scholarly journals Cell type-specific membrane potential changes in dorsolateral striatum accompanying reward-based sensorimotor learning

Function ◽  
2021 ◽  
Author(s):  
Tanya Sippy ◽  
Corryn Chaimowitz ◽  
Sylvain Crochet ◽  
Carl C H Petersen
Keyword(s):  
Membrane Potential ◽  
Dopamine Receptors ◽  
Cell Types ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Cell Type ◽  
Indirect Pathway ◽  
Cell Type Specific ◽  
Striatal Membrane ◽  
Sensory Evoked

Abstract The striatum integrates sensorimotor and motivational signals, likely playing a key role in reward-based learning of goal-directed behavior. However, cell type-specific mechanisms underlying reinforcement learning remain to be precisely determined. Here, we investigated changes in membrane potential dynamics of dorsolateral striatal neurons comparing naïve mice and expert mice trained to lick a reward spout in response to whisker deflection. We recorded from three distinct cell types: i) direct pathway striatonigral neurons, which express type 1 dopamine receptors; ii) indirect pathway striatopallidal neurons, which express type 2 dopamine receptors; and iii) tonically active, putative cholinergic, striatal neurons. Task learning was accompanied by cell type-specific changes in the membrane potential dynamics evoked by the whisker deflection and licking in successfully-performed trials. Both striatonigral and striatopallidal types of striatal projection neurons showed enhanced task-related depolarization across learning. Striatonigral neurons showed a prominent increase in a short latency sensory-evoked depolarization in expert compared to naïve mice. In contrast, the putative cholinergic striatal neurons developed a hyperpolarizing response across learning, driving a pause in their firing. Our results reveal cell type-specific changes in striatal membrane potential dynamics across the learning of a simple goal-directed sensorimotor transformation, helpful for furthering the understanding of the various potential roles of different basal ganglia circuits.

scholarly journals Transcriptome analysis for the development of cell-type specific labeling to study olfactory circuits

2020 ◽  
Author(s):  
Anzhelika Koldaeva ◽  
Cary Zhang ◽  
Yu-Pei Huang ◽  
Janine Reinert ◽  
Seiya Mizuno ◽  
...  
Keyword(s):  
Transcriptome Analysis ◽  
Mrna Level ◽  
Sensory System ◽  
Cell Types ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Cell Type ◽  
Cell Type Specific ◽  
Sensory Evoked ◽  
Driver Line

AbstractIn each sensory system of the brain, mechanisms exist to extract distinct features from stimuli to generate a variety of behavioural repertoires. These often correspond to different cell types at some stage in sensory processing. In the mammalian olfactory system, complex information processing starts in the olfactory bulb, whose output is conveyed by mitral and tufted cells (MCs and TCs). Despite many differences between them, and despite the crucial position they occupy in the information hierarchy, little is known how these two types of projection neurons differ at the mRNA level. Here, we sought to identify genes that are differentially expressed between MCs and TCs, with an ultimate goal to generate a cell-type specific Cre-driver line, starting from a transcriptome analysis using a large and publicly available single-cell RNA-seq dataset (Zeisel et al., 2018). Despite many genes showing differential expressions, we identified only a few that were abundantly and consistently expressed only in MCs. After further validating these putative markers using in-situ hybridization, two genes, namely Pkib and Lbdh2, remained as promising candidates. Using CRISPR/Cas9-mediated gene editing, we generated Cre-driver lines and analysed the resulting recombination patterns. This analysis indicated that our new inducible Cre-driver line, Lbhd2-CreERT2, can be used to genetically label MCs in a tamoxifen dose-dependent manner, as assessed by soma locations, projection patterns and sensory-evoked responses. Hence this line is a promising tool for future investigations of cell-type specific contributions to olfactory processing and demonstrates the power of publicly accessible data in accelerating science.

scholarly journals Transcriptional Diversity of Medium Spiny Neurons in the Primate Striatum

2020 ◽  
Author(s):  
Jing He ◽  
Michael Kleyman ◽  
Jianjiao Chen ◽  
Aydin Alikaya ◽  
Kathryn M. Rothenhoefer ◽  
...  
Keyword(s):  
Dorsal Striatum ◽  
Cell Types ◽  
Specific Information ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Cell Type ◽  
Indirect Pathway ◽  
Spiny Neurons ◽  
Single Nucleus ◽  
Cell Type Specific

