Biology subjects

VALJENT, E.

Publications and source records attributed to VALJENT, E..

2 recordsLinked to original sources

bioRxiv2025

Characterization of mice with cell type-specific Gnal loss of function provides insights on GNAL-linked dystonia

Isolated dystonia can be caused by loss-of-function mutations in the GNAL gene (DYT-GNAL). This gene encodes the olf heterotrimeric G protein subunit, which, together with {beta}2{gamma}7 subunits, mediates the stimulatory coupling of dopamine D1 and adenosine A2A receptors to adenylyl-cyclase. These receptors are expressed in distinct striatal projection neurons (SPNs) with complementary functions on motor behavior. To dissect the specific roles of Golf in each subpopulation of SPNs, we generated and characterized mouse models in which Gnal was conditionally deleted in neurons expressing either D1 receptors (D1-SPNs) or A2A receptors (A2A-SPNs). Our results confirmed the critical role of Golf in regulating adenylyl-cyclase 5 and its coupling with D1 and A2A receptors. Mice with a selective loss of Golf in D1-SPNs showed nocturnal hyperactivity, deficits in motor performances, but no overt abnormal movements or generalized motor disability. Our experiments also revealed that Golf in D1-SPNs is not systematically required for locomotor responses induced by D1 agonists or psychostimulants. Selective loss of Golf in A2A-SPNs did not affect motor abilities nor learning. However, this loss strikingly increased spontaneous locomotor activity that was not further enhanced by psychostimulant drugs (cocaine, D-amphetamine, methylphenidate) or a selective A2 agonist, KW6002, and was paradoxically reduced by caffeine Our study identified specific roles of Golf downstream of D1 and A2A receptors in the control of motor behavior and drug responses, highlighting their respective individual contribution in diseases associated with dysfunctional striatal signaling, including dystonia.

neuroscience↗

bioRxiv2024

Dopamine transmission in the anterior insula shapes the neural coding of anxiety

The anterior insula1-3 and dopamine neuromodulation4-11 both play key roles in the control of anxiety, yet how dopamine shapes anterior insula function to regulate anxiety remains unknown. Here we show that dopaminergic neurons of the ventral tegmental area preferentially target the anterior relative to the posterior insula, and that optogenetic activation of these neurons elicits dopamine signals in the anterior insula. Behaviorally, dopamine signals increased in the anterior insula during risk assessment and exploration of exposed spaces. Interestingly, neurons expressing the type-1 dopamine receptor (D1) are enriched in the anterior insula subdivision, where their optogenetic activation is anxiogenic. At the molecular level, direct D1 activation or blockade in the anterior insula bidirectionally controls anxiety, demonstrating a causal anxiogenic function of D1 in the anterior insula. Remarkably, systemic D1 activation also increased anxiety-related behaviors, together with a cellular activation of the anterior insula, and a disruption of neural coding in this region. As an example of the latter, systemic D1 activation oppositely regulated the coding reliability of exposed and protected areas, increasing the reliability of the neural code for exposed spaces. Together, our findings reveal an anterior insula D1-dependent mechanism by which dopamine can control anxiety, providing a framework for investigating dopamine dysregulation in models of anxiety disorders. Our study also introduces quantitative metrics applied to AI-based computational representations of neural activity to identify how neuromodulation reshapes neural coding of behaviors and contexts.

neuroscience↗