2019年抑郁症领域十大基础研究进展

1. Nature genetics—科学家新发现20个与双向情感障碍相关的基因位点

英文摘要：

Bipolardisorder is a highly heritable psychiatric disorder. We performed a genome-wideassociation study (GWAS) including 20,352 cases and 31,358 controls of Europeandescent, with follow-up analysis of 822 variants with P < 1 × 10-4 in anadditional 9,412 cases and 137,760 controls. Eight of the 19 variants that weregenome-wide significant (P < 5 × 10-8) in the discovery GWAS were notgenome-wide significant in the combined analysis, consistent with small effectsizes and limited power but also with genetic heterogeneity. In the combinedanalysis, 30 loci were genome-wide significant, including 20 newly identifiedloci. The significant loci contain genes encoding ion channels,neurotransmitter transporters and synaptic components. Pathway analysisrevealed nine significantly enriched gene sets, including regulation of insulinsecretion and endocannabinoid signaling. Bipolar I disorder is stronglygenetically correlated with schizophrenia, driven by psychosis, whereas bipolarII disorder is more strongly correlated with major depressive disorder. Thesefindings address key clinical questions and provide potential biologicalmechanisms for bipolar disorder.

参考文献：

Stahl et al (2019). Genome-wide association study identifies 30 loci associated withbipolar disorder. Nat Genet. 2019 May;51(5):793-803.

2. Science—抗抑郁药物通过诱导树突棘形成以持续修复抑郁症相关的前额叶环路功能障碍

英文摘要：

Theneurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Throughrepeated longitudinal imaging of medial prefrontal microcircuits in the livingbrain, we found that prefrontal spinogenesis plays a critical role insustaining specific antidepressant behavioral effects and maintaining long-termbehavioral remission. Depression-related behaviorwas associated with targeted, branch-specific elimination of postsynapticdendritic spines on prefrontal projection neurons. Antidepressant-dose ketaminereversed these effects by selectively rescuing eliminated spines and restoringcoordinated activity in multicellular ensembles that predict motivated escapebehavior. Prefrontal spinogenesis was required for the long-term maintenance ofantidepressant effects on motivated escape behavior but not for their initialinduction.

参考文献：

Moda-Sava et al (2019). Sustained rescue of prefrontal circuit dysfunction byantidepressant-induced spine formation. Science. 2019 Apr 12;364(6436).

3.Nature medicine—杏仁核投射到伏隔核的谷氨酸能纤维上的大麻素CB1受体调控抑郁症样行为

英文摘要：

Major depressive disorder is a devastating psychiatricdisease that afflicts up to 17% of the world's population. Postmortem brainanalyses and imaging studies of patients with depressionhave implicated basal lateral amygdala (BLA) dysfunction in the pathophysiologyof depression. However, the circuit and molecularmechanisms through which BLA neurons modulate depressivebehavior are largely uncharacterized. Here, in mice, we identified that BLAcholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement viaD2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronicsocial defeat selectively potentiated excitatory transmission of the CCK^BLA-D2^NAccircuit in susceptible mice via reduction of presynaptic cannabinoid type-1receptor (CB₁R). Knockdown of CB₁R in the CCK^BLA-D2^NAccircuit elevated synaptic activity and promoted stress susceptibility. Notably,selective inhibition of the CCK^BLA-D2^NAc circuit or administrationof synthetic cannabinoids in the NAc was sufficient to produceantidepressant-like effects. Overall, our studies reveal the circuit andmolecular mechanisms of depression.

参考文献：

Shen et al (2019). Cannabinoid CB1 receptors in the amygdalar cholecystokininglutamatergic afferents to nucleus accumbens modulate depressive-like behavior.Nat Med. 2019 Feb;25(2):337-349.

