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In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids [Smartseq]

ABSTRACT: Dopaminergic neurons located in the ventral Midbrain (vMid) innervate the striatum and cortex and are involved in movement control and reward-related cognition. Degeneration of dopaminergic neurons causes Parkinson’s disease (PD), while their over-activation is implicated in addiction. Thus, modeling the dopaminergic system is of broad relevance for disease research and drug discovery, although limited availability of patient material and inherent differences in animal model systems are restricting the study of distinctive human specific features such as development and neurodegeneration. Here, we show that spatially arranged assembloids can recapitulate dopaminergic innervation of striatum and cortex and offer methods for their use in cell replacement therapy and addiction research. We describe improved protocols for growing vMid, striatal and cortical organoids and use custom embedding molds to fuse them in a linear manner. Linear assembloids form functional long-range dopaminergic connections with striatal and cortical tissues that can release dopamine. We demonstrate that vMid grafts derived from hPSCs for cell replacement therapy of PD can integrate into the tissue and structurally mature. Additionally, we demonstrate that our model can be used to study dopaminergic circuit perturbations in the example of chronic cocaine treatment which causes morphological, functional and transcriptional changes that remained altered even after drug withdrawal. Our method opens new avenues for dopaminergic cell replacement therapy and the analysis of drugs affecting the dopaminergic system, directly in a human system.

ORGANISM(S): Homo sapiens

PROVIDER: GSE219246 | GEO | 2023/09/20

REPOSITORIES: GEO

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In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids [scRNAseq]

Project description:Dopaminergic neurons located in the ventral Midbrain (vMid) innervate the striatum and cortex and are involved in movement control and reward-related cognition. Degeneration of dopaminergic neurons causes Parkinson’s disease (PD), while their over-activation is implicated in addiction. Thus, modeling the dopaminergic system is of broad relevance for disease research and drug discovery, although limited availability of patient material and inherent differences in animal model systems are restricting the study of distinctive human specific features such as development and neurodegeneration. Here, we show that spatially arranged assembloids can recapitulate dopaminergic innervation of striatum and cortex and offer methods for their use in cell replacement therapy and addiction research. We describe improved protocols for growing vMid, striatal and cortical organoids and use custom embedding molds to fuse them in a linear manner. Linear assembloids form functional long-range dopaminergic connections with striatal and cortical tissues that can release dopamine. We demonstrate that vMid grafts derived from hPSCs for cell replacement therapy of PD can integrate into the tissue and structurally mature. Additionally, we demonstrate that our model can be used to study dopaminergic circuit perturbations in the example of chronic cocaine treatment which causes morphological, functional and transcriptional changes that remained altered even after drug withdrawal. Our method opens new avenues for dopaminergic cell replacement therapy and the analysis of drugs affecting the dopaminergic system, directly in a human system.

2023-09-20 | GSE219245 | GEO

Age-induced midbrain-striatum assembloids model early phenotypes of Parkinson’s disease [RNA-Seq]

Project description:Parkinson's disease (PD), one of the most common aging-associated neurodegenerative disorders, is characterised by nigrostriatal pathway dysfunction, caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the dopamine depletion in the striatum. State of the art, human in vitro models are enabling the study of the dopaminergic neurons' loss, but not the dysregulation of the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of PD. Therefore, it is conceivable that research conducted using these models overlooked numerous processes that contribute to disease's phenotypes. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids are capable of developing characteristics of the nigrostriatal connectivity, with dopamine release from the midbrain to striatum and synapses formation between midbrain and striatal neurons. Moreover, progerin-overexpressing assembloids acquire aging traits that lead to early phenotypes of PD. This new model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of PD.

2023-10-28 | GSE236458 | GEO

Age-induced midbrain-striatum assembloid models early phenotypes of Parkinson’s disease [scRNA-Seq]

Project description:Parkinson’s disease, one of the most common aging-associated neurodegenerative disorders, is characterised by nigrostriatal pathway dysfunction, caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the dopamine depletion in the striatum. State of the art, human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation of the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics necessary for the development of PD. Therefore, it is conceivable that research conducted using these models overlooked numerous processes that contribute to disease’s phenotypes. Here we present a method for the generation of a midbrain-striatum assembloid model with inducible aging. Aging is induced by expression of progerin. We show that these assembloids are capable of developing characteristics of the nigrostriatal connectivity, with dopamine release from the midbrain to striatum and synapses formation between midbrain and striatal neurons. Moreover, progerin-overexpressing assembloids acquire aging phenotypes that lead to early phenotypes of Parkinson’s disease. This new model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of PD.

2023-10-28 | GSE241631 | GEO

Expression data from Drd1a and Drd2 expressing neurons in striatum and cortex, at 6 weeks and 2 years of age

Project description:We performed a study of gene expression changes that occur during mouse aging in the striatum and cortex in specific neuronal populations. Using translating ribosome afifnity purificaiton, we captured cell type-specific mRNAs from Drd1a-expressing cortical neurons, Drd1a-expressing striatal neurons, Drd2-expressing cortical neurons, and Drd2-expressing striatal neurons. 31 total samples were anlayzed. We generated the followinf pairwise comparisons: Old (2 years) vs young (6 weeks) Drd1a expressing cortical cells; old (2 years) vs young (6 weeks) Drd2 expressing cortical cells; old (2 years) vs young (6 weeks) Drd1a expressing striatal cells; old (2 years) vs young (6 weeks) Drd2 expressing striatal cells. We used a restriction of Benjamini-Hochberg FDR <0.05, and a fold-change restriction of 1.2-fold.

