Biology subjects

Abe, T.

Publications and source records attributed to Abe, T..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Spatiotemporal EP4-fibulin-1 expression is associated with vascular intimal hyperplasia

AimsCyclooxygenase-2- and microsomal prostaglandin E synthase-1-derived prostaglandin E2 (PGE2) are involved in vascular intimal hyperplasia (IH). Although extensive studies have revealed the roles of PGE2 receptors (EPs) in IH, spatiotemporal EP expressions and downstream targets have not been fully elucidated. In this study, we focused on EP4 and investigated its role in vascular IH. Methods and ResultsWe generated EP4 reporter mice (Ptger4-IRES-nlsLacZ) and found prominent EP4 expression in the proliferative neointima 2 weeks after femoral artery wire injury. Expression of EP4 were returned to the baseline level 4 weeks after vascular injury (VI). Injury-induced IH was diminished in vascular smooth muscle cell (VSMC)-specific EP4 heterozygous deficient mice (Ptger4fl/+;SM22-Cre) 2 and 4 weeks after VI compared to SM22-Cre, whereas injury-induced IH was exacerbated in VSMC-specific EP4-overexpressing mice (Ptger4-Tg) compared to controls (non-Tg). Systemic EP4 antagonist administration reduced VI-induced IH in wild-type mice. We investigated the role of extracellular matrix proteins, as downstream regulated targets of EP4. Stimulation of EP4 increased mRNA and protein levels of fibulin-1 (a multifunctional glycoprotein) in Ptger4-Tg VSMCs. Fibulin-1C or -1D recombinant proteins increased VSMC proliferation, whereas proliferation was decreased in fibulin-1-deficient VSMCs. We generated multiple deletion mutants of fibulin-1C and found that EGF-like modules 6-8 appear to be involved in fibulin-1-mediated proliferation. Among binding partners of fibulin-1, extracellular matrix protein 1 (ECM1) was upregulated by EP4 stimulation, and fibulin-1 and ECM1 proteins additively enhanced VSMC proliferation. Similar to EP4 expression, both fibulin-1 and ECM1 were abundantly expressed in the neointima 2 weeks after VI. Furthermore, injury-induced IH was attenuated in VSMC-specific fibulin-1 deletion mice (Fbln1fl/fl;SM22-Cre) compared to Fbln1fl/fl. ConclusionsEP4 was upregulated in proliferative IH, and EP4-induced fibulin-1 cooperated with ECM1 to promote IH through VSMC proliferation. The calcium binding EGF-like modules 6-8 of fibulin-1 are indicated to regulate cell proliferation. A Translational PerspectiveRecent advances in drug-eluting stents have significantly contributed to the reduction of vascular IH. However, the detailed mechanism underlying IH after stenting remains to be elucidated. We found that prostaglandin E2-EP4-induced fibulin-1 plays a role in IH through VSMC proliferation. It is well recognized that prostaglandin E2 plays a role in IH, but inhibition of cyclooxygenase-2 has side effects such as thrombogenesis. Because EP4 and fibulin-1 were upregulated specifically in the neointima after vascular injury, oral or local administration of an EP4 antagonist or the downregulation of fibulin-1 would be potential therapeutic strategies to restrain IH.

physiology↗

bioRxiv2023

Insectivorous birds and bats outperform ants in the top-down regulation of arthropods across strata of a Japanese temperate forest

O_LIBirds, bats, and ants are recognized as significant arthropod predators. However, empirical studies reveal inconsistent trends in their relative roles in top-down control across strata. Here, we describe the differences between forest strata in the separate effects of birds, bats, and ants on arthropod communities and their cascading effects on plant damage. C_LIO_LIWe implemented a factorial design to exclude vertebrates and ants in both the canopy and understory. Additionally, we separately excluded birds and bats from the understory using diurnal and nocturnal exclosures. At the end of the experiments, we collected all arthropods and assessed herbivory damage. C_LIO_LIArthropods responded similarly to predator exclusion across forest strata, with a density increase of 81% on trees without vertebrates and 53% without both vertebrates and ants. Additionally, bird exclusion alone led to an 89% increase in arthropod density, while bat exclusion resulted in a 63% increase. Herbivory increased by 42% when vertebrates were excluded and by 35% when both vertebrates and ants were excluded. Bird exclusion alone increased herbivory damage by 28%, while the exclusion of bats showed a detectable but non-significant increase (by 22%). In contrast, ant exclusion had no significant effect on arthropod density or herbivory damage across strata. C_LIO_LIOur results reveal that the effects of birds and bats on arthropod density and herbivory damage are similar between the forest canopy and understory in this temperate forest. In addition, ants were not found to be significant predators in our system. Furthermore, birds, bats, and ants appeared to exhibit antagonistic relationships in influencing arthropod density. These findings highlight, unprecedentedly, the equal importance of birds and bats in maintaining ecological balance across different strata of a temperate forest. C_LI