4. Neuron—科学家揭示介导光疗抗抑郁作用的视网膜-外侧缰核神经环路

英文摘要：

Light plays a pivotal role in the regulation of affective behaviors. However, theprecise circuits that mediate the impact of light on depressive-likebehaviors are not well understood. Here, we show that light influences depressive-like behaviors through a disynaptic circuitlinking the retina and the lateral habenula (LHb). Specifically, M4-typemelanopsin-expressing retinal ganglion cells (RGCs) innervate GABA neurons inthe thalamic ventral lateral geniculate nucleus and intergeniculate leaflet(vLGN/IGL), which in turn inhibit CaMKIIα neurons in the LHb. Specificactivation of vLGN/IGL-projecting RGCs, activation of LHb-projecting vLGN/IGLneurons, or inhibition of postsynaptic LHb neurons is sufficient to decreasethe depressive-like behaviors evoked bylong-term exposure to aversive stimuli or chronic social defeat stress.Furthermore, we demonstrate that the antidepressive effects of light therapyrequire activation of the retina-vLGN/IGL-LHb pathway. These results reveal adedicated retina-vLGN/IGL-LHb circuit that regulates depressive-likebehaviors and provide a potential mechanistic explanation for light treatmentof depression.

参考文献：

Huang et al (2019). A Visual Circuit Related to Habenula Underlies the AntidepressiveEffects of Light Therapy. Neuron. 2019 Apr 3;102(1):128-142.e8.

5.Molecular Psychiatry—髓鞘碱性蛋白免疫可以产生持续的抗抑郁症作用

英文摘要：

Immune dysregulation, specifically of inflammatory processes, has been linked tobehavioral symptoms of depression in both humanand rodent studies. Here, we evaluated the antidepressant effects ofimmunization with altered peptide ligands of myelin basic protein (MBP)-MBP_87-99[A⁹¹,A⁹⁶], MBP_87-99[A⁹¹], and MBP_87-99[R⁹¹,A⁹⁶]-in different models of depressionand examined the mechanism by which these peptides protect againststress-induced depression. We found that a singledose of subcutaneously administered MBP_87-99[A⁹¹, A⁹⁶]produced antidepressant-like effects by decreasing immobility in the forcedswim test and by reducing the escape latency and escape failures in the learnedhelplessness paradigm. Moreover, immunization with MBP_87-99[A⁹¹,A⁹⁶] prevented and reversed depressive-likeand anxiety-like behaviors that were induced by chronic unpredictable stress(CUS). However, MBP_87-99[R⁹¹, A⁹⁶] tended toaggravate CUS-induced anxiety-like behavior. Chronic stress increased theproduction of peripheral and central proinflammatory cytokines and induced theactivation of microglia in the prelimbic cortex (PrL), which was blocked by MBP_87-99[A⁹¹,A⁹⁶]. Immunization with MBP-derived altered peptide ligands alsorescued chronic stress-induced deficits in p11, phosphorylated cyclic adenosinemonophosphate response element binding protein, and brain-derived neurotrophicfactor expression. Moreover, microinjections of recombinant proinflammatorycytokines and the knockdown of p11 in the PrL blunted the antidepressant-likebehavioral response to MBP_87-99[A⁹¹, A⁹⁶].Altogether, these findings indicate that immunization with altered MBP peptideproduces prolonged antidepressant-like effects in rats, and the behavioralresponse is mediated by inflammatory factors (particularly interleukin-6), andp11 signaling in the PrL. Immune-neural interactions may impact central nervoussystem function and alter an individual's response to stress.

