Depressive disorders are endemic as they affect around 16% of the population at some point over the lifespan, and they result in personal suffering, increased risk of suicide and notable socioeconomic burden. The core symptoms include low mood, low self‐esteem and a general loss of interest. Because the neurobiological mechanisms of depressive disorders remain poorly understood, and current treatments are only effective in approximately two‐thirds of patients, there is an intensive ongoing research on the molecular and neural mechanisms underlying depression and its therapies, to determine the factors of risk or resilience to depression and to identify new therapeutic targets. This Special Issue includes selected reviews and articles from human and animal‐based research, focusing on depressive disorders through an integrative analysis, from cellular, molecular and circuitry levels to behavioural and environmental analyses. It is dedicated to the memories of Ron Duman and Paul Greengard.

Depressive disorders can be considered a story of altered treatment of information by the brain, changing the perception of life events, thoughts and behaviour. To reach the required circuit level of understanding, recent research in the field of depression has benefitted from the development of optogenetic and chemogenetic tools that allowed manipulation of selected neuronal activity in vivo. This technical progress helped provide a better understanding of the pathophysiology of depression, and in particular establishing a causal link between changes in neuronal activity and behaviour. Biselli et al. (2019) reviewed the recent studies using these approaches to understand depressive‐like behaviours in rodents and highlighted their methodological limitations. Changes in several cortical and limbic brain structures, such as the prefrontal cortex, the amygdala, the nucleus accumbens and the hippocampal formation, have been associated with major depressive disorder (MDD). In animal models, preclinical studies demonstrated a critical role of the dentate gyrus not only in depressive‐like behaviours but also in the action of antidepressant drugs. Thanks to the development of imaging, optogenetic and chemogenetic tools, the role of specific circuits and cell types of the dentate gyrus in depression and its treatments has been extensively studied. On the basis of animal models and human data, Umschweif et al. (2019) reviewed this cellular and neuroanatomical progress, highlighting the role of the structural and molecular changes that affect the different types of dentate gyrus cells in depression in relation with their respective connectivity. The habenula, an epithalamic structure encoding aversive stimuli, has emerged in the past decade as a new player in the reward/aversion circuitries and in MDD. Metzger et al. (2019) reviewed the role of specific habenular networks in anxiety and depression, especially the relations between the medial and lateral habenula and the ventral tegmental area–nigra complex as well as those with the dorsal raphe. The aminergic systems have long been considered core neuromodulatory actors, studied for their role in depression and as targets of antidepressant drugs. While this attention mostly concerned the serotonergic and noradrenergic systems, the role of the dopaminergic system in motivation and reward function opened studies in relation with depression at the turn of this century. Following this motivation/reward lead, Döbrössy et al. (2020) reviewed the clinical and animal data showing that deep brain stimulation (DBS) of the medial forebrain bundle, one of the DBS targets under investigation for MDD, may be beneficial in treatment‐resistant depressed patients and in animal models of depression. Increased, and thus maladaptive, attention to aversive stimuli can also contribute to altered mood. Mineur and Picciotto (2019) proposed that the cholinergic system may be critical. In a conceptual framework where optimal homeostatic acetylcholine function contributes to harmonious brain activity, while deficits in acetylcholine induce memory and cognitive impairments, they reviewed data suggesting that high levels of cholinergic signalling may also be deleterious. High acetylcholine levels may impair theta rhythms and thus decrease limbic synchrony, thereby promoting an attention towards negative stimuli and enhancing the encoding of stressful events.

Changes in neurotrophic factors, particularly in brain‐derived neurotrophic factor (BDNF), and subsequent alterations in synaptic plasticity and synapse dynamics contribute to MDD. BDNF, the most widely expressed neurotrophin in the nervous system, regulates neuronal survival and differentiation, and critically participates in activity‐dependent synaptic plasticity mechanisms. After a brief description of BDNF neurobiology, Duman et al. (2019) very elegantly reviewed the preclinical and clinical literature on the role of BDNF in stress and depression, with a special focus on the key role of the activity‐dependent release of BDNF in rapid‐acting antidepressants’ action. The authors also extended this analysis to the contribution of the vascular endothelial growth factor (VEGF). Besides BDNF and VEGF, the fibroblast growth factors (FGF) system, a family of neurotrophic factors expressed during embryonic development, postnatally and in adulthood, has also been involved in critical neurological functions such as neurogenesis and neuroprotection. Xu et al. (2019) presented our current knowledge of abnormalities of FGF family members in depression, with a special focus on FGF 2, 9 and 22. They highlighted the role of FGF family members in modulating depression‐related molecules, including other neurotrophic factors, serotonin, glucocorticoid receptors and inflammatory factors.