ecology↗

bioRxiv2023

Col4a2-eGFP mouse model reveals the molecular and functional dynamics of basement membrane remodelling in hair follicle morphogenesis

The precisely controlled remodelling of the basement membrane (BM) is considered vital for morphogenesis. However, the molecular and tissue-level dynamics of the BM during morphogenesis and their functional significance remain largely unknown, especially in mammals, due to limited visualization tools. We developed knock-in mouse lines in which the endogenous collagen IV gene (Col4a2) was fused with a fluorescent tag. Through live imaging of developing hair follicles, we revealed a spatial gradient in the turnover rate of COL4A2 that is closely coupled with the BM expansion rate. The proliferation of epithelial progenitors coincided with the increased expansion of their underlying BM. Epithelial progenitors displaced with directionally expanding BM, but did not actively migrate on stable BM. The addition of a matrix metalloproteinase inhibitor delayed the turnover of COL4A2, restrained the expansion of the BM, and induced a directional shift in the division angle of epithelial progenitors, altering the hair follicle morphology. Our findings revealed spatially distinct BM dynamics within the continuous epithelial BM and affirmed their significance in orchestrating the proliferation, movement and fate of progenitor cells, as well as the macro-level shape of organs during development.

developmental biology↗

bioRxiv2023

Dietary Availability Acutely Governs Puberty Onset via Hypothalamic Neural Circuit

Reproduction poses a substantial burden, especially for mammalian females. Puberty onset serves as a vital checkpoint, regulated based on the bodys energy state, to prevent inappropriate reproductive activity under malnutrition. However, the neural basis of this puberty checkpoint remains poorly understood. Here, we demonstrate that peripubertal malnutrition in female mice reduces the synchronous activity episodes of arcuate kisspeptin neurons (SEskiss), which are critical regulators of the gonadotropin axis. Improved dietary availability boosts SEskiss frequency, facilitating puberty onset. Using a viral-genetic approach, we show that the activating agouti-related protein neurons in the arcuate nucleus (ARCAgrp neurons), a hunger center, suppresses SEskiss, even with enough food. Conversely, loss-of-function of ARCAgrp neurons enhances SEskiss during malnutrition, partly promoting irregular sexual maturation. Collectively, a neural circuit connecting feeding to reproductive centers is responsible for disinhibiting SEskiss frequency based on dietary availability, which sheds light on the neural basis of puberty checkpoint. HighlightsO_LIThe pulsatile activity of arcuate kisspeptin neurons emerges and grows before vaginal opening. C_LIO_LIPubertal impairment resulting from malnutrition is associated with a reduction in the pulsatile activity of kisspeptin neurons. C_LIO_LIPubertal recovery by food availability follows the elevated pulsatile activity of kisspeptin neurons during catch-up growth. C_LIO_LIThe arcuate Agrp neurons suppress the frequency of pulsatile activity of kisspeptin neurons under negative energy balance. C_LI

neuroscience↗

bioRxiv2023

Revisiting the role of cAMP in Drosophila aversive olfactory memory formation

In the olfactory aversive conditioning of Drosophila melanogaster, an odor, the conditioned stimulus (CS), is associated with electric shock, the unconditioned stimulus (US). The Rutabaga adenylyl cyclase in Kenyon cells (KCs) of the fly brain synthesizes cAMP, which is believed to serve as the coincidence detector synergistically stimulated by calcium/calmodulin evoked by the odor reception and GS released in response to the dopamine signaling elicited by electric shock. However, live imaging analyses revealed that olfactory stimulation itself prompted the activation of dopaminergic neurons and resulted in the elevation of cAMP levels in KCs that received dopamine, regardless of calcium signaling. This finding raises questions about the longstanding and fundamental comprehension of conditioning mechanisms, as the cAMP levels in conditioned stimulus-positive (CS+) KCs could not be distinguished from those in the rest of the KCs. Our findings suggest that cAMP concentrations do not function as a mnemonic engram to CS+ neurons. Rather, the collective dynamics of cAMP are capable of integratively encoding the valence ascribed to odors being perceived at a given time. Furthermore, our investigation revealed that associative conditioning induces modifications in dopamine levels in response to both CS and US, resulting in alterations in cAMP levels. The increase in cAMP exerts a deleterious effect on the acetylcholine transmission from KCs. Accordingly, we postulate that, during conditioning, cAMP depresses KCs, thereby skewing the valence of the CS+ odor towards a more aversive state for the conditioned flies, and ultimately culminating in the formation of aversive memories.