参考文献：

Han et al (2019). Systemic immunization with altered myelin basic protein peptideproduces sustained antidepressant-like effects. Mol Psychiatry. 2019 Aug 2

6.Molecular Psychiatry—促进觉醒的食欲素具有抗抑郁症作用

英文摘要：

Hypothalamic neuropeptide orexin has been implicated in the pathophysiology of psychiatricdisorders and accumulating clinical evidence indicates a potential link betweenorexin and depression. However, the exact role oforexin in depression, particularly the underlyingneural substrates and mechanisms, remains unknown. In this study, we reveal adirect projection from the hypothalamic orexinergic neurons to the ventralpallidum (VP), a structure that receives an increasing attention for its criticalposition in rewarding processing, stress responses, and depression.We find that orexin directly excites GABAergic VP neurons and prevents depressive-like behaviors in rats. Two orexin receptors,OX1R and OX2R, and their downstream Na⁺-Ca²⁺ exchangerand L-type Ca²⁺ channel co-mediate the effect of orexin.Furthermore, pharmacological blockade or genetic knockdown of orexin receptorsin VP increases depressive-like behaviors inforced swim test and sucrose preference test. Intriguingly, blockage oforexinergic inputs in VP has no impact on social proximity in socialinteraction test between novel partners, but remarkably strengthens socialavoidance under an acute psychosocial stress triggered by social rank. Notably,a significantly increased orexin level in VP is accompanied by an increase inserum corticosterone in animals exposed to acute stresses, including forcedswimming, food/water deprivation and social rank stress, rather than non-stresssituations. These results suggest that endogenous orexinergic modulation on VPis especially critical for protecting against depressivereactions to stressful events. The findings define an indispensable role forthe central orexinergic system in preventing depressionby promoting stress resilience.

参考文献：

Ji et al (2019). Orexin prevents depressive-like behavior by promoting stressresilience. Mol Psychiatry. 2019 Feb;24(2):282-293.

7.Nature neuroscience—迄今最大的GWAS研究发现102个与抑郁症相关的遗传变异

英文摘要：

Major depression is a debilitating psychiatric illnessthat is typically associated with low mood and anhedonia. Depression has a heritable component that has remaineddifficult to elucidate with current sample sizes due to the polygenic nature ofthe disorder. To maximize sample size, wemeta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls)from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269genes, and 15 genesets associated with depression,including both genes and gene pathways associated with synaptic structure andneurotransmission. An enrichment analysis provided further evidence of theimportance of prefrontal brain regions. In an independent replication sample of1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102associated variants were significant after multiple testing correction. Thesefindings advance our understanding of the complex genetic architecture of depression and provide several future avenues forunderstanding etiology and developing new treatment approaches.

参考文献：

Howard et al (2019). Genome-wide meta-analysis of depression identifies 102independent variants and highlights the importance of the prefrontal brainregions. Nat Neurosci. 2019 Mar;22(3):343-352.

8. Nature neurosci—科学家阐明介导慢性疼痛相关抑郁症的神经环路

英文摘要：

Comorbid depressive symptoms (CDS) in chronic pain are acommon health problem, but the neural circuit mechanisms underlying thesesymptoms remain unclear. Here we identify a novel pathway involving5-hydroxytryptamine (5-HT) projections from the dorsal raphe nucleus (5-HT^DRN)to somatostatin (SOM)-expressing and non-SOM interneurons in the centralnucleus of the amygdala (CeA). The SOM^CeA neurons project directlyto the lateral habenula, an area known involved in depression.Inhibition of the 5-HT^DRN→SOM^CeA pathway produced depression-like behavior in a male mouse model ofchronic pain. Activation of this pathway using pharmacological or optogeneticapproaches reduced depression-like behavior inthese mice. Human functional magnetic resonance imaging data showed thatcompared to healthy controls, functional connectivity between theCeA-containing centromedial amygdala and the DRN was reduced in patients withCDS but not in patients in chronic pain without depression.These findings indicate that a novel 5-HT^DRN→SOM^CeA→lateralhabenula pathway may mediate at least some aspects of CDS.

参考文献：

Zhou et al (2019). A neural circuit for comorbid depressive symptoms in chronicpain. Nat Neurosci. 2019 Oct;22(10):1649-1658.