AbstractThe striatum is the neural interface between dopamine reward signals and cortico-basal ganglia circuits responsible for value assignments, decisions, and actions. Medium spiny neurons (MSNs) make up the vast majority of striatal neurons and are traditionally classified as two distinct types: direct- and indirect-pathway MSNs. The direct- and indirect-pathway model has been useful for understanding some aspects of striatal functions, but it accounts for neither the anatomical heterogeneity, nor the functional diversity of the striatum. Here, we use single nucleus RNA-sequencing and Fluorescent In-Situ Hybridization to explore MSN diversity in the Rhesus macaque striatum. We identified MSN subtypes that correspond to the major subdivisions of the striatum. These include dorsal striatum subtypes associated with striosome and matrix compartments, as well as ventral striatum subtypes associated with the shell of the nucleus accumbens. We also describe a cell type that is anatomically restricted to “Neurochemically Unique Domains in the Accumbens and Putamen (NUDAPs)”. Together, these results help to advance nonhuman primate studies into the genomics era. The identified cell types provide a comprehensive blueprint for investigating cell type-specific information processing, and the differentially expressed genes lay a foundation for achieving cell type-specific transgenesis in the primate striatum.

scholarly journals Cell-type and subcellular compartment-specific APEX2 proximity labeling reveals activity-dependent nuclear proteome dynamics in the striatum

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
V. Dumrongprechachan ◽  
R. B. Salisbury ◽  
G. Soto ◽  
M. Kumar ◽  
M. L. MacDonald ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Functional Organization ◽  
Projection Neurons ◽  
Specific Information ◽  
Striatal Neurons ◽  
Cell Type ◽  
Indirect Pathway ◽  
Subcellular Compartment ◽  
Cell Type Specific ◽  
And Function

AbstractThe vertebrate brain consists of diverse neuronal types, classified by distinct anatomy and function, along with divergent transcriptomes and proteomes. Defining the cell-type specific neuroproteomes is important for understanding the development and functional organization of neural circuits. This task remains challenging in complex tissue, due to suboptimal protein isolation techniques that often result in loss of cell-type specific information and incomplete capture of subcellular compartments. Here, we develop a genetically targeted proximity labeling approach to identify cell-type specific subcellular proteomes in the mouse brain, confirmed by imaging, electron microscopy, and mass spectrometry. We virally express subcellular-localized APEX2 to map the proteome of direct and indirect pathway spiny projection neurons in the striatum. The workflow provides sufficient depth to uncover changes in the proteome of striatal neurons following chemogenetic activation of Gαq-coupled signaling cascades. This method enables flexible, cell-type specific quantitative profiling of subcellular proteome snapshots in the mouse brain.

scholarly journals Connectivity characterization of the mouse basolateral amygdalar complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Houri Hintiryan ◽  
Ian Bowman ◽  
David L. Johnson ◽  
Laura Korobkova ◽  
Muye Zhu ◽  
...  
Keyword(s):  
Granular Cell ◽  
Cell Types ◽  
Projection Neurons ◽  
Cell Type ◽  
Connectivity Map ◽  
Analysis Techniques ◽  
Domain Specific ◽  
Cell Type Specific ◽  
Unique Domain

AbstractThe basolateral amygdalar complex (BLA) is implicated in behaviors ranging from fear acquisition to addiction. Optogenetic methods have enabled the association of circuit-specific functions to uniquely connected BLA cell types. Thus, a systematic and detailed connectivity profile of BLA projection neurons to inform granular, cell type-specific interrogations is warranted. Here, we apply machine-learning based computational and informatics analysis techniques to the results of circuit-tracing experiments to create a foundational, comprehensive BLA connectivity map. The analyses identify three distinct domains within the anterior BLA (BLAa) that house target-specific projection neurons with distinguishable morphological features. We identify brain-wide targets of projection neurons in the three BLAa domains, as well as in the posterior BLA, ventral BLA, posterior basomedial, and lateral amygdalar nuclei. Inputs to each nucleus also are identified via retrograde tracing. The data suggests that connectionally unique, domain-specific BLAa neurons are associated with distinct behavior networks.

scholarly journals Connectivity characterization of the mouse basolateral amygdalar complex

2019 ◽  
Author(s):  
Houri Hintiryan ◽  
Ian Bowman ◽  
David L. Johnson ◽  
Laura Korobkova ◽  
Muye Zhu ◽  
...  
Keyword(s):  
Cell Body ◽  
Computational Analysis ◽  
Functional Characterization ◽  
Granular Cell ◽  
Cell Types ◽  
Projection Neurons ◽  
Cell Type ◽  
Analysis Techniques ◽  
Cell Type Specific

