Unit of Comparative Physiology, Department of Organism Biology, Uppsala University, Uppsala, Sweden.
Oramacell, Paris, France.
Front Neural Circuits. 2021 Nov 11;15:726893. doi: 10.3389/fncir.2021.726893. eCollection 2021.
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 -driven strategy targeting the 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.
腹侧被盖区（VTA）中的多巴胺（DA）神经元比之前认为的更加多样化，这一事实引起了广泛关注。在 VTA 的内侧，人们意外地发现了 TrpV1 mRNA 的存在。TrpV1 编码瞬时受体电位阳离子通道亚家族 V 成员 1（Transient Receptor Potential cation channel subfamily V member 1，TRPV1），也称为辣椒素受体，因其在外周神经元中对热和疼痛处理的作用而广为人知。相比之下，TRPV1 在大脑中的分布一直存在争议。在这里，我们假设 TrpV1 的身份定义了 VTA DA 神经元的一个独特亚群。为了探索这些大脑中的 TrpV1 神经元，我们采用了组织学分析和 Cre 驱动的小鼠遗传学方法。TrpV1 mRNA 在围产期最强表达，形成一条散在神经元带，贯穿 VTA 的内侧，延伸到下丘脑的后部。在 VTA 中，大多数 TrpV1 与酪氨酸羟化酶（Tyrosine hydroxylase，Th）和囊泡单胺转运体 2（Vesicular monoamine transporter 2，Vmat2）共定位，证实了 DA 表型。然而，TrpV1 也与囊泡谷氨酸转运体 2（Vesicular glutamate transporter 2，Vglut2）大量共定位，代表谷氨酸（GLU）释放的能力。因此，这些 TrpV1/Th/Vglut2/Vmat2 神经元构成了 DA-GLU 共释放神经元的分子和解剖学上的独特亚群。为了评估行为影响，我们在小鼠中实施了一种靶向 基因的 驱动策略。这种操作足以改变安非他命诱导的运动行为。药物的急性效应在对照水平上被放大，这表明在药物-na ve 状态下存在超敏性，类似于“预敏化”表型。然而，随着重复注射，没有观察到逐渐增加。本研究确定了一个独特的 TrpV1 VTA 亚群作为对安非他命反应的关键调节成分。此外，在选定的 VTA 神经元中表达编码 TRPV1 的基因，为这个异质但具有临床重要性的脑区的药物干预开辟了新的可能性。
