Biology subjects

Lin, D.

Publications and source records attributed to Lin, D..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Association between the oral microbiome and brain resting state connectivity in schizophrenia

Recent microbiome-brain axis findings have shown evidence of the modulation of microbiome community as an environmental mediator in brain function and psychiatric illness. This work is focused on the role of the microbiome in understanding a rarely investigated environmental involvement in schizophrenia (SZ), especially in relation to brain circuit dysfunction. We leveraged high throughput microbial 16s rRNA sequencing and functional neuroimaging techniques to enable the delineation of microbiome-brain network links in SZ. N=213 SZ and healthy control (HC) subjects were assessed for the oral microbiome. Among them, 139 subjects were scanned by resting-state functional magnetic resonance imaging (rsfMRI) to derive brain functional connectivity. We found a significant microbiome compositional shift in SZ beta diversity (weighted UniFrac distance, p= 6x10-3; Bray-Curtis distance p = 0.021). Fourteen microbial species involving pro-inflammatory and neurotransmitter signaling and H2S production, showed significant abundance alterations in SZ. Multivariate analysis revealed one pair of microbial and functional connectivity components showing a significant correlation of 0.46. Thirty five percent of microbial species and 87.8% of brain functional network connectivity from each component also showed significant differences between SZ and HC with strong performance in classifying SZ from HC, with an area under curve (AUC) = 0.84 and 0.87, respectively. The results suggest a potential link between oral microbiome dysbiosis and brain functional connectivity alteration in relation to SZ, possibly through immunological and neurotransmitter signaling pathways and the hypothalamic-pituitary-adrenal axis, supporting for future work in characterizing the role of oral microbiome in mediating effects on SZ brain functional activity.

microbiology↗

bioRxiv2023

Estrogenic control of reward prediction errors and reinforcement learning

Gonadal hormones act throughout the brain1, and neuropsychiatric disorders vary in symptom severity over the reproductive cycle, pregnancy, and perimenopause2-4. Yet how hormones influence cognitive processes is unclear. Exogenous 17{beta}-estradiol modulates dopamine signaling in the nucleus accumbens core (NAcc)5,6, which instantiates reward prediction errors (RPEs) for reinforcement learning7-16. Here we show that endogenous 17{beta}-estradiol enhances RPEs and sensitivity to previous rewards by reducing dopamine reuptake proteins in the NAcc. Rats performed a task with different reward states; they adjusted how quickly they initiated trials across states, balancing effort against expected rewards. NAcc dopamine reflected RPEs that predicted and causally influenced initiation times. Elevated endogenous 17{beta}-estradiol increased sensitivity to reward states by enhancing dopaminergic RPEs in the NAcc. Proteomics revealed reduced dopamine transporter expression. Finally, knockdown of midbrain estrogen receptors suppressed reinforcement learning. 17{beta}-estradiol therefore controls RPEs via dopamine reuptake, mechanistically revealing how hormones influence neural dynamics for motivation and learning.

neuroscience↗

bioRxiv2023

The feature landscape of visual cortex

Understanding computations in the visual system requires a characterization of the distinct feature preferences of neurons in different visual cortical areas. However, we know little about how feature preferences of neurons within a given area relate to that areas role within the global organization of visual cortex. To address this, we recorded from thousands of neurons across six visual cortical areas in mouse and leveraged generative AI methods combined with closed-loop neuronal recordings to identify each neurons visual feature preference. First, we discovered that the mouses visual system is globally organized to encode features in a manner invariant to the types of image transformations induced by self-motion. Second, we found differences in the visual feature preferences of each area and that these differences generalized across animals. Finally, we observed that a given areas collection of preferred stimuli ( own-stimuli) drive neurons from the same area more effectively through their dynamic range compared to preferred stimuli from other areas ( other-stimuli). As a result, feature preferences of neurons within an area are organized to maximally encode differences among own-stimuli while remaining insensitive to differences among other-stimuli. These results reveal how visual areas work together to efficiently encode information about the external world.