ABSTRACTThe basolateral amygdalar complex (BLA) is implicated in behavioral processing ranging from fear acquisition to addiction. Newer methods like optogenetics have enabled the association of circuit-specific functionality to uniquely connected BLA cell types. Thus, a systematic and detailed connectivity profile of BLA projection neurons to inform granular, cell type-specific interrogations is warranted. In this work, we applied computational analysis techniques to the results of our circuit-tracing experiments to create a foundational, comprehensive, multiscale connectivity atlas of the mouse BLA. The analyses identified three domains within the classically defined anterior BLA (BLAa) that house target-specific projection neurons with distinguishable cell body and dendritic morphologies. Further, we identify brain-wide targets of projection neurons located in the three BLAa domains as well as in the posterior BLA (BLAp), ventral BLA (BLAv), lateral (LA), and posterior basomedial (BMAp) nuclei. Projection neurons that provide input to each nucleus are also identifed. Functional characterization of some projection-defined BLA neurons were demonstrated via optogenetic and recording experiments. Hypotheses relating function to connection-defined BLA cell types are proposed.

scholarly journals Single-cell analysis of Foxp1-driven mechanisms essential for striatal development

2019 ◽  
Author(s):  
Ashley G. Anderson ◽  
Ashwinikumar Kulkarni ◽  
Matthew Harper ◽  
Genevieve Konopka
Keyword(s):  
Single Cell ◽  
Target Genes ◽  
Single Cell Analysis ◽  
Cell Types ◽  
Brain Regions ◽  
Projection Neurons ◽  
Loss Of Function ◽  
Cell Type ◽  
Motor Information ◽  
Cell Type Specific

AbstractThe striatum is a critical forebrain structure for integrating cognitive, sensory, and motor information from diverse brain regions into meaningful behavioral output. However, the transcriptional mechanisms that underlie striatal development and organization at single-cell resolution remain unknown. Here, we show that Foxp1, a transcription factor strongly linked to autism and intellectual disability, regulates organizational features of striatal circuitry in a cell-type-dependent fashion. Using single-cell RNA-sequencing, we examine the cellular diversity of the early postnatal striatum and find that cell-type-specific deletion ofFoxp1in striatal projection neurons alters the cellular composition and neurochemical architecture of the striatum. Importantly, using this approach, we identify the non-cell autonomous effects produced by disruptingFoxp1in one cell-type and the molecular compensation that occurs in other populations. Finally, we identify Foxp1-regulated target genes within distinct cell-types and connect these molecular changes to functional and behavioral deficits relevant to phenotypes described in patients withFOXP1loss-of-function mutations. These data reveal cell-type-specific transcriptional mechanisms underlying distinct features of striatal circuitry and identify Foxp1 as a key regulator of striatal development.

scholarly journals Gap Junctions Between Striatal D1 Neurons and Cholinergic Interneurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Yuqi Ren ◽  
Yang Liu ◽  
Minmin Luo
Keyword(s):  
Gap Junctions ◽  
Electrical Coupling ◽  
Cell Types ◽  
Projection Neurons ◽  
Chemical Synapse ◽  
Cell Type ◽  
Cholinergic Interneurons ◽  
Optogenetic Stimulation ◽  
Electrophysiological Recordings ◽  
Cell Type Specific

The striatum participates in numerous important behaviors. Its principal projection neurons use GABA and peptides as neurotransmitters and interact extensively with interneurons, including cholinergic interneurons (ChIs) that are tonically active. Dissecting the interactions between projection neurons and ChIs is important for uncovering the role and mechanisms of the striatal microcircuits. Here, by combining several optogenetic tools with cell type-specific electrophysiological recordings, we uncovered direct electrical coupling between D1-type projection neurons and ChIs, in addition to the chemical transmission between these two major cell types. Optogenetic stimulation or inhibition led to bilateral current exchanges between D1 neurons and ChIs, which can be abolished by gap junction blockers. We further confirmed the presence of gap junctions through paired electrophysiological recordings and dye microinjections. Finally, we found that activating D1 neurons promotes basal activity of ChIs via gap junctions. Collectively, these results reveal the coexistence of the chemical synapse and gap junctions between D1 neurons and ChIs, which contributes to maintaining the tonically active firing patterns of ChIs.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

scholarly journals Histone modifications form a cell-type-specific chromosomal bar code that persists through the cell cycle

