
ショウジョウバエの社会的ネットワーク行動は、神経ペプチドDrosulfakininによって制御され、発達初期の社会経験によって適応的に変化する。


coremsg

Drosophila establishes social clusters in groups, yet the underlying principles remain poorly understood. Here we performed a systemic analysis of social network behavior (SNB) that quantifies individual social distance (SD) in a group over time. The SNB assessment in 175 inbred strains from the Drosophila Genetics Reference Panel revealed a tight association of short SD with long developmental time, low food intake, and hypoactivity. The developmental inferiority in short-SD individuals was compensated by their group culturing. By contrast, developmental isolation silenced the beneficial effects of social interactions in adults and blunted the plasticity of SNB under physiological challenges. Transcriptome analyses showed genetic diversity for SD traits, whereas social isolation reprogrammed select genetic pathways, regardless of SD phenotypes. In particular, social deprivation suppressed the expression of the neuropeptide Drosulfakinin ( Dsk ) in three pairs of adult brain neurons. Male-specific DSK signaling to Cholecystokinin-like receptor 17D1 mediated the SNB plasticity. In fact, transgenic manipulations of the DSK signaling were sufficient to imitate the state of social experience. Given the functional conservation of mammalian Dsk homologs, we propose that animals have evolved a dedicated neural mechanism to encode early-life experience and transform group properties adaptively.

### Competing Interest Statement

The authors have declared no competing interest.

Drosulfakinin signaling encodes early-life memory for adaptive social plasticity

自然集団のショウジョウバエにおける社会的ネットワーク行動の遺伝的基盤と可塑性

title_rewrite


TIMM50 欠乏は、酸化的リン酸化系とミトコンドリアリボソームの機能低下を引き起こし、神経細胞の ATP 産生能力と神経活動を低下させる。


TIMM50, an essential TIM23 complex subunit, is suggested to facilitate the import of ∼60% of the mitochondrial proteome. In this study, we characterized a TIMM50 disease causing mutation in human fibroblasts, and noted significant decreases in TIM23 core protein levels (TIMM50, TIMM17A/B, and TIMM23). Strikingly, TIMM50 deficiency had no impact on the steady state levels of most of its substrates, challenging the currently accepted import dogma of the essential general import role of TIM23 and suggesting that fully functioning TIM23 complex is not essential for maintaining the steady state level of the majority of mitochondrial proteins. As TIMM50 mutations have been linked to severe neurological phenotypes, we aimed to characterize TIMM50 defects in manipulated mammalian neurons. TIMM50 knockdown in mouse neurons had a minor effect on the steady state level of most of the mitochondrial proteome, supporting the results observed in patient fibroblasts. Amongst the few affected TIM23 substrates, a decrease in the steady state level of components of the intricate oxidative phosphorylation and mitochondrial ribosome complexes was evident. This led to declined respiration rates in fibroblasts and neurons, reduced cellular ATP levels and defective mitochondrial trafficking in neuronal processes, possibly contributing to the developmental defects observed in patients with TIMM50 disease. Finally, increased electrical activity was observed in TIMM50 deficient mice neuronal cells, which correlated with reduced levels of KCNJ10 and KCNA2 plasma membrane potassium channels, likely underlying the patients’ epileptic phenotype.

### Competing Interest Statement

The authors have declared no competing interest.

Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50

ミトコンドリア輸送タンパク質-timm50-の欠乏が引き起こす生化学的および神経生理学的影響


ミトコンドリア輸送タンパク質 TIMM50 の欠乏が引き起こす生化学的および神経生理学的影響



GluK1 カイネート受容体のアミノ末端ドメインにあるスプライス挿入は、受容体の脱感作特性、アゴニスト感受性、電位依存性ブロックなどの機能的特性を変化させる。また、これらの特性はカイネート受容体の補助タンパク質Netoタンパク質によって異なる様式で調節される。


Kainate receptors are key modulators of synaptic transmission and plasticity in the central nervous system. Different kainate receptor isoforms with distinct spatiotemporal expressions have been identified in the brain. The GluK1-1 splice variant receptors, which are abundant in the adult brain, have an extra fifteen amino acids inserted in the amino-terminal domain (ATD) of the receptor resulting from alternative splicing of exon 9. However, the functional implications of this post-transcriptional modification are not yet clear. We employed a multi-pronged approach using cryogenic electron microscopy, electrophysiology, and other biophysical and biochemical tools to understand the structural and functional impact of this splice insert in the extracellular domain of GluK1 receptors. Our study reveals that the splice insert alters the key gating properties of GluK1 receptors and their modulation by the cognate auxiliary Neuropilin and tolloid-like (Neto) proteins 1 and 2. Mutational analysis identified the role of crucial splice residues that influence receptor properties and their modulation. Furthermore, the cryoEM structure of the variant shows that the presence of exon 9 in GluK1 does not affect the receptor architecture or domain arrangement in the desensitized state. Our study thus provides the first detailed structural and functional characterization of GluK1-1a receptors, highlighting the role of the splice insert in modulating receptor properties and their modulation.

