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.
Highlights
Dopamine (DA) neurons of the ventral tegmental area (VTA) are critical to limbic and cognitive functions, and, exert a major impact on behavioral regulation
Scattered, but distinct, TrpV1+ cells were detected in a continuum stretching rostrally from the posterior hypothalamic nucleus (PHA) and retromammillary nucleus (RM) of the caudal hypothalamus through to, and including, all VTA subnuclei (IF, rostral linear nucleus (RLi), caudal linear nucleus (CLi), PN, and parabrachial pigmented (PBP)), as well as the A8 DA area of the caudal midbrain (Figures 1A1-A9 and Supplementary Figure 1)
We present a series of findings that allow us to classify a distinct VTA neuron subtype according to its expression of the TrpV1 gene
Summary
Dopamine (DA) neurons of the ventral tegmental area (VTA) are critical to limbic and cognitive functions, and, exert a major impact on behavioral regulation. Their dysfunction is correlated with the severe neuropsychiatric disorder, including addiction, attention deficit/hyperactivity disorder (ADHD), schizophrenia, and the affective/cognitive non-motor domain of Parkinson’s disease (PD) (Björklund and Dunnett, 2007). The Slc6a3 (Dat) gene, encoding the dopamine transporter (DAT), which mediates DA reuptake after vesicular release, shows a mediallow-lateralhigh expression pattern in the VTA (Lammel et al, 2008; Papathanou et al, 2018). The density of DA neurons differs across VTA subnuclei (Morales and Margolis, 2017)
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