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
John A. Halsall ◽  
Simon Andrews ◽  
Felix Krueger ◽  
Charlotte E. Rutledge ◽  
Gabriella Ficz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Histone Modifications ◽  
Expression Patterns ◽  
Cell Types ◽  
Cell Type ◽  
Bar Code ◽  
Genes Encoding ◽  
Cell Type Specific ◽  
Rolling Windows

AbstractChromatin configuration influences gene expression in eukaryotes at multiple levels, from individual nucleosomes to chromatin domains several Mb long. Post-translational modifications (PTM) of core histones seem to be involved in chromatin structural transitions, but how remains unclear. To explore this, we used ChIP-seq and two cell types, HeLa and lymphoblastoid (LCL), to define how changes in chromatin packaging through the cell cycle influence the distributions of three transcription-associated histone modifications, H3K9ac, H3K4me3 and H3K27me3. We show that chromosome regions (bands) of 10–50 Mb, detectable by immunofluorescence microscopy of metaphase (M) chromosomes, are also present in G1 and G2. They comprise 1–5 Mb sub-bands that differ between HeLa and LCL but remain consistent through the cell cycle. The same sub-bands are defined by H3K9ac and H3K4me3, while H3K27me3 spreads more widely. We found little change between cell cycle phases, whether compared by 5 Kb rolling windows or when analysis was restricted to functional elements such as transcription start sites and topologically associating domains. Only a small number of genes showed cell-cycle related changes: at genes encoding proteins involved in mitosis, H3K9 became highly acetylated in G2M, possibly because of ongoing transcription. In conclusion, modified histone isoforms H3K9ac, H3K4me3 and H3K27me3 exhibit a characteristic genomic distribution at resolutions of 1 Mb and below that differs between HeLa and lymphoblastoid cells but remains remarkably consistent through the cell cycle. We suggest that this cell-type-specific chromosomal bar-code is part of a homeostatic mechanism by which cells retain their characteristic gene expression patterns, and hence their identity, through multiple mitoses.

scholarly journals An analytical method for the identification of cell type-specific disease gene modules

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jinting Guan ◽  
Yiping Lin ◽  
Yang Wang ◽  
Junchao Gao ◽  
Guoli Ji
Keyword(s):  
Disease Gene ◽  
Gene Interaction ◽  
Cell Types ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Disease ◽  
Cell Type Specific ◽  
Gene Modules ◽  
Disease Associated Genes

Abstract Background Genome-wide association studies have identified genetic variants associated with the risk of brain-related diseases, such as neurological and psychiatric disorders, while the causal variants and the specific vulnerable cell types are often needed to be studied. Many disease-associated genes are expressed in multiple cell types of human brains, while the pathologic variants affect primarily specific cell types. We hypothesize a model in which what determines the manifestation of a disease in a cell type is the presence of disease module comprised of disease-associated genes, instead of individual genes. Therefore, it is essential to identify the presence/absence of disease gene modules in cells. Methods To characterize the cell type-specificity of brain-related diseases, we construct human brain cell type-specific gene interaction networks integrating human brain nucleus gene expression data with a referenced tissue-specific gene interaction network. Then from the cell type-specific gene interaction networks, we identify significant cell type-specific disease gene modules by performing statistical tests. Results Between neurons and glia cells, the constructed cell type-specific gene networks and their gene functions are distinct. Then we identify cell type-specific disease gene modules associated with autism spectrum disorder and find that different gene modules are formed and distinct gene functions may be dysregulated in different cells. We also study the similarity and dissimilarity in cell type-specific disease gene modules among autism spectrum disorder, schizophrenia and bipolar disorder. The functions of neurons-specific disease gene modules are associated with synapse for all three diseases, while those in glia cells are different. To facilitate the use of our method, we develop an R package, CtsDGM, for the identification of cell type-specific disease gene modules. Conclusions The results support our hypothesis that a disease manifests itself in a cell type through forming a statistically significant disease gene module. The identification of cell type-specific disease gene modules can promote the development of more targeted biomarkers and treatments for the disease. Our method can be applied for depicting the cell type heterogeneity of a given disease, and also for studying the similarity and dissimilarity between different disorders, providing new insights into the molecular mechanisms underlying the pathogenesis and progression of diseases.

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