Single-Cell Analysis of Foxp1-Driven Mechanisms Essential for Striatal Development DOI Creative Commons
Ashley G. Anderson, Ashwinikumar Kulkarni, Matthew J. Harper

et al.

Cell Reports, Journal Year: 2020, Volume and Issue: 30(9), P. 3051 - 3066.e7

Published: March 1, 2020

The striatum is a critical forebrain structure integrating cognitive, sensory, and motor information from diverse brain regions into meaningful behavioral output. However, the transcriptional mechanisms underlying striatal development at single-cell resolution remain unknown. Using RNA sequencing (RNA-seq), we examine cellular diversity of early postnatal show that Foxp1, transcription factor strongly linked to autism intellectual disability, regulates composition, neurochemical architecture, connectivity in cell-type-dependent fashion. We also identify Foxp1-regulated target genes within distinct cell types connect these molecular changes functional deficits relevant phenotypes described patients with FOXP1 loss-of-function mutations. this approach, could non-cell-autonomous effects produced by disrupting one type compensation occurs other populations. These data reveal cell-type-specific regulated Foxp1 underlie features circuitry.

Language: Английский

Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin? DOI Creative Commons
Ryuji Kaji, Kailash P. Bhatia, Ann M. Graybiel

et al.

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2017, Volume and Issue: 89(5), P. 488 - 492

Published: Oct. 31, 2017

Dystonia is a disorder of motor programmes controlling semiautomatic movements or postures, with clinical features such as sensory trick , which suggests sensorimotor mismatch the basis. was originally classified basal ganglia disease. It now regarded ‘ network’ including cerebellum, but exact pathogenesis being unknown. Rare autopsy studies have found pathology both in striatum and functional disorganisation reported somatosensory cortex patients. Recent animal showed physiologically tight di synaptic connections between cerebellum striatum. We review evidence light this new interaction ganglia, put forward hypothesis that dystonia can be induced by aberrant afferent inputs from cerebellum.

Language: Английский

Citations

116
Dystonia and Parkinson's disease: What is the relationship? DOI Creative Commons
Aakash Shetty, Kailash P. Bhatia, Anthony E. Lang

et al.

Neurobiology of Disease, Journal Year: 2019, Volume and Issue: 132, P. 104462 - 104462

Published: May 9, 2019

Dystonia and Parkinson's disease are closely linked disorders sharing many pathophysiological overlaps. can be seen in 30% or more of the patients suffering with PD sometimes precede overt parkinsonism. The response early dystonia to introduction dopamine replacement therapy (levodopa, agonists) is variable; commonly occurs following levodopa initiation. Similarly, parkinsonism mutations various DYT genes including those involved synthesis pathway. Pharmacological blockade receptors cause both tardive these movement syndromes occur other neurodegenerative, genetic, toxic metabolic diseases. Pallidotomy past currently deep brain stimulation largely involving GPi effective treatment options for However, physiological mechanisms underlying two different disorder poorly understood. Interestingly, DBS such as blepharospasm bilateral pallidal result features Advances our understanding responses may provide better explanations relationship between disease.

Language: Английский

Citations

99
Two-photon imaging in mice shows striosomes and matrix have overlapping but differential reinforcement-related responses DOI Creative Commons

Bernard Bloem,

Rafiq Huda, Mriganka Sur

et al.

eLife, Journal Year: 2017, Volume and Issue: 6

Published: Dec. 18, 2017

Striosomes were discovered several decades ago as neurochemically identified zones in the striatum, yet technical hurdles have hampered study of functions these striatal compartments. Here we used 2-photon calcium imaging neuronal birthdate-labeled Mash1-CreER;Ai14 mice to image simultaneously activity striosomal and matrix neurons performed an auditory conditioning task. With this method, circumscribed tdTomato-labeled neuropil that correspond striosomes verified immunohistochemically. Neurons both responded reward-predicting cues active during or after consummatory licking. However, found quantitative differences response strength: fired more encoded information about expected outcome learned task, whereas strongly modulated by recent reward history. These findings open possibility harnessing vivo determine contributions circuit function.

Language: Английский

Citations

97
Functional Dissection of Basal Ganglia Inhibitory Inputs onto Substantia Nigra Dopaminergic Neurons DOI Creative Commons
Rebekah C. Evans, Emily L Twedell, Manhua Zhu

et al.

Cell Reports, Journal Year: 2020, Volume and Issue: 32(11), P. 108156 - 108156

Published: Sept. 1, 2020

Substantia nigra (SNc) dopaminergic neurons respond to aversive stimuli with inhibitory pauses in firing followed by transient rebound activation. We tested integration of synaptic inputs onto SNc from genetically defined populations dorsal striatum (striosome and matrix) external globus pallidus (GPe; parvalbumin- Lhx6-positive), examined their contribution pause-rebound firing. Activation striosome projections, which target "dendron bouquets" the pars reticulata (SNr), consistently quiets relief inhibition triggers activity. Striosomal postsynaptic currents (IPSCs) display a prominent GABA-B receptor-mediated component that strengthens impact SNr dendrite synapses on somatic excitability enables rebounding. By contrast, GPe projections activate GABA-A receptors soma proximal dendrites but do not result Lastly, optical mapping shows selectively inhibits ventral population neurons, are intrinsically capable Therefore, we define distinct striatonigral circuit for generating dopamine rebound.

Language: Английский

Citations

90
A Genetically Defined Compartmentalized Striatal Direct Pathway for Negative Reinforcement DOI Creative Commons
Xiong Xiao, Hanfei Deng, Alessandro Furlan

et al.