neuroscience↗

bioRxiv2023

CytoPipeline & CytoPipelineGUI: An R package suite for building and visualizing automated pre-processing pipelines for flow cytometry data

BackgroundWith the increase of the dimensionality in flow cytometry data over the past years, there is a growing need to replace or complement traditional manual analysis (i.e. iterative 2D gating) with automated data analysis pipelines. A crucial part of these pipelines consists of pre-processing and applying quality control filtering to the raw data, in order to use high quality events in the downstream analyses. This part can in turn be split into a number of elementary steps : signal compensation or unmixing, scale transformation, debris, doublets and dead cells removal, batch effect correction, etc. However, assembling and assessing the pre-processing part can be challenging for a number of reasons. First, each of the involved elementary steps can be implemented using various methods and R packages. Second, the order of the steps can have an impact on the downstream analysis results. Finally, each method typically comes with its specific, non standardized diagnostic and visualizations, making objective comparison difficult for the end user. ResultsHere, we present CytoPipeline and CytoPipelineGUI, two R packages to build, compare and assess pre-processing pipelines for flow cytometry data. To exemplify these new tools, we present the steps involved in designing a pre-processing pipeline on a real life dataset and demonstrate different visual assessment use cases. We also set up a benchmarking comparing two pre-processing pipelines differing by their quality control methods, and show how the package visualization utilities can provide crucial user insight into the obtained benchmark metrics. ConclusionCytoPipeline and CytoPipelineGUI are two Bioconductor R packages that help building, visualizing and assessing pre-processing pipelines for flow cytometry data. They increase productivity during pipeline development and testing, and complement benchmarking tools, by providing user intuitive insight into benchmarking results.

bioinformatics↗

bioRxiv2023

Deletion of CD44 promotes adipogenesis by regulating PPARγ and cell cycle-related pathways

CD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressing Pparg expression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPAR{ballotbox} and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.

cell biology↗

bioRxiv2023

PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hy-pertension

Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PA) leading to increased pulmonary vascular resistance and right heart failure. Central to the remodeling process is a switch of the smooth muscle cells in small PAs (PASMC) to a proliferative, apoptosis-resistant phenotype. There is reason to suspect that the plasminogen activator system may play an important role in the remodeling program in PAH based on its roles in vascular post-injury restenosis, fibrosis, angiogenesis and tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of the plasminogen activators - urokinase-type and tissue-type (uPA and tPA, respectively). Immunohisto- chemical and immunoblot analyses revealed that PAI-1 was deficient in smooth muscle areas of small remodeled PAs and early-passage PASMC from subjects with PAH compared to non-PAH controls. PAI1-/- male and female mice developed spontaneous pulmonary vascular remodeling and pulmonary hypertension (PH) as evidenced by significant increase in PA medial thickness, systolic right ventricular pressure, and right ventricular hypertrophy. Lastly, the uPA inhibitors upamostat (WX-671) and amiloride analog BB2-30F down-regulated mTORC1 and SMAD3, restored PAI-1 levels, reduced proliferation, and induced apoptosis in human PAH PASMC. We examined the effect of inhibition of uPA catalytic activity by BB2-30F on the development of SU5416/Hypoxia (SuHx)-induced PH in mice. Vehicletreated SuHx-exposed mice had up-regulated mTORC1 in small PAs, developed pulmonary vascular remodeling and PH, as evidenced by significant increase of PA MT, sRVP, RV hypertrophy, and a significant decrease in the pulmonary artery acceleration time/pulmonary ejection time (PAAT/PET) ratio compared to age- and sex-matched normoxia controls, whereas BB2-30F-treated group was protected from all these pathological changes. Taken together, our data strongly suggest that PAI-1 down- regulation in PASMC from human PAH lungs promotes PASMC hyper-proliferation, remodeling, and spontaneous PH due to unopposed uPA activation. Further studies are needed to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate the progression and/or reverse pulmonary vascular remodeling and PH.

