Midbrain Dopamine Neurons Defined by TrpV1 Modulate Psychomotor Behavior

Abstract

Dopamine (DA) neurons of the ventral tegmental area (VTA) continue to gain attention as far more heterogeneous than previously realized. Within the medial aspect of the VTA, the unexpected presence of TrpV1 mRNA has been identified. TrpV1 encodes the Transient Receptor Potential cation channel subfamily V member 1, TRPV1, also known as the capsaicin receptor, well recognized for its role in heat and pain processing by peripheral neurons. In contrast, the brain distribution of TrpV1 has been debated. Here, we hypothesized that the TrpV1+ identity defines a distinct subpopulation of VTA DA neurons. To explore these brain TrpV1+ neurons, histological analyses and Cre-driven mouse genetics were employed. TrpV1 mRNA was most strongly detected at the perinatal stage forming a band of scattered neurons throughout the medial VTA, reaching into the posterior hypothalamus. Within the VTA, the majority of TrpV1 co-localized with both Tyrosine hydroxylase (Th) and Vesicular monoamine transporter 2 (Vmat2), confirming a DA phenotype. However, TrpV1 also co-localized substantially with Vesicular glutamate transporter 2 (Vglut2), representing the capacity for glutamate (GLU) release. These TrpV1+/Th+/Vglut2+/Vmat2+ neurons thus constitute a molecularly and anatomically distinct subpopulation of DA-GLU co-releasing neurons. To assess behavioral impact, a TrpV1Cre-driven strategy targeting the Vmat2 gene in mice was implemented. This manipulation was sufficient to alter psychomotor behavior induced by amphetamine. The acute effect of the drug was accentuated above control levels, suggesting super-sensitivity in the drug-na ve state resembling a “pre-sensitized” phenotype. However, no progressive increase with repeated injections was observed. This study identifies a distinct TrpV1+ VTA subpopulation as a critical modulatory component in responsiveness to amphetamine. Moreover, expression of the gene encoding TRPV1 in selected VTA neurons opens up for new possibilities in pharmacological intervention of this heterogeneous, but clinically important, brain area.

Wireless Stimulation of the Subthalamic Nucleus with Nanoparticles Modulates Key Monoaminergic Systems Similar to Contemporary Deep Brain Stimulation

“…4A-B). The VTA dopaminergic neurons play an important role in the mesolimbic circuitry, which is implicated in reward, limbic, cognitive as well as psychomotor behavior [41][42][43].…”

“…In addition, antidromic propagation in the VTA projections, and/or orthodromic activation of GABAergic cells in the VTA or passing-by fibers from the subthalamic area to the VTA could inhibit VTA dopaminergic cells [39,40]. Current literature present ample evidence that challenged VTA dopaminergic system could affect psychomotor behavior [38,43].…”

Increased sucrose consumption in mice gene-targeted for Vmat2 selectively in NeuroD6-positive neurons of the ventral tegmental area

“…The midbrain dopamine (DA) system has been implicated in reinforcement learning, reward prediction error ( Schultz et al, 1997 ), motivation ( Berke, 2018 ), incentive salience ( Berridge and Robinson, 1998 ) and in diseases where these functions are compromised, such as substance use disorder ( Lüscher, 2016 ). Expanding on the classical classification of DA circuits into nigrostriatal and mesolimbic systems ( Björklund and Dunnett, 2007 ), recent studies have focused on the heterogeneity of DA neurons within the midbrain, in terms of gene expression, projection patterns and behavioral role ( Chung et al, 2005 ; Greene et al, 2005 ; Lammel et al, 2008 , 2011 , 2012 ; Poulin et al, 2014 , 2018 ; Viereckel et al, 2016 ; Bimpisidis et al, 2019 ; Heymann et al, 2020 ; König et al, 2020 ; Serra et al, 2021 ). Characterizing differences between previously considered homogeneous DA populations will lead in deciphering the functional role of distinct subpopulations, make it possible to selectively target them for treatment of disease and eventually avoiding unwanted side effects that might occur by targeting the DA system as a whole.…”

“…Exploiting the unique gene expression patterns of different neuronal subtypes has been recently employed to unravel the projection patterns and role in behavior of distinct neuronal subpopulations within the VTA ( Bimpisidis et al, 2019 ; Heymann et al, 2020 ; König et al, 2020 ; Kramer et al, 2021 ; Serra et al, 2021 ). For example, Heymann and colleagues ( Heymann et al, 2020 ) used genetic and viral approaches to target VTA neurons characterized by specific expression of peptides.…”

“…However, the two different subpopulations act in synergy to optimize behavior ( Heymann et al, 2020 ). More recently, Serra and colleagues, using conditioned knock-out (cKO) approaches, showed that the medially located VTA DA population characterized by the expression of TrpV1 is involved in modulating amphetamine-induced locomotion ( Serra et al, 2021 ).…”