Graduate Program in Neuroscience, University of Washington, Seattle, Washington, USA.
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
Genes Brain Behav. 2022 Sep;21(7):e12801. doi: 10.1111/gbb.12801. Epub 2022 Mar 18.
The lateral habenula (LHb) is a small, bilateral, epithalamic nucleus which processes aversive information. While primarily glutamatergic, LHb neurons express genes coding for many neuropeptides, such as Adcyap1 the gene encoding pituitary adenylate cyclase-activating polypeptide (PACAP), which itself has been associated with anxiety and stress disorders. Using Cre-dependent viral vectors, we targeted and characterized these neurons based on their anatomical projections and found that they projected to both the raphe and rostromedial tegmentum but only weakly to ventral tegmental area. Using RiboTag to capture ribosomal-associated mRNA from these neurons and reanalysis of existing single cell RNA sequencing data, we did not identify a unique molecular phenotype that characterized these PACAP-expressing neurons in LHb. In order to understand the function of these neurons, we conditionally expressed hM Dq DREADD selectively in LHb PACAP-expressing neurons and chemogenetically excited these neurons during behavioral testing in the open field test, contextual fear conditioning, sucrose preference, novelty suppressed feeding, and conditioned place preference. We found that Gq activation of these neurons produce behaviors opposite to what is expected from the LHb as a whole-they decreased anxiety-like and fear behavior and produced a conditioned place preference. In conclusion, PACAP-expressing neurons in LHb represents a molecularly diverse population of cells that oppose the actions of the remainder of LHb neurons by being rewarding or diminishing the negative consequences of aversive events.
外侧缰核（LHb）是一个小的、双侧的、丘脑核团，处理厌恶性信息。虽然主要是谷氨酸能的，但 LHb 神经元表达许多神经肽的基因，如 Adcyap1，编码垂体腺苷酸环化酶激活肽（PACAP），PACAP 本身与焦虑和应激障碍有关。使用 Cre 依赖性病毒载体，我们根据它们的解剖学投射来靶向和描述这些神经元，发现它们投射到中缝核和穹隆腹侧被盖区，但仅弱投射到腹侧被盖区。使用 RiboTag 从这些神经元中捕获核糖体相关的 mRNA，并重新分析现有的单细胞 RNA 测序数据，我们没有确定一个独特的分子表型来描述 LHb 中的这些 PACAP 表达神经元。为了了解这些神经元的功能，我们在 LHb 中的 PACAP 表达神经元中条件性表达 hM Dq DREADD，并在旷场测试、情境恐惧条件反射、蔗糖偏好、新奇抑制性摄食和条件性位置偏好的行为测试中化学兴奋这些神经元。我们发现，这些神经元的 Gq 激活产生的行为与整个 LHb 所预期的相反——它们减少了焦虑样和恐惧行为，并产生了条件性位置偏好。总之，LHb 中的 PACAP 表达神经元代表了一个分子多样性的细胞群体，通过奖励或减少厌恶性事件的负面后果来对抗 LHb 其余神经元的作用。