cell biology↗

bioRxiv2023

Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for a century. However, laboratory mice capture a narrow subset of the genetic variation found in wild mouse populations. This consideration inherently restricts the scope of potential discovery in laboratory models and narrows the pool of potentially identified phenotype-associated variants and pathways. Wild mouse populations are reservoirs of predicted functional and disease-associated alleles, but the sparsity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently imported, sequenced, and phenotyped a set of 11 wild-derived inbred strains developed from wild-caught Mus musculus domesticus. Each of these "Nachman strains" immortalizes a unique wild haplotype sampled from five environmentally diverse locations across North and South America: Saratoga Springs, New York, USA; Gainesville, Florida, USA; Manaus, Brazil; Tucson, Arizona, USA; and Edmonton, Alberta, Canada. Whole genome sequence analysis reveals that each strain carries between 4.73-6.54 million single nucleotide differences relative to the mouse reference assembly, with 42.5% of variants in the Nachman strain genomes absent from classical inbred mouse strains. We phenotyped the Nachman strains on a customized pipeline to assess the scope of disease-relevant neurobehavioral, biochemical, physiological, metabolic, and morphological trait variation. The Nachman strains exhibit significant inter-strain variation in >90% of 1119 surveyed traits and expand the range of phenotypic diversity captured in classical inbred strain panels alone. Taken together, our work introduces a novel wild-derived inbred mouse strain resource that will enable new discoveries in basic and preclinical research. These strains are currently available through The Jackson Laboratory Repository under laboratory code NachJ.

genetics↗

bioRxiv2023

The Quest to Identify USP8 Inhibitors for Parkinsons Disease, a PAINful Experience.

Pan Assay INterference compoundS (PAINS) are known to be a source of false positives in High Throughput Screening (HTS) campaigns. This has become a major problem in medicinal chemistry, often resulting in undesirable project outcomes and increased overall cost. Our recent campaign to identify inhibitors of USP8 that could be used in the treatment of Parkinsons disease identified several PAINS that worked via a variety of mechanisms. Herein, we discuss the process developed to identify not only the PAINS but also confirming the interference mechanism causing their activity. We found in this project that our USP8 assay was susceptible to multiple modes of interference, making it difficult to identify genuine hit molecules. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/556294v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@b917a6org.highwire.dtl.DTLVardef@1bfac47org.highwire.dtl.DTLVardef@c78e1dorg.highwire.dtl.DTLVardef@1434fdd_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

Epigenomic Analyses Identify FOXM1 As a Key Regulator of Anti-Tumor Immune Response in Esophageal Adenocarcinoma

Unlike most cancer types, the incidence of esophageal adenocarcinoma (EAC) has rapidly escalated in the western world over recent decades. Using whole genome bisulfite sequencing (WGBS), we identify the transcription factor (TF) FOXM1 as an important epigenetic regulator of EAC. FOXM1 plays a critical role in cellular proliferation and tumor growth in EAC patient-derived organoids and cell line models. We identify ERBB2 as an upstream regulator of the expression and transcriptional activity of FOXM1. Unexpectedly, Gene Set Enrichment Analysis (GSEA) unbiased screen reveals a prominent anti-correlation between FOXM1 and immune response pathways. Indeed, syngeneic mouse models show that FOXM1 inhibits the infiltration of CD8+ T cells into the tumor microenvironment. Consistently, FOXM1 suppresses CD8+ T cell chemotaxis in vitro and antigen-dependent CD8+ T cell killing. This study characterizes FOXM1 as a significant EAC-promoting TF and elucidates its novel function in regulating anti-tumor immune response.