9.Molecular Psychiatry—肠道微生物可能通过增加腹侧海马的炎症反应进而导致抑郁症样行为

英文摘要：

Chronic exposure to stress is associated with increased incidence of depression, generalized anxiety, and PTSD. However,stress induces vulnerability to such disorders only in a sub-population ofindividuals, as others remain resilient. Inflammation has emerged as a putativemechanism for promoting stress vulnerability. Using a rodent model of socialdefeat, we have previously shown that rats with short-defeat latencies(SL/vulnerable rats) show increased anxiety- and depression-likebehaviors, and these behaviors are mediated by inflammation in the ventralhippocampus. The other half of socially defeated rats show long-latencies todefeat (LL/resilient) and are similar to controls. Because gut microbiota areimportant activators of inflammatory substances, we assessed the role of thegut microbiome in mediating vulnerability to repeated social defeat stress. Weanalyzed the fecal microbiome of control, SL/vulnerable, and LL/resilient ratsusing shotgun metagenome sequencing and observed increased expression ofimmune-modulating microbiota, such as Clostridia, in SL/vulnerable rats. Wethen tested the importance of gut microbiota to the SL/vulnerable phenotype. Inotherwise naive rats treated with microbiota from SL/vulnerable rats, there washigher microglial density and IL-1β expression in the vHPC, and higher depression-like behaviors relative to rats that receivedmicrobiota from LL/resilient rats, non-stressed control rats, orvehicle-treated rats. However, anxiety-like behavior during social interactionwas not altered by transplant of the microbiome of SL/vulnerable rats intonon-stressed rats. Taken together, the results suggest the gut microbiomecontributes to the depression-like behavior andinflammatory processes in the vHPC of stress vulnerable individuals.

参考文献：

Pearson-Leary et al (2019). The gut microbiome regulates the increases in depressive-typebehaviors and in inflammatory processes in the ventral hippocampus of stressvulnerable rats. Mol Psychiatry. 2019 Mar 4.

10. Neuron— mGlu2和mGlu3负性变构化合物可通过增强丘脑-皮层的神经传递以改善抑郁症

英文摘要：

Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu₂)and 3 (mGlu₃) exert rapid antidepressant-like effects by enhancingprefrontal cortex (PFC) glutamate transmission; however, the receptor subtypecontributions and underlying mechanisms remain unclear. Here, we leveragednewly developed negative allosteric modulators (NAMs), transgenic mice, andviral-assisted optogenetics to test the hypothesis that selective inhibition ofmGlu₂ or mGlu₃ potentiates PFC excitatory transmissionand confers antidepressant efficacy in preclinical models. We found thatsystemic treatment with an mGlu₂ or mGlu₃ NAM rapidlyactivated biophysically unique PFC pyramidal cell ensembles. Mechanisticstudies revealed that mGlu₂ and mGlu₃ NAMs enhancethalamocortical transmission and inhibit long-term depressionby mechanistically distinct presynaptic and postsynaptic actions. Consistentwith these actions, systemic treatment with either NAM decreased passive copingand reversed anhedonia in two independent chronic stress models, suggestingthat both mGlu₂ and mGlu₃ NAMs induce antidepressant-likeeffects through related but divergent mechanisms of action.

参考文献：

Joffe et al (2019). mGlu2 and mGlu3 Negative Allosteric Modulators DivergentlyEnhance Thalamocortical Transmission and Exert Rapid Antidepressant-likeEffects. Neuron. 2019 Oct 16

2019年十大研究进展名录

1. 年终盘点：2019年帕金森病十大基础研究进展

2. 年终盘点：2019年帕金森病十大临床研究进展

3. 年终盘点：2019年阿尔茨海默病十大基础研究进展

4. 年终盘点：2019年阿尔茨海默病十大临床研究进展

5. 年终盘点：2019年神经科学领域十大基础研究进展

2018年十大研究进展名录

1.盘点2018年阿尔茨海默病十大研究突破

2.盘点2018年帕金森病十大研究突破

3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症（ALS）十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破

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