neuroscience↗

bioRxiv2023

Testing immediate dosage compensation by irradiation of heavy-ion beams to Drosophila miranda

Many organisms with heteromorphic sex chromosomes have a mechanism of dosage compensation (DC) in which X-linked genes are upregulated in males to mitigate dosage imbalance between sexes and between chromosomes. However, how quickly the DC is established during evolution remains elusive. In this study, irradiating the heavy-ion beams to Drosophila miranda that have young sex chromosomes, the so-called neo-sex chromosomes, we induced deletions on the neo-Y chromosome to mimic the situation of Y-chromosome degeneration in which functional neo-Y-linked genes were just nonfunctionalized and tested if their neo-X-linked gametologs were immediately upregulated. Since the males with the 2-Gy irradiation of iron-ion beam showed a lower fertility, we sequenced the genomes and transcriptomes of six F1 males derived from these males. Our pipeline identified 82 neo-Y-linked genes in which deletions were predicted in the F1 males. However, all but three of them had paralogs in addition to their neo-X-linked gametologs. Moreover, candidate deletions in the remaining three genes that showed one-to-one gametologous relationship with the neo-X-linked genes occurred in UTRs and did not affect the expression levels of these genes. Therefore, we were unable to directly evaluate whether DC immediately operated on the neo-X-linked genes in response to the disruption of their neo-Y-linked gametologs. Yet, our observation that the deletions occurred less frequently in one-to-one gametologs indirectly suggests that DC unlikely operated on the neo-X-linked genes immediately after the pseudogenization of their neo-Y-linked gametologs in D. miranda. Therefore, dosage imbalance due to deletions in the neo-Y-linked genes without paralogs may not have effectively been compensated and individuals with such deletions could have become lethal. We speculate that the neo-sex chromosomes in D. miranda may be too young to establish the immediate DC. Future studies on sex chromosomes with different ages will further evaluate our tentative conclusion.

evolutionary biology↗

bioRxiv2023

A Prefrontal Neural Circuit for Maternal Behavioural Leaning in Mice

Maternal behaviors, which are crucial for the survival of mammalian infants, require the coordinated operation of multiple brain regions to process infant cues, make decisions, and execute motor plans. Although these processes likely demand higher cognitive functions, the prefrontal areas that regulate limbic parental programs remains poorly understood. Here, we show that the orbitofrontal cortex (OFC) excitatory projection neurons promote alloparental caregiving behaviors in female mice. By chronic microendoscopy, we observed robust yet adaptable representations of pup-directed anticipatory and motor-related activities within the OFC. Some of these plastic responses were significantly overlapped with those related to nonsocial reward signals. The inactivation of OFC output reduced the phasic activities of midbrain dopamine (DA) neurons specifically tied to pup retrieval and impaired the modulation of DA release to the ventral striatum during the acquisition of alloparental behaviors. These findings suggest that the OFC transiently boosts DA activity during the acquisition phase, thereby facilitating the manifestation of alloparental behaviors.

neuroscience↗

bioRxiv2022

Collective gradient sensing by swimming bacteria without clustering

We characterize the taxis enhancement of swimming bacteria by collective migration without apparent clustering. We confine dilute Salmonella suspension in a shallow channel and evaluate the thermotaxis response to local heating and diffusion. By combining cell tracking analysis and numerical simulation based on simple modeling, we show that the alignment interaction suppresses orientation fluctuation, strengthens migration bias, and also prevents the dispersion of accumulated population. The results show a prominent example of how a collective motion of active matter implements a biological function.

