Cameron Sarah, Weston-Green Katrina, Newell Kelly A
School of Medical, Indigenous and Health Sciences and Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia.
Transl Psychiatry. 2024 Dec 19;14(1):499. doi: 10.1038/s41398-024-03199-x.
The habenula is an epithalamic brain structure that acts as a neuroanatomical hub connecting the limbic forebrain to the major monoamine centres. Abnormal habenula activity is increasingly implicated in depression, with a surge in publications on this topic in the last 5 years. Direct activation of the habenula is sufficient to induce a depressive phenotype in rodents, suggesting a causative role in depression. However, the molecular basis of habenula dysfunction in depression remains elusive and it is unclear how the preclinical advancements translate to the clinical field.
A systematic literature search was conducted following the PRISMA guidelines. The two search terms depress* and habenula* were applied across Scopus, Web of Science and PubMed databases. Studies eligible for inclusion must have examined the habenula in clinical cases of depression or preclinical models of depression and compared their measures to an appropriate control.
Preclinical studies (n = 63) measured markers of habenula activity (n = 16) and neuronal firing (n = 22), largely implicating habenula hyperactivity in depression. Neurotransmission was briefly explored (n = 15), suggesting imbalances within excitatory and inhibitory habenula signalling. Additional preclinical studies reported neuroconnectivity (n = 1), inflammatory (n = 3), genomic (n = 3) and circadian rhythm (n = 3) abnormalities. Seven preclinical studies (11%) included both males and females. From these, 5 studies (71%) reported a significant difference between the sexes in at least one habenula measure taken. Clinical studies (n = 24) reported abnormalities in habenula connectivity (n = 15), volume (n = 6) and molecular markers (n = 3). Clinical studies generally included male and female subjects (n = 16), however, few of these studies examined sex as a biological variable (n = 6).
Both preclinical and clinical evidence suggest the habenula is disrupted in depression. However, there are opportunities for sex-specific analyses across both areas. Preclinical evidence consistently suggests habenula hyperactivity as a primary driver for the development of depressive symptoms. Clinical studies support gross habenula abnormalities such as altered activation, connectivity, and volume, with emerging evidence of blood brain barrier dysfunction, however, progress is limited by a lack of detailed molecular analyses and limited imaging resolution.
缰核是一种丘脑上脑结构，作为神经解剖学枢纽，连接边缘前脑和主要的单胺能中枢。缰核活动异常与抑郁症的关系日益密切，在过去5年中，关于该主题的出版物激增。直接激活缰核足以在啮齿动物中诱发抑郁表型，提示其在抑郁症中起因果作用。然而，抑郁症中缰核功能障碍的分子基础仍不清楚，目前尚不清楚临床前的研究进展如何转化到临床领域。
按照PRISMA指南进行系统的文献检索。在Scopus、科学网和PubMed数据库中使用“depress*”和“habenula*”这两个检索词。纳入研究必须在抑郁症临床病例或抑郁症临床前模型中研究了缰核，并将其测量结果与适当的对照组进行比较。
临床前研究（n = 63）测量了缰核活动标志物（n = 16）和神经元放电（n = 22），在很大程度上表明抑郁症中缰核活动亢进。对神经传递进行了简要探索（n = 15），提示缰核兴奋性和抑制性信号传导失衡。其他临床前研究报告了神经连接性（n = 1）、炎症（n = 3）、基因组（n = 3）和昼夜节律（n = 3）异常。七项临床前研究（11%）纳入了雄性和雌性动物。其中，5项研究（71%）报告在至少一项缰核测量指标上存在性别差异。临床研究（n = 24）报告了缰核连接性（n = 15）、体积（n = 6）和分子标志物（n = 3）异常。临床研究通常纳入了男性和女性受试者（n = 16），然而，这些研究中很少将性别作为生物学变量进行研究（n = 6）。
临床前和临床证据均表明抑郁症中缰核受到破坏。然而，这两个领域都有进行性别特异性分析的机会。临床前证据一致表明缰核活动亢进是抑郁症状发展的主要驱动因素。临床研究支持缰核的总体异常，如激活、连接性和体积改变，以及血脑屏障功能障碍的新证据，然而，由于缺乏详细的分子分析和有限的成像分辨率，进展有限。
