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 naïve 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.

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Elements regulating an alternatively spliced exon of the rat fibronectin gene

Molecular and Cellular Biology ◽

10.1128/mcb.13.9.5301-5314.1993 ◽

1993 ◽

Vol 13 (9) ◽

pp. 5301-5314 ◽

Cited By ~ 1

Author(s):

G S Huh ◽

R O Hynes

Keyword(s):

Splice Sites ◽

Cell Type ◽

Long Distance ◽

Sequence Elements ◽

Alternatively Spliced ◽

A Cell ◽

Cell Type Specific ◽

Alternatively Spliced Exons

We have investigated the regulation of splicing of one of the alternatively spliced exons in the rat fibronectin gene, the EIIIB exon. This 273-nucleotide exon is excluded by some cells and included to various degrees by others. We find that EIIIB is intrinsically poorly spliced and that both its exon sequences and its splice sites contribute to its poor recognition. Therefore, cells which recognize the EIIIB exon must have mechanisms for improving its splicing. Furthermore, in order for EIIB to be regulated, a balance must exist between the EIIIB splice sites and those of its flanking exons. Although the intron upstream of EIIIB does not appear to play a role in the recognition of EIIIB for splicing, the intron downstream contains sequence elements which can promote EIIIB recognition in a cell-type-specific fashion. These elements are located an unusually long distance from the exon that they regulate, more than 518 nucleotides downstream from EIIIB, and may represent a novel mode of exon regulation.

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Identification of cell-type-specific promoters within the brain using lentiviral vectors

Gene Therapy ◽

10.1038/sj.gt.3302898 ◽

2007 ◽

Vol 14 (7) ◽

pp. 575-583 ◽

Cited By ~ 22

Author(s):

J P Chhatwal ◽

S E Hammack ◽

A M Jasnow ◽

D G Rainnie ◽

K J Ressler

Keyword(s):

Lentiviral Vectors ◽

Cell Type ◽

Cell Type Specific ◽

The Brain

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Neuronal cell-type-specific alternative splicing: A mechanism for specifying connections in the brain?

Neurogenesis ◽

10.1080/23262133.2015.1122699 ◽

2015 ◽

Vol 2 (1) ◽

pp. e1122699 ◽

Cited By ~ 2

Author(s):

Joshua Shing Shun Li ◽

Grace Ji-eun Shin ◽

S Sean Millard

Keyword(s):

Alternative Splicing ◽

Neuronal Cell ◽

Cell Type ◽

Specific Alternative ◽

Cell Type Specific ◽

The Brain

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Cell-Type-Specific Interleukin 1 Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities

Immunity ◽

10.1016/j.immuni.2018.12.012 ◽

2019 ◽

Vol 50 (2) ◽

pp. 317-333.e6 ◽

Cited By ~ 25

Author(s):

Xiaoyu Liu ◽

Daniel P. Nemeth ◽

Daniel B. McKim ◽

Ling Zhu ◽

Damon J. DiSabato ◽

...

Keyword(s):

Interleukin 1 ◽

Cell Type ◽

Cell Type Specific ◽

The Brain

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Restricted Transgene Expression in the Brain with Cell-Type Specific Neuronal Promoters

Human Gene Therapy Methods ◽

10.1089/hgtb.2012.073 ◽

2012 ◽

Vol 23 (4) ◽

pp. 242-254 ◽

Cited By ~ 25

Author(s):

Aurélie Delzor ◽

Noelle Dufour ◽

Fanny Petit ◽

Martine Guillermier ◽

Diane Houitte ◽

...

Keyword(s):

Transgene Expression ◽

Cell Type ◽

Cell Type Specific ◽

The Brain

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Cell-type specific patterned stimulus-independent neuronal activity in the Drosophila visual system during synapse formation

10.1101/376871 ◽

2018 ◽

Author(s):

Orkun Akin ◽

Bryce T. Bajar ◽

Mehmet F. Keles ◽

Mark A. Frye ◽

S. Lawrence Zipursky

Keyword(s):

Visual System ◽

Synapse Formation ◽

Neural Circuit ◽

Specific Activity ◽

System Development ◽

Nervous System Development ◽

Adult Brain ◽

Cell Type ◽

Cell Type Specific

SummaryStereotyped synaptic connections define the neural circuits of the brain. In vertebrates, stimulus-independent activity contributes to neural circuit formation. It is unknown whether this type of activity is a general feature of nervous system development. Here, we report patterned, stimulus-independent neural activity in the Drosophila visual system during synaptogenesis. Using in vivo calcium, voltage, and glutamate imaging, we found that all neurons participate in this spontaneous activity, which is characterized by brain-wide periodic active and silent phases. Glia are active in a complementary pattern. Each of the 15 examined of the over 100 specific neuron types in the fly visual system exhibited a unique activity signature. The activity of neurons that are synaptic partners in the adult was highly correlated during development. We propose that this cell type-specific activity coordinates the development of the functional circuitry of the adult brain.