The relation between inflammation and depression has been a topic of increased interest since the late 1990s, following evidence that immune challenges can induce depressive‐like “sickness behaviour” and that rapid onset of MDD can be an adverse effect of interferon therapy. After presenting the main players of brain immunity, Troubat et al. (2020) discussed how neuroinflammation interacts with three neurobiological correlates of MDD: monoamine depletion, the endocrine hypothalamus–pituitary–adrenal (HPA) axis and neurogenesis. A research article from Nothdurfter et al. (2019) further showed in depressed patients that the pro‐inflammatory cytokine interleukin 17 might be a biomarker of treatment resistance in MDD. The question of individual susceptibility or resilience to the pathology and sensitivity/resistance to treatments is critical. The review from Dudek et al. (2019) covered the human and animal insights into the neurobiology of vulnerability versus resilience in stress and depression. They proposed strong causal links among the endocrine stress response, an exacerbated immune response and neurovascular dysfunction in depression physiopathology and resilience, highlighting the importance of sex‐related differences. This progress in our knowledge of depression illustrates a strong research trend that goes beyond local neurotransmitter and brain structure alterations towards a more integrated view at the whole body level. In this regard, another contributor to inflammation and body/mind relation recently came to light: the microbiota. Indeed, studies pointed out a possible implication of the gut microbiota–brain axis in the pathophysiology of MDD through inflammasome activation and brain–blood barrier alteration. The review of Carlessi et al. (2019) tackled this question, focusing on studies showing that changes in the gut microbiota can contribute to systemic inflammation, which modulates central nervous system functions.

Providing an integrated view of the neurobiology of depression is challenging and requires appropriate animal models to gain mechanistic insights that are not accessible in patients yet. Over the past 25 years, the animal‐based research in the field mostly relied on physical, psychological or social stress‐related models. While these models are relevant, they provide a partly biased mechanistic view of MDD because stress is far from being the only risk factor for this psychiatric disorder. In fact, it raises major questions for the field: Is there a unified mechanism explaining depression, or could various/independent mechanisms converge towards similar symptoms? Should we then consider the study of various forms of depression rather than depression as a single entity? Would the mechanism(s) leading to depression(s) vary depending on the considered aetiology? Are there both aetiology‐specific aspects and shared/converging mechanisms underlying depression? If this is the case, what would be the shared molecular and neuroanatomical hubs underlying given symptoms? Those are critical questions to address if depression is considered as a syndrome (collection of symptoms) that could emerge from heterogeneous mechanisms. If such heterogeneity indeed exists, it may have a significant influence on the development of treatment strategies. For example, molecular insights from stress‐related models already highlighted some mechanistic differences between repeated physical stressors and social stress. In this context, Kremer et al. (2020) described the present state‐of‐the‐art in modelling chronic pain as another aetiology of MDD. Indeed, chronic pain is an important co‐morbidity of mood disorders, and the presence of pain‐induced depressive‐like behaviours has now been successfully modelled in rodents. Interestingly, neuropathic pain has been shown to induce depressive‐like behaviours without affecting the HPA axis, thus differing from chronic stress on this aspect. Based on clinical knowledge, access to a variety of animal models relying on different aetiologies may prove useful to the field.