cancer biology↗

bioRxiv2023

Monitoring norepinephrine release in vivo using next-generation GRABNE sensors

Norepinephrine (NE) is an essential biogenic monoamine neurotransmitter, yet researches using prototype NE sensors were limited by their low sensitivities. Here, we developed next-generation versions of GPCR activation-based NE sensors (GRABNE2m and GRABNE2h) with a superior response, high sensitivity and selectivity to NE both in vitro and in vivo. Notably, these sensors can detect NE release triggered by either optogenetic or behavioral stimuli in freely moving mice, producing robust signals in the locus coeruleus and hypothalamus. With the development of a novel transgenic mouse line, we recorded both NE release and calcium dynamics with dual-color fiber photometry throughout the sleep-wake cycle; moreover, dual-color mesoscopic imaging revealed cell type-specific spatiotemporal dynamics of NE and calcium during sensory processing and locomotion. Thus, these new GRABNE sensors are valuable tools for monitoring the precise spatiotemporal release of NE in vivo, providing new insights into the physiological and pathophysiological roles of NE.

neuroscience↗

bioRxiv2023

Biologically-informed self-supervised learning for segmentation of subcellular spatial transcriptomics data

Recent advances in subcellular imaging transcriptomics platforms have enabled high-resolution spatial mapping of gene expression, while also introducing significant analytical challenges in accurately identifying cells and assigning transcripts. Existing methods grapple with cell segmentation, frequently leading to fragmented cells or oversized cells that capture contaminated expression. To this end, we present BIDCell, a self-supervised deep learning-based framework with biologically-informed loss functions that learn relationships between spatially resolved gene expression and cell morphology. BIDCell incorporates cell-type data, including single-cell transcriptomics data from public repositories, with cell morphology information. Using a comprehensive evaluation framework consisting of metrics in five complementary categories for cell segmentation performance, we demonstrate that BIDCell outperforms other state-of-the-art methods according to many metrics across a variety of tissue types and technology platforms. Our findings underscore the potential of BIDCell to significantly enhance single-cell spatial expression analyses, including cell-cell interactions, enabling great potential in biological discovery.

bioinformatics↗

bioRxiv2023

Faulty Metabolism: A Potential Instigator of an Aggressive Phenotype in Cdk5-dependent Medullary Thyroid Carcinoma

Mechanistic modeling of cancers such as Medullary Thyroid Carcinoma (MTC) to emulate patient-specific phenotypes is challenging. The discovery of potential diagnostic markers and druggable targets in MTC urgently requires clinically relevant animal models. Here we established orthotopic mouse models of MTC driven by aberrantly active Cdk5 using cell-specific promoters. Each of the two models elicits distinct growth differences that recapitulate the less or more aggressive forms of human tumors. The comparative mutational and transcriptomic landscape of tumors revealed significant alterations in mitotic cell cycle processes coupled with the slow-growing tumor phenotype. Conversely, perturbation in metabolic pathways emerged as critical for aggressive tumor growth. Moreover, an overlapping mutational profile was identified between mouse and human tumors. Gene prioritization revealed putative downstream effectors of Cdk5 which may contribute to the slow and aggressive growth in the mouse MTC models. In addition, Cdk5/p25 phosphorylation sites identified as biomarkers for Cdk5-driven neuroendocrine tumors (NETs) were detected in both slow and rapid onset models and were also histologically present in human MTC. Thus, this study directly relates mouse and human MTC models and uncovers vulnerable pathways potentially responsible for differential tumor growth rates. Functional validation of our findings may lead to better prediction of patient-specific personalized combinational therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/544755v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@196ed2dorg.highwire.dtl.DTLVardef@1ad2d59org.highwire.dtl.DTLVardef@7c6e84org.highwire.dtl.DTLVardef@13bd7db_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICGRP driven aberrant Cdk5 activation develops early onset aggressive MTC C_LIO_LIGenetic alterations in mouse and human tumors disrupt common pathways C_LIO_LIAggressive tumor model characterized by alterations in metabolic pathways C_LIO_LISlow growing tumor model elicits disruption of mitotic spindle assembly C_LI

cancer biology↗

bioRxiv2023

DNA methylation signatures of early life adversity are exposure-dependent in wild baboons