2014-12-13 | E-GEOD-64140 | biostudies-arrayexpress

Expression data from Drd1a and Drd2 expressing neurons in striatum and cortex, at 6 weeks and 2 years of age

2014-12-13 | GSE64140 | GEO

Transcriptomic (RNA-seq) analysis of wild-type and Nolz1-/- (Zfp503) mutant striatal tissue reveals altered expression of several genes involved in striatal projection neuron specification.

Project description:Midbrain dopaminergic (DA) axons make long longitudinal projections towards target areas in the forebrain, including the striatum. After demonstrating a striatal specific requirement of transcriptional regulator Nolz1 (Zfp503) in regulating DA axon guidance and innervation, we performed RNA-seq analysis on both wild-type and Nolz1-/- mutant striatal tissue. The gene expression analysis revealed a requirement of Nolz1 in regulating striatal projection neuron specification. The RNA-seq results reveal several secreted factors that underlie the observed guidance defects and resulted in the identification of proteins that can restore DA axonal outgrowth.

2020-05-12 | E-MTAB-8240 | biostudies-arrayexpress

Addiction-associated genetic variants implicate brain cell type- and region-specific cis-regulatory elements in addiction neurobiology

Project description:Recent large genome-wide association studies (GWAS) have identified multiple confident risk loci linked to addiction-associated behavioral traits. Genetic variants linked to addiction-associated traits lie largely in non-coding regions of the genome, likely disrupting cis-regulatory element (CRE) function. CREs tend to be highly cell type-specific and may contribute to the functional development of the neural circuits underlying addiction. Yet, a systematic approach for predicting the impact of risk variants on the CREs of specific cell populations is lacking. To dissect the cell types and brain regions underlying addiction-associated traits, we applied LD score regression to compare GWAS to genomic regions collected from human and mouse assays for open chromatin, which is associated with CRE activity. We found enrichment of addiction-associated variants in putative regulatory elements marked by open chromatin in neuronal (NeuN+) nuclei collected from multiple prefrontal cortical areas and striatal regions known to play major roles in reward and addiction. To further dissect the cell type-specific basis of addiction-associated traits, we also identified enrichments in human orthologs of open chromatin regions of mouse neuron subtypes: cortical excitatory, PV, D1, and D2. Lastly, we developed machine learning models from mouse cell type-specific regions of open chromatin to further dissect human NeuN+ open chromatin regions into cortical excitatory or striatal D1 and D2 neurons and predict the functional impact of addiction-associated genetic variants. Our results suggest that different neuron subtypes within the reward system play distinct roles in the variety of traits that contribute to addiction.

2021-07-13 | GSE161374 | GEO

Postnatal Conditional Knockout of Bcl11b in Striatal Projection Neurons Mimics the Transcriptional Signature of Huntington’s Disease

Project description:Dysregulation of the striatum is linked to multiple diseases including Huntington’s (HD), Parkinson’s, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neuronal cell type in the striatum and are critical to motor control. The transcription factor Bcl11b (also known as CTIP2) is known to regulate of MSN differentiation, striatal striosome (patch) development and the architecture of the striatum during development. However, the function of Bcl11b adult striatal neurons in vivo has not been investigated. Therefore, we conditionally knocked out Bcl11b specifically in MSNs using D9-cre under the control of a regulatory elements of the mouse Ppp1r1b gene encoding DARPP-32 resulting in knockout around 5-6 weeks of age. Transcriptomic and behavioral analysis were performed on these mice.

2022-11-02 | GSE185476 | GEO

Pramipexole induced place preference promoted after L-dopa therapy and nigral dopaminergic loss: linking behavior to transcriptional modifications

Project description:Symptoms of the dopamine dysregulation syndrome in patients with Parkinson’s disease (PD) are close to those observed in psychostimulant addiction. This suggests that dopamine replacement therapy shares some properties with potentially addictive drugs. A remaining challenge is to understand the neuroadaptations leading to compulsive dopaminergic medication use. To this end, the reinforcing properties of the D2/D3 agonist pramipexole (PPX) were assessed after chronic exposure to L-dopa in an alpha-synuclein PD rat model.

2015-10-28 | GSE74382 | GEO

Single nuclei transcriptomics of human and monkey striatum implicates DNA damage, neuroinflammation, and neurodegeneration signaling in opioid use disorder

Project description:The striatum in the brain is involved in various behavioral functions, including reward, and disease processes, such as opioid use disorder (OUD). Further understanding of the role of striatal subregions in reward behaviors and their potential associations with OUD requires molecular identification of specific striatal cell types in human brain. The human striatum contains subregions based on different anatomical, functional, and physiological properties, with the dorsal striatum further divided into caudate and putamen. Both caudate and putamen are associated with alterations in reward processing, formation of habits, and development of negative affect states in OUD. Using single nuclei RNA-sequencing of human postmortem caudate and putamen, we identified canonical neuronal cell types in striatum (e.g., dopamine receptor 1 or 2 expressing neurons, D1 or D2) and less abundant subpopulations, including D1/D2 hybrid neurons and multiple classes of interneurons. By comparing unaffected subjects to subjects with OUD, we found neuronal-specific differences in pathways related to neurodegeneration, interferon response, and DNA damage. DNA damage markers were also elevated in striatal neurons of rhesus macaques following chronic opioid administration. We identified sex-dependent differences in the expression of stress-induced transcripts (e.g., FKBP5) among astrocytes and oligodendrocytes from female subjects with OUD. Thus, we describe striatal cell types and leverage these data to gain insights into molecular alterations in human striatum associated with opioid addiction.

2023-11-28 | GSE233279 | GEO

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