Many risk factors, including environmental and genetic, are associated with the development of MDD symptoms. One of the most intriguing risks is the heritability of stress consequences, with transgenerational impact independent from genetic factors. The review from Cunningham et al. (2019) covered the evidence, in a variety of models, for paternal transgenerational epigenetic mechanisms contributing to stress phenotypes in offspring. The authors highlighted stress‐induced changes in DNA methylation and in non‐coding RNAs regulation that may affect gametes and subsequent generations, with differences in the impact on male and female offspring. Long‐term consequences of stress that increase susceptibility to MDD can also display sexual dimorphism affecting myelin and the oligodendrocyte lineage cells, a cell population involved in brain development and neuronal conduction. This topic was addressed by Boda (2019) in this Special Issue. She also reported data illustrating how myelin and oligodendroglia respond to depression treatment, proposing this non‐neuronal substrate as a therapeutic target of interest.

Progress in characterizing depression symptoms and their detection has also been made in the psychiatric field. In their articles, Rochet et al. (2020) studied a method to evaluate olfactory and emotional perception in patients with minor depressive symptoms, and McIvor et al. (2020) reported that depressed patients can exhibit alterations in self‐referential processing and in sensitivity to the emotional context of stimuli.

The most extreme consequence of MDD is probably suicide. While this frightening phenomenon, which overrides the basic instinct of survival, mostly escapes animal‐based research, understanding its biological bases is of utmost importance. In a narrative review, Lengvenyte et al. (2019) covered the present knowledge of the neurobiology of suicidal behaviours. The authors described the main findings of epidemiological, genetic, neuroanatomical, neuropsychological, immunological and neuroendocrinological studies addressing this question.

While this Special Issue highlights various aspects of research on depression, it is of course far from being exhaustive considering the extent of the field. However, it covers the state‐of‐the‐art on specific technical and mechanistic aspects of such research. Strikingly, the complexity of depression emerges as a research trend per se, by addressing brain circuits, molecular actors, organs beside brain as well as body/mind relations, heterogeneity of susceptibility and resilience factors, variety of aetiologies, inter‐individual differences including individual attributes such as sex, age, socioeconomic factors and life style. By acknowledging this reality and addressing it as a scientific question, the research effort has become more robust and been directed towards a relevant translational path over the last two decades. Reaching such more global understanding of this psychiatric disease is however still a challenge upfront.

抑郁症是地方性疾病，因为它们在整个生命周期中的某个时候会影响大约16％的人口，并导致个人痛苦，自杀风险增加和明显的社会经济负担。核心症状包括情绪低落，自尊心低下和普遍失去兴趣。由于对抑郁症的神经生物学机制仍知之甚少，目前的治疗方法仅对约三分之二的患者有效，因此，正在进行一项有关抑郁症及其治疗的分子和神经机制的深入研究，以确定风险因素或对抑郁症的适应力，并确定新的治疗目标。本期特刊包含基于人和动物的研究的部分评论和文章，重点通过综合分析关注抑郁症，从细胞，分子和电路水平到行为和环境分析。它致力于纪念Ron Duman和Paul Greengard。