The early life environment can profoundly shape the trajectory of an animals life, even years or decades later. One mechanism proposed to contribute to these early life effects is DNA methylation. However, the frequency and functional importance of DNA methylation in shaping early life effects on adult outcomes is poorly understood, especially in natural populations. Here, we integrate prospectively collected data on fitness-associated variation in the early environment with DNA methylation estimates at 477,270 CpG sites in 256 wild baboons. We find highly heterogeneous relationships between the early life environment and DNA methylation in adulthood: aspects of the environment linked to resource limitation (e.g., low-quality habitat, early life drought) are associated with many more CpG sites than other types of environmental stressors (e.g., low maternal social status). Sites associated with early resource limitation are enriched in gene bodies and putative enhancers, suggesting they are functionally relevant. Indeed, by deploying a baboon-specific, massively parallel reporter assay, we show that a subset of windows containing these sites are capable of regulatory activity, and that, for 88% of early drought-associated sites in these regulatory windows, enhancer activity is DNA methylation-dependent. Together, our results support the idea that DNA methylation patterns contain a persistent signature of the early life environment. However, they also indicate that not all environmental exposures leave an equivalent mark and suggest that socioenvironmental variation at the time of sampling is more likely to be functionally important. Thus, multiple mechanisms must converge to explain early life effects on fitness-related traits. Significance statementThe environment animals face when young can affect how they function throughout life. Long-lasting changes in DNA methylation--a chemical mark deposited on DNA that can affect gene activity--have been hypothesized to contribute to early life effects. But evidence for persistent, early environment-associated differences in DNA methylation is lacking in wild animals. Here, we show that early life adversity in wild baboons predicts DNA methylation levels in adulthood, especially for animals born in low resource environments and drought conditions. We also show that some of the changes we observe in DNA methylation have the capacity to influence gene activity levels. Together, our results support the idea that early experiences can become biologically embedded in the genomes of wild animals.

genomics↗

bioRxiv2023

Stitching flexible electronics into the brain

Understanding complex neuronal networks requires monitoring long-term neuronal activity in various regions of the brain. Significant progress has been made in multi-site implantations of well-designed probes, such as multi-site implantation of Si-based and polymer-based probes. However, these multi-probe strategies have been limited by the sizes and weights of interfaces to the multiple probes and the inability to track the activity of the same neurons and changes in neuronal activity over longer time periods. Here, we report a long single flexible probe that can be implanted by stitching into multiple regions of the mouse brain and subsequently transmit chronically-stable neuronal signals from the multiple sites via a single low-mass interface. We implanted the probe at four different sites using a glass capillary needle or two sites using an ultrathin metal needle. In-vitro tests in brain-mimicking hydrogel showed that multi-site probe implantations achieved a high connection yield of >86%. In-vivo histological images at each site of probes, implanted by stitching using either glass capillary or ultrathin metal insertion needles exhibit seamless tissue-probe interfaces with negligible chronic immune response. In addition, electrophysiology studies demonstrated the ability to track single neuron activities at every injection site with chronic stability over at least one month. Notably, the measured spike amplitudes and signal-to-noise ratios at different implantation sites showed no statistically significant differences. Multi-site stitching implantation of flexible electronics in the brain opens up new opportunities for both fundamental neuroscience research and electrotherapeutic applications.

bioengineering↗

bioRxiv2023

Hepatic conversion of acetyl-CoA to acetate plays crucial roles in energy stresses

Accumulating evidences indicate that acetate is increased in energy stresses such as diabetes mellitus and prolonged starvation. However, it is largely unknown how and where acetate is produced and what is its biological significance. We observed overproduction of acetate in an amount comparable to ketone bodies in patients and mice with diabetes or starvation. Mechanistically, ACOT 12&8 are dramatically upregulated in liver to convert FFA-derived acetyl-CoA to acetate and CoA. This conversion not only provides large amount of acetate which fuels brain preferentially rather than muscle, but also recycles CoA which is required for sustained fatty acid oxidation and ketogenesis. Taken together, we suggest that acetate is an emerging novel "ketone body" and may be used as a parameter to evaluate the progression of energy stress in the future.

biochemistry↗

bioRxiv2023

Hardwired to attack: Transcriptionally defined amygdala subpopulations play distinct roles in innate social behaviors.