### Competing Interest Statement

The authors have declared no competing interest.

Functional Implications of the Exon 9 Splice Insert in GluK1 Kainate Receptors

gluk1-カイネート受容体のエクソン9スプライス挿入の機能的意義


GluK1 カイネート受容体のエクソン9スプライス挿入の機能的意義



慢性ストレスによるうつ様行動は、VTAドパミン神経の活動低下に関連し、その機序にTRPC6チャネルの発現低下が関与している。


The slow-intrinsic-pacemaker dopaminergic (DA) neurons originating in the ventral tegmental area (VTA) are implicated in various mood- and emotion-related disorders, such as anxiety, fear, stress and depression. Abnormal activity of projection-specific VTA DA neurons is the key factor in the development of these disorders. Here, we describe the crucial role for the NALCN and TRPC6, non-selective cation channels in mediating the subthreshold inward depolarizing current and driving the firing of action potentials of VTA DA neurons in physiological condition. Furthermore, we demonstrate that down-regulation of TRPC6 protein expression in the VTA DA neurons likely contributes to the reduced activity of projection-specific VTA DA neuron in chronic mild unpredictable stress (CMUS) depressive mice. In consistent with these, selective knockdown of TRPC6 channels in the VTA DA neurons conferred mice with depression-like behavior. This current study suggests down-regulation of TRPC6 expression/function is involved in reduced VTA DA neuron firing and chronic stress-induced depression-like behavior of mice.

### Competing Interest Statement

The authors have declared no competing interest.

The cation channel mechanisms of subthreshold inward depolarizing currents in the VTA dopaminergic neurons and their roles in the chronic-stress-induced depression-like behavior

慢性ストレス誘発うつ様行動における-vta-ドパミン神経の活動低下とtrpc6-チャネルの役割


慢性ストレス誘発うつ様行動における VTA ドパミン神経の活動低下とTRPC6 チャネルの役割



ゼブラフィンチの歌の時間的構造は、神経細胞の内在的性質、特に過剰抑制からの反跳性興奮に関連している。


Neuronal intrinsic excitability is a mechanism implicated in learning and memory that is distinct from synaptic plasticity. Prior work in songbirds established that intrinsic properties (IPs) of premotor basal-ganglia-projecting neurons (HVCX) relate to learned song. Here we find that temporal song structure is related to specific HVCX IPs: HVCX from birds who sang longer songs including longer invariant vocalizations (harmonic stacks) had IPs that reflected increased post-inhibitory rebound. This suggests a rebound excitation mechanism underlying the ability of HVCX neurons to integrate over long periods of time and represent sequence information. To explore this, we constructed a network model of realistic neurons showing how in-vivo HVC bursting properties link rebound excitation to network structure and behavior. These results demonstrate an explicit link between neuronal IPs and learned behavior. We propose that sequential behaviors exhibiting temporal regularity require IPs to be included in realistic network-level descriptions.

### Competing Interest Statement

The authors have declared no competing interest.

Bursts from the past: Intrinsic properties link a network model to zebra finch song

過去からの発火-学習された鳥の歌と神経細胞の内在的性質の関係


過去からの発火: 学習された鳥の歌と神経細胞の内在的性質の関係



調節性T細胞は、エンケファリン産生を介して、マウスの基底体性感受性を調節する。


CD4+CD25+Foxp3+ regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene ( Penk ), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells. We then present various evidence suggesting that Penk is regulated in part by members of the TNF receptor family and the transcription factor Batf. Using mice in which the promoter activity of Penk can be tracked with a fluorescent reporter, we also show that Penk expression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin. Functionally, Treg cells proficient or deficient for Penk suppress equally well the proliferation of effector T cells in vitro and autoimmune colitis in vivo . In contrast, inducible ablation of Penk in Treg leads to heat hyperalgesia in both male and female mice. Overall, our results indicate that Treg might play a key role at modulating basal somatic sensitivity in mice through the production of analgesic opioid peptides.

### Competing Interest Statement

The authors have declared no competing interest.