抑郁症可以被认为是大脑改变信息处理方式，改变对生活事件，思想和行为的认知的故事。为了达到所需的回路理解水平，抑郁症领域的最新研究得益于光遗传学和化学遗传学工具的发展，这些工具允许在体内操纵选定的神经元活动。这一技术进步有助于更好地了解抑郁症的病理生理学，尤其是在神经元活动与行为之间建立因果关系。Biselli等。（2019）回顾了使用这些方法的最新研究，以了解啮齿动物的抑郁样行为并强调了它们的方法学局限性。几种皮质和边缘脑结构的变化，例如前额叶皮层，杏仁核，伏隔核和海马结构，都与重度抑郁症（MDD）相关。在动物模型中，临床前研究表明，齿状回不仅在抑郁样行为中而且在抗抑郁药的作用中都起着至关重要的作用。由于成像，光遗传学和化学遗传学工具的发展，已经广泛研究了齿状回的特定电路和细胞类型在抑郁症及其治疗中的作用。根据动物模型和人类数据，Umschweif等人。（2019）回顾了这种细胞和神经解剖学的进展，强调了结构和分子变化的作用，这些变化影响抑郁症中不同类型的齿状回细胞及其各自的连通性。过去的十年中，哈贝努拉是一种编码厌恶刺激的上丘脑结构，已成为奖励/厌恶回路和MDD中的新角色。Metzger等。（2019）回顾了特定的ben神经网络在焦虑和抑郁中的作用，尤其是内侧和外侧lateral肌与腹侧被盖区-黑质复合体以及背侧ra肌之间的关系。长期以来，人们一直认为胺能系统是神经调节的核心角色，对其在抑郁症中的作用以及作为抗抑郁药的靶标进行了研究。尽管这种关注主要涉及血清素能和去甲肾上腺素能系统，但是多巴胺能系统在动机和奖赏功能中的作用在本世纪初与抑郁症相关的研究开创了。遵循这种动机/奖励领导，Döbrössy等人。（2020年）审查了临床和动物数据，结果显示内侧前脑束的深层脑刺激（DBS）是正在接受MDD研究的DBS靶标之一，可能对耐抑郁的抑郁症患者和抑郁症动物模型有益。对厌恶性刺激的注意增加，进而适应不良，也可能导致情绪改变。Mineur和Picciotto（2019）提出胆碱能系统可能至关重要。在概念框架中，最佳的稳态乙酰乙酰胆碱功能有助于协调大脑的活动，而乙酰胆碱的缺乏会诱发记忆力和认知障碍，他们回顾了表明高水平胆碱能信号传导也可能有害的数据。高乙酰胆碱水平可能会损害θ节律，从而降低边缘性同步性，从而引起人们对消极刺激的注意，并增强压力事件的编码。

神经营养因子的变化，尤其是脑源性神经营养因子（BDNF）的变化，以及随后突触可塑性和突触动力学的改变，都有助于MDD。BDNF是神经系统中表达最广泛的神经营养蛋白，它调节神经元的存活和分化，并关键地参与依赖活动的突触可塑性机制。在简短描述BDNF神经生物学后，Duman等人。（2019）非常优雅地回顾了BDNF在压力和抑郁中的作用的临床前和临床文献，特别关注BDNF的活性依赖性释放在快速抗抑郁药作用中的关键作用。作者还将该分析扩展到了血管内皮生长因子（VEGF）的贡献。除BDNF和VEGF外，成纤维细胞生长因子（FGF）系统是在胚胎发育期间，出生后和成年后表达的神经营养因子家族，也参与了重要的神经功能，例如神经发生和神经保护。徐等。（2019）展示了我们目前对抑郁症中FGF家族成员异常的了解，特别着重于FGF 2、9和22.他们强调了FGF家族成员在调节与抑郁症相关的分子中的作用，包括其他神经营养因子，血清素，糖皮质激素受体和炎症因素。

自从1990年代末以来，炎症和抑郁之间的关系一直是人们越来越感兴趣的话题，此前有证据表明免疫挑战可以诱发抑郁样的“病态行为”，而MDD的迅速发作可能是干扰素治疗的不良反应。在介绍了脑部免疫的主要参与者之后，Troubat等人。（2020）讨论了神经炎症如何与MDD的三个神经生物学相关性相互作用：单胺消耗，内分泌下丘脑-垂体-肾上腺（HPA）轴和神经发生。Nothdurfter等人的一篇研究文章。（2019）在抑郁症患者中进一步表明促炎性细胞因子白介素17可能是MDD治疗耐药性的生物标志物。个体对病理的敏感性或适应性以及对治疗的敏感性/抗性的问题至关重要。Dudek等人的评论。（2019）涵盖了人类和动物对神经生物学的洞察力，这些神经生物学是脆弱性与抵御压力和抑郁力的能力。他们提出内分泌应激反应，加剧的免疫反应以及抑郁症的生理病理和弹性中的神经血管功能障碍之间的强因果关系，突出了性别相关差异的重要性。我们对抑郁症知识的进步说明了一种强大的研究趋势，该趋势已超越了局部神经递质和大脑结构的改变，从而在整个人体水平上得到了更全面的了解。在这方面，最近引起炎症和身心关系的另一个因素是微生物群。确实，研究指出，通过炎症小体激活和脑血屏障改变，肠道微生物群-脑轴可能对MDD的病理生理有影响。Carlessi等人的评论。（2019）解决了这个问题，重点在于研究表明肠道菌群的变化可以导致全身性炎症，从而调节中枢神经系统功能。

