receptors and D2 receptors (D1-SPNs and D2-SPNs), without regard to SPNs coexpressing both receptors (D1/D2-SPNs). We developed an approach that enables the targeting of these hybrid SPNs and demonstrated that although these SPNs are less abundant, they play a major role in guiding the motor function of the other two main populations. D1/D2-SPNs project exclusively to the external globus pallidus (GPe) and have specific electrophysiological features with distinctive integration of DA signals. Optogenetic stimulation and loss-of-function experiments indicated that D1/D2-SPNs potentiate the prokinetic and antikinetic functions of D1-SPNs and D2-SPNs, respectively, and restrain the integrated motor response to psychostimulants. Overall, our findings demonstrate the essential role of this third unacknowledged population of D1/D2 coexpressing neurons, which orchestrates the fine-tuning of DA regulation in the thalamo-cortico-striatal loops. One-Sentence SummaryD1/D2 SPNs modulate the motor function of both D1- and D2-SPNs

neuroscience↗

bioRxiv2019

mTOR-RhoA signalling impairments in direct striatal projection neurons induce altered behaviours and striatal physiology in mice

As an integrator of molecular pathways, mTOR has been associated with diseases including neurodevelopmental, psychiatric and neurodegenerative disorders as autism, schizophrenia, and Huntingtons disease. An important brain area involved in all these diseases is the striatum. However, the mechanisms behind how mTOR is involved in striatal physiology and its relative role in distinct neuronal populations in these striatal-related diseases still remain to be clarified. Taking advantage of the D1-mTOR KO mice (males), we combined behavioural, biochemical, electrophysiological and morphological analysis aiming to untangle the role of mTOR in direct pathway striatal projection neurons (dMSNs) and how this would impact on striatal physiology. Our results indicate deep behavioural changes in absence of mTOR in dMSNs such as decreased spontaneous locomotion, impaired social interaction and repetitive behaviour. These were accompanied by a Kv1.1-induced increase in the fast phase of afterhyperpolarization and decreased distal spines density that were mechanistically independent of protein synthesis but dependent of RhoA activity. These results identify mTOR RhoA signaling as an important regulator of striatal functions through an intricate mechanism involving RhoA and culminating in Kv1.1 overfunction, which could be targeted to treat striatal-related mTORopathies.

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