biophysics↗

bioRxiv2022

PCNA recruits cohesin loader Scc2/NIPBL to ensure sister chromatid cohesion

Sister chromatid cohesion is essential for faithful chromosome segregation and genome duplication during cell division. Failure to establish cohesion during S phase by the ring-shaped multiprotein complex cohesin leads to genomic instability1-4. Replisome-associated proteins are required to generate cohesion by two independent pathways5. One mediates conversion of cohesins bound to unreplicated DNA ahead of replication forks into cohesive entities behind them, while the second promotes cohesin de novo loading onto newly-replicated DNAs6. The latter process depends on the cohesin loader Scc2/NIPBL and the alternative PCNA loader CTF18-RFC. However, the precise mechanism of de novo cohesin loading during replication is unknown. Here we show that PCNA physically recruits yeast cohesin loader Scc2 via its C-terminal PCNA-interacting protein motif. Binding to PCNA is crucial, as scc2-pip mutant deficient in Scc2-PCNA interaction is defective in cohesion when combined with replisome mutants of the cohesin conversion pathway. Moreover, scc2-pip mutant becomes inviable without its partner Scc4/MAU2 that localizes cohesin loader to centromeres. Importantly, the role of NIPBL recruitment to PCNA for cohesion generation is conserved in vertebrate cells. Our results demonstrate that PCNA, the maestro of replication-linked functions, is also crucially involved in the cohesion establishment through de novo cohesin loading onto replicated DNA.

cell biology↗

bioRxiv2022

Pacsin 2-dependent N-cadherin internalization regulates the migration behaviour of malignant cancer cells

Cell migration is essential for both physiological and pathological processes such as embryonic morphogenesis, wound repair and metastasis of cancer cells. Collective cell migration is the coordinated movement of multiple cells connected with cadherin-based adherence junctions. Cadherins undergo dynamic intracellular trafficking and their surface level is determined by a balance between endocytosis, recycling and degradation. However, regulatory mechanisms of cadherin turnover in the collective cell migration remain to be elucidated. In this study, we show that a BAR domain protein pacsin 2 plays an essential role in collective cell migration by regulating the internalization of N-cadherin in human bladder cancer cells T24. Pacsin 2 and its associating GTPase dynamin 2 colocalized with N-cadherin at the cell periphery in T24 cells. Depletion of either pacsin 2 or dynamin 2 induced interdigitating cell-cell contacts enriched with N-cadherin. Imaging analyses of the wound healing assay showed that pacsin 2-depleted T24 cells migrated in a collective and directed manner in contrast with randomly migrating control cells. Furthermore, cell-surface biotinylation assay showed that internalization of N-cadherin is attenuated in pacsin 2-depleted cells. Interestingly, the GST-pulldown assay demonstrated that the SH3 domain of pacsin 2 binds to the cytoplasmic domain of N-cadherin, suggesting that surface levels of N-cadherin are regulated by pacsin 2-mediated endocytosis. These data support new insights into a novel endocytic route of N-cadherin in collective cell migration providing pacsin 2 as a possible therapeutic target for cancer metastasis.

cell biology↗

bioRxiv2022

Increased mitochondrial Ca2+ contributes to health decline with age and Duchene muscular dystrophy in C. elegans.

Sarcopenia is a geriatric syndrome characterized by an age-related decline in skeletal muscle mass and strength. Here, we show that suppression of mitochondrial calcium uniporter (MCU)-mediated Ca2+ influx into mitochondria in the body wall muscles of the nematode Caenorhabditis elegans improved the sarcopenic phenotypes, blunting movement and mitochondrial structural and functional decline with age. We found that normally aged muscle cells exhibited elevated resting mitochondrial Ca2+ levels and increased mitophagy to eliminate damaged mitochondria. Similar to aging muscle, we found that suppressing MCU function in muscular dystrophy improved movement via reducing elevated resting mitochondrial Ca2+ levels. Taken together, our results reveal that elevated resting mitochondrial Ca2+ levels contribute to muscle decline with age and in muscular dystrophy. Further, modulation of MCU activity may act as a potent pharmacological target in various conditions involving muscle loss.