Cell, Journal Year: 2020, Volume and Issue: 183(1), P. 211 - 227.e20

Published: Sept. 15, 2020

Language: Английский

Citations

78
Transcriptional and anatomical diversity of medium spiny neurons in the primate striatum DOI Creative Commons
Jing He, Michael Kleyman,

Jianjiao Chen

et al.

Current Biology, Journal Year: 2021, Volume and Issue: 31(24), P. 5473 - 5486.e6

Published: Nov. 1, 2021

Language: Английский

Citations

58
Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction DOI Creative Commons
Zhenhua Liu, Nannan Yang, Jie Dong

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: June 17, 2022

Abstract Endocannabinoid (eCB), 2 -arachidonoyl-glycerol (2-AG), the most abundant eCB in brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations 2-AG synthase diacylglycerol lipase β ( DAGLB ) to an early onset autosomal recessive Parkinsonism. is main human and mouse substantia nigra (SN) dopaminergic neurons (DANs). In mice, SN levels were markedly correlated with motor performance during locomotor skill acquisition. Genetic knockdown of Daglb nigral DANs substantially reduced impaired learning, particularly across-session learning. Conversely, pharmacological inhibition degradation increased levels, DAN activity dopamine release rescued learning deficits. Together, demonstrate that -deficiency contributes pathogenesis Parkinsonism, reveal importance DAGLB-mediated biosynthesis regulating neuronal release, suggest potential benefits augmentation alleviating

Language: Английский

Citations

40
Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease DOI Creative Commons
A. Matsushima, S. Sebastian Pineda, Jill R. Crittenden

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 17, 2023

Abstract Striatal projection neurons (SPNs), which progressively degenerate in human patients with Huntington’s disease (HD), are classified along two axes: the canonical direct-indirect pathway division and striosome-matrix compartmentation. It is well established that indirect-pathway SPNs susceptible to neurodegeneration transcriptomic disturbances, but less known about how axis compromised HD relation axis. Here we show, using single-nucleus RNA-sequencing data from male Grade 1 patient post-mortem brain samples zQ175 R6/2 mouse models, axes multiplexed differentially HD. In HD, striosomal most depleted SPN population. distinctiveness of diminished more than SPNs. Furthermore, loss distinction prominent within These results open possibility compartments late early stages progression, respectively, contributing symptoms, thus calling for distinct therapeutic strategies.

Language: Английский

Citations

40
Striosomes and Matrisomes: Scaffolds for Dynamic Coupling of Volition and Action DOI Creative Commons
Ann M. Graybiel, A. Matsushima

Annual Review of Neuroscience, Journal Year: 2023, Volume and Issue: 46(1), P. 359 - 380

Published: April 18, 2023

Striosomes form neurochemically specialized compartments of the striatum embedded in a large matrix made up modules called matrisomes. Striosome-matrix architecture is multiplexed with canonical direct-indirect organization striatum. Striosomal functions remain to be fully clarified, but key information emerging. First, striosomes powerfully innervate nigral dopamine-containing neurons and can completely shut down their activity, following rebound excitation. Second, receive limbic cognition-related corticostriatal afferents are dynamically modulated relation value-based actions. Third, spatially interspersed among matrisomes interneurons influenced by local global neuromodulatory oscillatory activities. Fourth, tune engagement motivation perform reinforcement learning, manifest stereotypical behaviors, navigate valence conflicts discriminations. We suggest that, at an algorithmic level, could serve as distributed scaffolds provide formats striatal computations generated through development refined learning. propose that affect subjective states. By transforming corticothalamic other inputs functional striatum, they implement state transitions nigro-striato-nigral circuits bodily cognitive actions according internal motives whose compromised neuropsychiatric conditions.

Language: Английский

Citations

27
The cannabinoid-1 receptor is abundantly expressed in striatal striosomes and striosome-dendron bouquets of the substantia nigra DOI Creative Commons
Margaret I. Davis, Jill R. Crittenden,

Austin Y. Feng

et al.

PLoS ONE, Journal Year: 2018, Volume and Issue: 13(2), P. e0191436 - e0191436

Published: Feb. 21, 2018

Presynaptic cannabinoid-1 receptors (CB1-R) bind endogenous and exogenous cannabinoids to modulate neurotransmitter release. CB1-Rs are expressed throughout the basal ganglia, including striatum substantia nigra, where they play a role in learning control of motivated actions. However, pattern CB1-R expression across different striatal compartments, microcircuits efferent targets, contribution CB1-R-expressing neurons this pattern, unclear. We use combination conventional techniques novel genetic models evaluate striosome (patch) matrix compartments striatum, nigral targets medium spiny projection (MSNs). protein mRNA follow descending dorsolateral-to-ventromedial intensity gradient caudal with elevated striosomes relative surrounding matrix. The lateral predominance contrasts that classical striosomal marker, mu opioid receptor (MOR), which is most prominently rostromedial striosomes. similar Drd2 dopamine immunoreactivity opposite Substance P. This topology maintained downstream globus pallidus nigra. Dense striatonigral fibers extend dorsally within nigra pars reticulata, colocalize bundles ventrally extending, striosome-targeted, dendrites dopamine-containing compacta (striosome-dendron bouquets). Within fluorescently labeled MSN collaterals Cre recombinase-mediated deletion from cortical or MSNs, MSN-selective reintroduction knockout mice, demonstrate principal source dorsolateral local collaterals. These data suggest for striosome-dendron bouquet projections anatomically poised mediate presynaptic disinhibition both MSNs midbrain response endocannabinoids cannabinomimetics.

Language: Английский

Citations

74