Symposium
Dissecting neural circuit basis of depression and bipolar disorder
シンポジウム
うつ病・双極性障害の神経回路を探る |
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| 7月27日（土）8：45～9:10 第2会場（朱鷺メッセ 2F メインホールA）
3S02m-1
双極性障害モデルマウスにおける縫線核と視床室傍核の役割
Mie Kubota-Sakashita（窪田－坂下 美恵），Tadafumi Kato（加藤 忠史）
理研CBS 精神疾患動態
Neuronal structures such as prefrontal cortex, cingulate cortex, nucleus accumbens, amygdala, hippocampus, brainstem monoaminergic nuclei are implicated in affective disorders. However, no specific regions or neuronal circuits related to pathogenesis of bipolar disorder (BD) have been identified. Based on neuroimaging and genetic studies in patients with BD, relationship between mitochondrial defects and BD were suspected. Thus, we focused on mutations of two genes, ANT1 and Polg1 (polymerase γ) which are known to be causative of a hereditary mitochondrial disease, chronic progressive opthalmoplegia (CPEO). The patients with CPEO sometimes exhibits comorbidity with BD or depression. We investigated brain-specific ANT1 knockout mice and CamKIIα promotor-driven mutant Polg1 transgenic (Tg) mice as model animals of BD. We previously reported that Tg mice showed BD-like phenotypes and brain-specific accumulation of mtDNA deletions. The mtDNA deletions cause a loss of mitochondrial proteins such as cytochrome c oxidase (COX). In the brain of mutant Polg1 Tg mice, the mtDNA-affected cells were frequently detected by immunohistochemistry with antibodies against COX in the paraventricular thalamic nucleus (PVT). Additionally, an anatomical screen in aged mice showed accumulation of COX-negative cells in the raphe nuclei (RN) which is a major origin of serotonergic projections. Both nuclei commonly express monoamine oxidase B (MAOB). This implicated that the PVT and serotonin (5HT) neurons might be susceptible to mitochondrial dysfuntion, because MAO is known as a major source of reactive oxygen species (ROS). Behavioral analysis of ANT1 heterozygous conditional knockout (cKO) mice using lntelliCage revealed a selective diminution in delay discounting, which indicates an increase in serotonergic activity. Neurons in the RN of the ANT1 heterozygous cKO mice showed hyperexcitability, along with enhanced 5HT turnover in the nucleus accumbens and upregulation of MAOB in the RN. The results were consistent with the results of behavioral analyses. These findings demonstrate that mutations in causative genes of a mitochondrial disease cause behavioral abnormalities. This suggests that abnormalities of a neural network including the PVT and the RN, possibly associated with mitochondrial dysfunction caused by ROS generation by MAOB, might play a pathological role in BD. | | 7月27日（土）9:10～9:35 第2会場（朱鷺メッセ 2F メインホールA）
3S02m-2
うつ病症状の多様性における手綱核神経回路の役割
Hidenori Aizawa（相澤 秀紀）
広島大院医歯薬神経生物
Habenula is phylogenetically conserved structure, its neural circuit is found across species. Lesion and electrophysiological studies in the animals suggested that it is involved with regulation of the monoaminergic activity through projection to the brain stem nuclei. Since the studies in the animal model of depression and human functional imaging indicated that increase activity of the habenula was associated with the depressive phenotypes, this structure has attracted a surge of interest in neuroscience research. According to the pathway- and cell type-specific dissection of the habenular function in the animals, we begin to understand how the heterogeneity of the habenula accounts for alteration of the diverse physiological functions in depression. Indeed, recent studies revealed that subnuclei embedded in the habenula showed a wide variety of molecular profile not only in neuron but in glial cells implementing the multifaceted regulatory mechanism for output from the habenula. In this review, we overview the known facts on mediolateral dichotomy in the habenular structure, then discuss heterogeneity of the habenular structure from the anatomical and functional viewpoint to understand its emerging role in diverse neural functions relevant to the depressive phenotypes. Despite the prevalent use of antidepressants acting on the monoamine metabolisms, ~30% of patients with major depression are reported to be treatment-resistant. Thus, cellular mechanism deciphering such diversity in depressive symptoms would be a promising candidate for development of new antidepressant. | | 7月27日（土）9:35～10:00 第2会場（朱鷺メッセ 2F メインホールA）
3S02m-3
ストレス感受性とレジリエンス形成の分子神経メカニズム
Shusaku Uchida（内田 周作）
京都大院医・MIC・SKプロジェクト
Stressful events are potent adverse environmental factors that can predispose individuals to psychiatric disorders such as depression. Exposure to chronic stress can be differently perceived by individuals and can have persistent sequelae depending on the level of stress resilience or vulnerability of each person. While stress vulnerability may influence depression, the molecular and neural mechanisms underlying the susceptibility and resilience to chronic stress within the brain are poorly understood. Recent studies suggest that stress-induced aberrant synaptic and structural plasticity may be key underlying mechanisms of stress susceptibility. Neuroplasticity is regulated by a complex gene expression program and multiple lines of evidence implicate aberrant transcriptional regulation of neuroplasticity-associated genes in the pathophysiology of depression. An increasing evidence has provided key insights into the biological significance of epigenetic regulation of gene expression in behavioral response to chronic stress. The medial prefrontal cortex (mPFC) is vulnerable to damage from a variety of psychosocial stressors and aberrant structural and functional changes in this brain structure have been implicated in the pathophysiology of depression. In addition, there is growing evidence indicating that environmental challenges alter neural activity in this brain structure. However, little is known about the role of epigenetic mechanisms within the mPFC in chronic stress-induced aberrant neuronal plasticity and depression-like behavior. In this symposium, I will focus on causal and mechanistic evidence implicating altered functions and connectivity of the mPFC circuits in the establishment and the maintenance of stress resilience and susceptibility. I also touch upon recent findings suggesting a role for epigenetic mechanisms in these processes and briefly discuss promising avenues of future investigation. | | 7月27日（土）10:00～10:25 第2会場（朱鷺メッセ 2F メインホールA）
3S02m-4
Brain-wide neural oscillatory networks predict depression vulnerability
Rainbo Hultman（Hultman Rainbo）
University of Iowa
Major depressive disorder (MDD) was recently deemed by the World Health Organization to be the number one cause of disability across the globe. However, very little progress has been made in understanding the underlying mechanisms of this disorder, and, as such, very few new therapeutics have been developed. Recent breakthroughs in human studies and animal models suggest that functional connectivity across multiple brain regions may provide important mechanistic information that would facilitate personalized mechanism-based therapeutic treatment. Here, the use of multi-site in vivo recordings will be presented as a way of probing brain-wide neural oscillations on a millisecond timescale in a preclinical rodent model of depression. Machine learning approaches can augment interpretation of the millions of data points collected by these methods by using patterns of electrical connectivity to define depression-related emotional states. This relationship between electrical connectivity patterns and emotional/behavioral states can then be validated using out-of-sample testing across different depression-vulnerability paradigms. Maps of brain-wide activity may be useful for identifying new therapeutic targets that impact specific brain network activity patterns. By identifying molecular drivers that reverse specific patterns of depressive activity, we can look for therapeutics related to a specific underlying etiology, thus paving a way for precision medicine for MDD treatment. Data will be presented providing the initial proof of principle demonstration of this approach to identify therapeutic targets for anti-depressant development, using a combination of RNA-Seq, viral in vivo molecular manipulations, and behavioral analyses. | |
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