cell biology↗

bioRxiv2022

Automatic Sleep Stage Classification with Optimized Selection of EEG Channels

Visual inspection of Polysomnography (PSG) recordings by sleep experts based on established guidelines has been the gold standard in sleep stage classification. This approach is expensive, time consuming and mostly limited to experimental research and clinical cases of major sleep disorders. Various automatic approaches to sleep scoring have been emerging in the past years and are opening the way to a quick computational assessment of sleep architecture that may find its way to the clinics. With the hope to make sleep scoring a fully automated process in the clinics, we report here an ensemble algorithm that aims at not only predicting sleep stages but of doing so with an optimized minimal number of EEG channels. For that, we combine a genetic algorithm based optimization with a classification framework that minimizes the number of channels used by the machine learning algorithm to quantify sleep stages. This resulted in a scoring with an F1 score of 0.793 for the fully automatic model and 0.806 for the model trained on 10 percent of the unseen subject, both with only 3 EEG channels. The ensemble algorithm is based on a combination of extremely randomized trees and MiniRocket classifiers. The algorithm was trained, validated and tested on night sleep PSG data collected from 7 subjects. The novelty of our approach lies on the use of the minimum information needed for automated sleep scoring, based on a systematic search that concurrently selects the optimal-minimum number of EEG channels and the best performing features for the machine learning classifier. The optimization framework presented in this work may enable new designs for sleep scoring devices suited to studies in the comfort of the homes, easily and inexpensively and in this way facilitate experimental and clinical studies in large populations.

neuroscience↗

bioRxiv2022

AI-based search for convergently expanding, advantageous mutations in SARS-CoV-2 by focusing on oligonucleotide frequencies

Among mutations that occur in SARS-CoV-2, efficient identification of mutations advantageous for viral replication and transmission is important to characterize and defeat this rampant virus. Mutations rapidly expanding frequency in a viral population are candidates for advantageous mutations, but neutral mutations hitchhiking with advantageous mutations are also likely to be included. To distinguish these, we focus on mutations that appear to occur independently in different lineages and expand in frequency in a convergent evolutionary manner. Batch-learning SOM (BLSOM) can separate SARS-CoV-2 genome sequences according by lineage from only providing the oligonucleotide composition. Focusing on remarkably expanding 20-mers, each of which is only represented by one copy in the viral genome, allows us to correlate the expanding 20-mers to mutations. Using visualization functions in BLSOM, we can efficiently identify mutations that have expanded remarkably both in the Omicron lineage, which is phylogenetically distinct from other lineages, and in other lineages. Most of these mutations involved changes in amino acids, but there were a few that did not, such as an intergenic mutation.

bioinformatics↗

bioRxiv2022

Cytoplasmic processing of human transfer RNAs

Biogenesis of different classes of eukaryotic RNAs proceeds via different pathways that require strict spatiotemporal resolution. The intracellular organization has evolved to provide order for RNA processing to coordinate different maturation steps with specific enzymatic reaction. In higher eukaryotes, processing of transfer RNAs (tRNAs) is postulated to be almost entirely intranuclear, while in lower eukaryotes like yeast, tRNA maturation is both nuclear and cytoplasmic. Here, we show that tRNA processing is largely cytosolic event in human cells. After transcription, unprocessed precursors of tRNAs (pre-tRNAs) bound by La protein are exported from the nucleus into the cytoplasm. Using cell fractionation analysis and pre-tRNA-specific fluorescence in situ hybridization (FISH) protocol, we show tRNA splicing/ligation and end-processing takes place in the cytoplasm where majority of processing enzymes is also located. We propose here a model where processing of intron-less and intron-containing pre-tRNAs is cytoplasmic similarly to the observed in lower eukaryotes, although tRNA splicing precedes 5- and 3-end processing in human cells unlike in yeast.

molecular biology↗

bioRxiv2022

Clonal spreading of tumor-infiltrating T cells underlies the robust antitumor immune responses

The repertoire of tumor-infiltrating T cells is an emerging perspective for characterizing effective antitumor T-cell responses. Oligoclonal expansion of tumor T-cell repertoire has been evaluated; however, their association with antitumor effects is unclear. We demonstrated that the polyclonal fraction of the tumor-reactive T-cell repertoire consisting of relatively minor clones increased in tumor-bearing mice treated with anti-PD-L1 or anti-CD4 monoclonal antibody, which was correlated with antitumor effect. Meanwhile, the size of the oligoclonal fraction consisting of major clones remained unchanged. Moreover, the polyclonal fraction was enriched in progenitor exhausted T cells, which are essential for a durable antitumor response, and was more dependent on CCR7+ migratory dendritic cells, which are responsible for priming tumor-reactive T cells in the tumor-draining lymph nodes. These results suggest that the expansion of diverse tumor-reactive clones ("clonal spreading") is an important mechanism by which anti-PD-L1 and anti-CD4 treatments induce robust and durable antitumor T-cell responses.

