Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary, Calgary, AB T2N 4N1, Canada.
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary, Calgary, AB T2N 4N1, Canada
J Neurosci. 2024 Sep 25;44(39):e0682242024. doi: 10.1523/JNEUROSCI.0682-24.2024.
Dopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues, and circuit-specific signaling drives different aspects of motivated behavior. Orexin (ox; also known as hypocretin) and dynorphin (dyn) are coexpressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors. Given that Ox1R activation increases VTA firing, and KOR decreases firing, it is unclear how the coreleased peptides contribute to the net activity of DA neurons. We tested if optical stimulation of LH neuromodulates VTA neuronal activity via peptide release and if the effects of optically driven LH release segregate based on VTA projection targets including the basolateral amygdala (BLA) or the lateral or medial shell of the nucleus accumbens (lAcbSh, mAchSh). Using a combination of circuit tracing, optogenetics, and patch-clamp electrophysiology in male and female orexin mice, we showed a diverse response of LH optical stimulation on VTA neuronal firing, which is not mediated by fast transmitter release and is blocked by antagonists to KOR and Ox1R signaling. Additionally, where optical stimulation of LH inputs in the VTA inhibited firing of the majority of BLA-projecting VTA neurons, optical stimulation of LH inputs in the VTA bidirectionally affects firing of either lAcbSh- or mAchSh-projecting VTA neurons. These findings indicate that LH corelease may influence the output of the VTA by balancing ensembles of neurons within each population which contribute to different aspects of reward seeking.
腹侧被盖区（VTA）中的多巴胺（DA）神经元对与动机相关的线索作出反应，而特定于回路的信号传导驱动了动机行为的不同方面。食欲素（ox；也称为下丘脑泌素）和强啡肽（dyn）是共表达的外侧下丘脑（LH）神经肽，投射到 VTA。这些肽通过食欲素 1（Ox1R）或κ阿片受体（KOR）对 VTA 神经元的放电活动产生相反的影响。鉴于 Ox1R 的激活增加 VTA 的放电，而 KOR 则降低放电，因此尚不清楚共释放的肽如何有助于 DA 神经元的净活动。我们测试了 LH 神经元的光刺激是否通过肽释放来调节 VTA 神经元的活动，以及光驱动的 LH 释放的效果是否根据 VTA 投射目标（包括基底外侧杏仁核（BLA）或伏隔核的外侧或内侧壳（lAcbSh、mAchSh））而分离。在雄性和雌性食欲素小鼠中，我们结合了回路追踪、光遗传学和膜片钳电生理学，显示 LH 光刺激对 VTA 神经元放电有不同的反应，这种反应不是由快速递质释放介导的，并且被 KOR 和 Ox1R 信号传导的拮抗剂阻断。此外，LH 输入在 VTA 中的光刺激抑制了大多数投射到 BLA 的 VTA 神经元的放电，而 LH 输入在 VTA 中的光刺激则双向影响投射到 lAcbSh 或 mAchSh 的 VTA 神经元的放电。这些发现表明，LH 共释放可能通过平衡每个群体内的神经元集合来影响 VTA 的输出，这些神经元集合有助于寻求奖励的不同方面。