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Cell type-specific biotin labeling in vivo resolves regional neuronal proteomic differences in mouse brain

10.1101/2021.08.03.454921 ◽

2021 ◽

Author(s):

Sruti Rayaprolu ◽

Sara Bitarafan ◽

Ranjita Betarbet ◽

Sydney N Sunna ◽

Lihong Cheng ◽

...

Keyword(s):

Mouse Brain ◽

Neurological Diseases ◽

Neuronal Cell ◽

Cell Types ◽

Proteomic Profiling ◽

Cell Type ◽

Specific Expression ◽

Cell Type Specific ◽

The Brain

Isolation and proteomic profiling of brain cell types, particularly neurons, pose several technical challenges which limit our ability to resolve distinct cellular phenotypes in neurological diseases. Therefore, we generated a novel mouse line that enables cell type-specific expression of a biotin ligase, TurboID, via Cre-lox strategy for in vivo proximity-dependent biotinylation of proteins. Using adenoviral-based and transgenic approaches, we show striking protein biotinylation in neuronal cell bodies and axons throughout the mouse brain. We quantified more than 2,000 neuron-derived proteins following enrichment that mapped to numerous subcellular compartments. Synaptic, transmembrane transporters, ion channel subunits, and disease-relevant druggable targets were among the most significantly enriched proteins. Remarkably, we resolved brain region-specific proteomic profiles of Camk2a neurons with distinct functional molecular signatures and disease associations that may underlie regional neuronal vulnerability. Leveraging the neuronal specificity of this in vivo biotinylation strategy, we used an antibody-based approach to uncover regionally unique patterns of neuron-derived signaling phospho-proteins and cytokines, particularly in the cortex and cerebellum. Our work provides a proteomic framework to investigate cell type-specific mechanisms driving physiological and pathological states of the brain as well as complex tissues beyond the brain.

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COMP-16. COMPREHENSIVE TRANSCRIPTOMIC ANALYSIS OF SINGLE CELLS FROM RECURRENT AND PRIMARY GLIOBLASTOMA TO PREDICT CELL-TYPE SPECIFIC THERAPEUTICS

Neuro-Oncology ◽

10.1093/neuonc/noz175.259 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi64-vi64

Author(s):

Robert Suter ◽

Vasileios Stathias ◽

Anna Jermakowicz ◽

Alexa Semonche ◽

Michael Ivan ◽

...

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Tumor Heterogeneity ◽

Drug Response ◽

Adult Brain ◽

Cell Populations ◽

Cell Type ◽

Single Cell Rna Sequencing ◽

Cell Type Specific ◽

Recurrent Gbm

Abstract Glioblastoma (GBM) remains the most common adult brain tumor, with poor survival expectations, and no new therapeutic modalities approved in the last decade. Our laboratories have recently demonstrated that the integration of a transcriptional disease signature obtained from The Cancer Genome Atlas’ GBM dataset with transcriptional cell drug-response signatures in the LINCS L1000 dataset yields possible combinatorial therapeutics. Considering the extreme intra-tumor heterogeneity associated with the disease, we hypothesize that the utilization of single-cell RNA-sequencing (scRNA-seq) of patient tumors will further strengthen our predictive model by providing insight on the unique transcriptomes of the cellular niches present within these tumors, and into the transcriptional dynamics of these same cellular niches. By sequencing single-cell transcriptomes from recurrent GBM tumors resected from patients at the University of Miami, and integrating our datasets with previously published scRNA-seq data from primary GBM tumors, we are able to gain additional insight into the differences between these clinical distinctions. We have analyzed the differential expression of kinases both across and within distinct cell populations of primary and recurrent GBM tumors. This transcriptional map of kinase expression represents the heterogeneity of potential targets within individual tumors and between recurrent and primary GBM. Additionally, by generating disease signatures unique to each cellular population, and integrating these with transcriptional drug-response signatures from LINCS, we are able to predict compounds to target specific cell populations within GMB tumors. Additional computational techniques such as RNA velocity analysis and cell cycle scoring elucidate temporal insights to further prioritize these cell-type specific therapeutics, and reveal the intra-cellular dynamics present within these tumors. Collectively, our studies suggest that we have developed a novel omics pipeline based on the single cell RNA-sequencing of individual GBM cells that addresses intra-tumor heterogeneity, and may lead to novel therapeutic combinations for the treatment of this incurable disease.

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