Enkephalin-mediated modulation of basal somatic sensitivity by regulatory T cells in mice

マウスにおける調節性t細胞によるエンケファリン介在性の基底体性感受性調節


マウスにおける調節性T細胞によるエンケファリン介在性の基底体性感受性調節



ショウジョウバエのOPA1遺伝子欠損は、ヒトの自動優性視神経萎縮症の病理を模倣し、ヒトOPA1遺伝子の発現によりその変性が部分的に回復する。さらに、ヒトOPA1遺伝子の特定の変異は、この回復を抑制することで、機能低下型と優性阻害型の変異を区別できる。


Autosomal dominant optic atrophy (DOA) is a progressive form of blindness caused by degeneration of retinal ganglion cells and their axons, mainly caused by mutations in the OPA1 mitochondrial dynamin like GTPase ( OPA1 ) gene. OPA1 encodes a dynamin-like GTPase present in the mitochondrial inner membrane. When associated with OPA1 mutations, DOA can present not only ocular symptoms but also multi-organ symptoms (DOA plus). DOA plus often results from point mutations in the GTPase domain, which are assumed to have dominant negative effects. However, the presence of mutations in the GTPase domain does not always result in DOA plus. Therefore, an experimental system to distinguish between DOA and DOA plus is needed. In this study, we found that loss-of-function mutations of the dOPA1 gene in Drosophila can imitate the pathology of optic nerve degeneration observed in DOA. We successfully rescued this degeneration by expressing the human OPA1 ( hOPA1 ) gene, indicating that hOPA1 is functionally interchangeable with dOPA1 in the fly system. However, mutations previously identified did not ameliorate the dOPA1 deficiency phenotype. By expressing both WT and DOA plus mutant hOPA1 forms in the optic nerve of dOPA1 mutants, we observed that DOA plus mutations suppressed the rescue, facilitating the distinction between loss-of-function and dominant negative mutations in hOPA1 . This fly model aids in distinguishing DOA from DOA plus and guides initial hOPA1 mutation treatment strategies.

### Competing Interest Statement

The authors have declared no competing interest.

Drosophila model to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy

自動優性視神経萎縮症の病理学的意義を明らかにするためのショウジョウバエモデル


慢性疼痛関連記憶障害の脆弱性は、海馬歯状回におけるS1P/S1PR1シグナル伝達の機能不全によって引き起こされる。


Memory impairment in chronic pain patients is substantial and common, and few therapeutic strategies are available. Chronic pain-related memory impairment has susceptible and unsusceptible features. Therefore, exploring the underlying mechanisms of its vulnerability is essential for developing effective treatments. Here, combining two spatial memory tests (Y-maze test and Morris water maze), we segregated chronic pain mice into memory impairment-susceptible and -unsusceptible subpopulations in a chronic neuropathic pain model induced by chronic constrictive injury of the sciatic nerve. RNA-seq analysis and gain/loss-of-function study revealed that S1P/S1PR1 signaling is a determinant for vulnerability to chronic pain-related memory impairment. Knockdown of the S1PR1 in the DG promoted a susceptible phenotype and led to structural plasticity changes of reduced excitatory synapse formation and abnormal spine morphology as observed in susceptible mice, while overexpression of the S1PR1 and pharmacological administration of S1PR1 agonist in the DG promoted an unsusceptible phenotype and prevented the occurrence of memory impairment, and rescued the morphological abnormality. Finally, GO enrichment analysis and biochemical evidence indicated that down-regulation of S1PR1 in susceptible mice may impair DG structural plasticity via interaction with actin cytoskeleton rearrangement-related signaling pathways including Itga2 and its downstream Rac1/Cdc42 signaling and Arp2/3 cascade. These results reveal a novel mechanism and provide a promising preventive and therapeutic molecular target for vulnerability to chronic pain-related memory impairment.

### Competing Interest Statement

The authors have declared no competing interest.

Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment

慢性疼痛関連記憶障害の脆弱性を駆動するs1p-s1pr1シグナル伝達の機能不全


慢性疼痛関連記憶障害の脆弱性を駆動するS1P/S1PR1シグナル伝達の機能不全



光周期の変化に応じて、特定の神経細胞の軸索分枝で神経伝達物質の分離が可逆的に起こり、概日リズムと睡眠-覚醒のタイミングの同期化を促進する。


Changes in day length, conveyed by the preoptic area, drive axonal neurotransmitter reorganization in median raphe dual serotonin–glutamate neurons to regulate behaviour and sleep timing, highlighting a photoperiod-sensitive brain circuit.

Adaptation to photoperiod via dynamic neurotransmitter segregation - Nature

光周期への適応-動的な神経伝達物質の分離


光周期への適応:動的な神経伝達物質の分離



アレルゲン反応回路の中心的な神経ノードは、脳幹のDbh+ニューロンであり、これらのニューロンが気道収縮を調節することが明らかになった。


Mapping a full allergen circuit from the lung to the brainstem and back, repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract neurons in a mast cell-, interleukin-4- and vagal nerve-dependent manner.

Brainstem Dbh+ neurons control allergen-induced airway hyperreactivity - Nature

アレルゲン誘発性気道過敏症を制御する脳幹dbh-ニューロン


アレルゲン誘発性気道過敏症を制御する脳幹Dbh+ニューロン