提供抑郁症神经生物学的综合观点具有挑战性，并且需要适当的动物模型来获得尚无法在患者中获得的机制见解。在过去的25年中，该领域中基于动物的研究主要依赖于与身体，心理或社会压力有关的模型。尽管这些模型是相关的，但它们提供了MDD的部分偏见的力学观点，因为压力远不是该精神疾病的唯一危险因素。实际上，这引起了该领域的主要问题：是否有一个统一的机制来解释抑郁症，还是各种/独立机制趋于相似症状？那么，我们是否应该将对各种形式的抑郁症的研究而不是作为一个整体的抑郁症考虑？导致抑郁的机制会因所考虑的病因而有所不同吗？抑郁症是否既有病因学方面又有共享/趋同的机制？如果是这样，给定症状背后的共享分子和神经解剖学枢纽将是什么？这些是要解决的关键问题，即是否将抑郁症视为可能来自异类机制的综合症（症状的集合）。如果确实存在这种异质性，则可能会对治疗策略的发展产生重大影响。例如，来自压力相关模型的分子洞察力已经强调了重复的物理压力源和社会压力之间的一些机械差异。在这种情况下，Kremer等。（2020年）将目前在慢性疼痛建模中的最新技术描述为MDD的另一种病因。的确，慢性疼痛是情绪障碍的重要合并症，现在已经成功地在啮齿动物中模拟了疼痛引起的抑郁样行为。有趣的是，神经性疼痛已显示出可诱发类似抑郁的行为，而不会影响HPA轴，因此在这方面不同于慢性应激。基于临床知识，依赖于不同病因的各种动物模型的访问可能对本领域有用。

许多危险因素，包括环境和遗传因素，都与MDD症状的发展有关。最引人入胜的风险之一是压力后果的可遗传性，其跨代影响与遗传因素无关。坎宁安等人的评论。（2019）在各种模型中涵盖了父系跨代表观遗传机制导致后代应激表型的证据。作者强调了应力诱导的DNA甲基化和非编码RNA调控的变化，这些变化可能影响配子和后代，其对雄性和雌性后代的影响也不同。压力的长期后果会增加对MDD的易感性，还可能表现出性双态性，影响髓磷脂和少突胶质细胞谱系细胞，这是一种参与大脑发育和神经元传导的细胞群。Boda（2019）。她还报道了表明髓磷脂和少突胶质细胞对抑郁症治疗有何反应的数据，并提出将这种非神经元底物作为治疗目标。

在精神病学领域中，在表征抑郁症状及其检测方面也取得了进展。在他们的文章中，Rochet等人。（2020）研究了一种评估轻度抑郁症状患者嗅觉和情绪感知的方法，McIvor等（2020）。（2020）报告说，抑郁症患者的自我参照过程和对刺激情绪的敏感性可能会发生变化。

MDD的最极端后果可能是自杀。尽管这种可怕的现象凌驾于生存的基本本能上，但大多逃脱了以动物为基础的研究，但了解其生物学基础至关重要。在叙述性评论中，Lengvenyte等人。（2019）涵盖了自杀行为的神经生物学的当前知识。作者描述了针对这个问题的流行病学，遗传，神经解剖学，神经心理学，免疫学和神经内分泌学研究的主要发现。

尽管本期专刊着重介绍了抑郁症的各个方面，但考虑到该领域的范围，当然还远远不够。但是，它涵盖了此类研究的特定技术和机制方面的最新技术。令人惊讶的是，抑郁症的复杂性本身就成为研究趋势，其方法是解决大脑回路，分子行为者，大脑旁边的器官以及身体/心灵的关系，易感性和适应力因素的异质性，各种病因，个体差异属性，例如性别，年龄，社会经济因素和生活方式。通过承认这一现实并将其作为一个科学问题加以解决，在过去的二十年中，研究工作变得更加稳健，并朝着相关的翻译道路发展。