Social behaviors are innate and supported by dedicated neural circuits, but it remains unclear whether these circuits are developmentally hardwired or established through social experience. Here, we revealed distinct response patterns and functions in social behavior of medial amygdala (MeA) cells originating from two embryonically parcellated developmental lineages. MeA cells in male mice that express the transcription factor Foxp2 (MeAFoxp2) are specialized for processing male conspecific cues even before puberty and are essential for adult inter-male aggression. In contrast, MeA cells derived from the Dbx1-lineage (MeADbx1) respond broadly to social cues and are non-essential for male aggression. Furthermore, MeAFoxp2 and MeADbx1 cells show differential anatomical and functional connectivity. Altogether, our results support a developmentally hardwired aggression circuit at the level of the MeA and we propose a lineage-based circuit organization by which a cells embryonic transcription factor profile determines its social information representation and behavior relevance during adulthood. HighlightsO_LIMeAFoxp2 cells in male mice show highly specific responses to male conspecific cues and during attack while MeADbx1 cells are broadly tuned to social cues. C_LIO_LIThe male-specific response of MeAFoxp2 cells is present in naive adult males and adult social experience refines the response by increasing its trial-to-trial reliability and temporal precision. C_LIO_LIMeAFoxp2 cells show biased response to males even before puberty. C_LIO_LIActivation of MeAFoxp2, but not MeADbx1, cells promote inter-male aggression in naive male mice. C_LIO_LIInactivation of MeAFoxp2, but not MeADbx1, cells suppresses inter-male aggression. C_LIO_LIMeAFoxp2 and MeADbx1 cells show differential connectivity at both the input and output levels. C_LI

neuroscience↗

bioRxiv2023

Neural dynamics in the limbic system during male social behaviors

Sexual and aggressive behaviors are two evolutionarily conserved social behaviors vital for an animals survival and reproductive success. While an increasing number of brain regions in the limbic system have been identified as functionally relevant for these two types of behaviors, an understanding of how social cues are represented across brain regions and how social behaviors are generated via this network activity remains elusive. To gain a holistic view of the neural responses during social behaviors, we utilized multi-fiber photometry to simultaneously record Ca2+ signals of estrogen receptor alpha (Esr1)-expressing cells from 13 limbic brain regions in male mice during sexual and aggressive behaviors and compare the response magnitude and temporal patterns across regions. We find that conspecific sensory information, as well as social action initiation signals, are widely distributed in the limbic system and can be decoded from the network activity. Cross-region correlation analysis reveals striking increases in functional connectivity in the network during the action initiation phase of social behaviors whereas advanced copulation is accompanied by a "dissociated" network state. Based on the response patterns, we propose a mating-biased network (MBN) and an aggression-biased network (ABN) for mediating male sexual and aggressive behaviors, respectively.

neuroscience↗

bioRxiv2023

Antagonistic Neural Circuits Drive Opposing Behaviors towards the Young in Females

In many species, including mice, females show strikingly different pup-directed behaviors based on their reproductive state1,2. Naive wild female mice often kill pups while lactating females are dedicated to pup caring3,4. The neural mechanisms that mediate infanticide and its switch to maternal behaviors during motherhood remain unclear. Here, based on the hypothesis that maternal and infanticidal behaviors are supported by distinct and competing neural circuits5,6, we used the medial preoptic area (MPOA), a key site for maternal behaviors7-11, as a starting point and identified three MPOA-connected brain regions that drive differential negative pup-directed behaviors. Further functional manipulation and in vivo recording revealed that estrogen receptor alpha (Esr1) expressing cells in the principal nucleus of the bed nucleus of stria terminalis (BNSTprEsr1) are necessary, sufficient, and naturally activated during infanticide in female mice. Furthermore, MPOAEsr1 and BNSTprEsr1 neurons form reciprocal inhibition and change their excitability in opposite directions with reproductive state. The shift in balance between BNSTprEsr1 and MPOAEsr1 cell activity is likely a key mechanism for the behavioral switch during motherhood.

neuroscience↗