immunology↗

bioRxiv2021

Global inflammatory response in in vitro organ cultured testes using single-cell RNA-sequencing

In vitro functional sperm production is important for understanding spermatogenesis and for the treatment of male infertility. Here, we describe similarities and differences between testis tissues in vivo and in vitro and clarify abnormalities in the early stage of in vitro spermatogenesis at single-cell resolution. While in vitro spermatogenesis progressed similarly to in vivo spermatogenesis until the early pachytene spermatocyte stage, a noticeable acute inflammatory response occurred in immune cells and non-immune testicular somatic cells immediately after cultivation. Inhibitor treatment revealed that NLRP3 inflammasome signaling is key to the inflammation. We observed damaged/dead germ cell accumulation in cultured testis, which may be due to dysfunctional phagocytosis by Sertoli cells. Our data revealed abnormal testicular milieu of in vitro cultured testes caused by tissue-wide sterile inflammation, in which the danger-associated molecular pattern-NLRP3 inflammasome axis may be a key element.

molecular biology↗

bioRxiv2021

Dynamics of peripheral blood flow across sleep stages

Study ObjectivesPulse rate variability (PRV) derived from peripheral blood flow has been reported as a surrogate parameter for heart rate variability (HRV). However, there are currently no studies reporting systematic comparisons of PRV with HRV in a normal sleep state. Whether PRV can provide similar information regarding sleep stages remains unclear. Peripheral blood flow may also be modulated differently across sleep stages. Thus, we aimed to investigate blood flow dynamics and compare PRV with HRV across sleep stages to see if blood flow can provide further information about sleep stages. MethodsWe performed electrocardiography and simultaneously measured blood flow from the right index finger and ear concha of 45 healthy participants (13 women; mean age, 22.5 {+/-} 3.4 years) during one night of sleep. Time-domain, frequency-domain, and non-linear indices of PRV/HRV, and time- and frequencydomain blood flow parameters were calculated. ResultsFinger-PRV results showed similar patterns to HRV results for most parameters. Finger-blood flow parameters in the time and frequency domains also showed information about the different sleep stages. Further, both finger- and ear-blood flow results showed 0.2-0.3 Hz oscillations that varied with sleep stages, with a significant increase in N3, suggesting a modulation (of respiration) within this frequency band. ConclusionsThese results suggest that PRV can provide as much information as HRV for different sleep stages. Furthermore, the results show that blood flow + PRV could be more advantageous than HRV alone in the assessment of the sleep state and related autonomic nervous activity. Statement of SignificanceThe research provides comprehensive information on peripheral blood flow (BF) activity across sleep stages for the first time, as the major novelty of our work. The second contribution is a systematic study comparing BF-derived pulse rate variability (PRV) with heart rate variability across sleep stages in a normal sleep state. We believe that our work makes a significant contribution to the literature because it provides comprehensive information on the potential of BF+PRV as a new biomarker for assessing the sleep state. Further, this study contributes to developing a more convenient method of assessing the sleep state in the clinical and home/work setting.

physiology↗

bioRxiv2021

Plasticity of Neural Connections Underlying Oxytocin-mediated Parental Behaviors of Male Mice

The adult brain can flexibly adapt behaviors to specific life-stage demands. For example, while sexually naive male mice are aggressive to the conspecific young, they start to provide caregiving to infants around the time when their own young are expected. How such behavioral plasticity is implemented at the level of neural connections remains poorly understood. Using viral-genetic approaches, here we establish hypothalamic oxytocin neurons as key regulators of parental caregiving behaviors of male mice. We then used rabies virus-mediated unbiased screen to identify excitatory neural connections originating from the lateral hypothalamus to the oxytocin neurons to be drastically strengthened when male mice become fathers. These connections are functionally relevant, as their activation suppresses pup-directed aggression in virgin males. These results demonstrate the life-stage associated, long-distance, and cell-type-specific plasticity of neural connections in the hypothalamus, the brain region classically assumed to be hard-wired. Highlight- OT is indispensable for parental caregiving behavior of male mice - Activation of OT neurons triggers paternal caregiving behavior in otherwise infanticidal sexually-naive male mice partly via OT ligand - Unbiased rabies virus-mediated screening reveals enhanced connectivity originated from excitatory LHA neurons to OT neurons in fathers. - This structural plasticity can support behavioral plasticity

neuroscience↗