scholarly journals Distinct neural progenitor pools in the ventral telencephalon generate diversity in striatal spiny projection neurons

2019 ◽  
Author(s):  
Fran van Heusden ◽  
Anežka Macey-Dare ◽  
Rohan N. Krajeski ◽  
Andrew Sharott ◽  
Tommas Jan Ellender
Keyword(s):  
Neural Progenitor ◽  
Neural Progenitors ◽  
Projection Neurons ◽  
Spine Density ◽  
Striatal Neurons ◽  
Indirect Pathway ◽  
Pulse Label ◽  
Cortical Input ◽  
Intermediate Progenitors ◽  
Lateral Ganglionic Eminence

AbstractHeterogeneous populations of neural progenitors in the embryonic lateral ganglionic eminence (LGE) generate all GABAergic spiny projection neurons (SPNs) found in the striatum. Here we investigate how this diversity in neural progenitors relates to diversity of adult striatal neurons and circuits. Using a combination of in utero electroporation to fluorescently pulse-label striatal neural progenitors in the LGE, brain slice electrophysiology, electrical and optogenetic circuit mapping and immunohistochemistry, we characterise a population of neural progenitors enriched for apical intermediate progenitors (aIPs) and a distinct population of other progenitors (OPs) and their neural offspring. We find that neural progenitor origin has subtle but significant effects on the properties of striatal SPNs. Although aIP and OP progenitors can both generate D1-expressing direct pathway as well as D2-expressing indirect pathway SPNs found intermingled in the striatum, the aIP derived SPNs are found in more medial aspects of the striatum, exhibit more complex dendritic arbors with higher spine density and differentially sample cortical input. Moreover, optogenetic circuit mapping of the aIP derived neurons show that they further integrate within striatal circuits and innervate both local D1 and D2 SPNs. These results show that it is possible to fluorescently pulse-label distinct neural progenitor pools within the LGE and provide the first evidence that neural progenitor heterogeneity can contribute to the diversity of striatal SPNs.

scholarly journals Radial glial lineage progression and differential intermediate progenitor amplification underlie striatal compartments and circuit organization

2018 ◽  
Author(s):  
Sean M. Kelly ◽  
Ricardo Raudales ◽  
Miao He ◽  
Jannifer Lee ◽  
Yongsoo Kim ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Late Phase ◽  
Projection Neurons ◽  
Limited Capacity ◽  
Indirect Pathway ◽  
Intermediate Progenitors ◽  
Lateral Ganglionic Eminence ◽  
Glial Progenitors ◽  
Radial Glial ◽  
Glial Lineage

SUMMARYThe circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of and relationships between these organizations are unknown, leaving a conceptual gap in understanding the cortico-basal ganglia system. Through genetic fate mapping, we demonstrate that striosome-matrix compartmentalization arises from a lineage program embedded in lateral ganglionic eminence radial glial progenitors mediating neurogenesis through two distinct types of intermediate progenitors (IPs). The early phase of this program produces striosomal spiny projection neurons (SPNs) through fate-restricted apical IPs (aIPSs) with limited capacity; the late phase produces matrix SPNs through fate-restricted basal IPs (bIPMs) with expanded capacity. Remarkably, direct and indirect pathway SPNs arise within both aIPS and bIPM pools, suggesting that striosome-matrix architecture is the fundamental organizational plan of basal ganglia circuitry organization.

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 Dysregulation of the basal ganglia indirect pathway prior to cell loss in the Q175 mouse model of Huntington's disease

2021 ◽  
Author(s):  
Joshua Callahan ◽  
David L Wokosin ◽  
Mark D Bevan
Keyword(s):  
Basal Ganglia ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Ex Vivo ◽  
Cell Loss ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Cortical Input ◽  
Psychomotor Symptoms

The psychomotor symptoms of Huntington's disease (HD) are linked to degeneration of the basal ganglia indirect pathway. To determine how this pathway is perturbed prior to cell loss, optogenetic- and reporter-guided electrophysiological interrogation approaches were applied to early symptomatic 6-month-old Q175 HD mice. Although cortical activity was unaffected, indirect pathway striatal projection neurons were hypoactive in vivo, consistent with reduced cortical input strength and dendritic excitability. Downstream parvalbumin-expressing prototypic external globus pallidus (GPe) neurons were hyperactive in vivo and exhibited elevated autonomous firing ex vivo. Optogenetic inhibition of prototypic GPe neurons ameliorated the abnormal hypoactivity of postsynaptic subthalamic nucleus (STN) and putative arkypallidal neurons in vivo. In contrast to STN neurons, autonomous arkypallidal activity was unimpaired ex vivo. Together with previous studies, these findings demonstrate that basal ganglia indirect pathway neurons are highly dysregulated in Q175 mice through changes in presynaptic activity and/or intrinsic properties 6-12 months before cell loss.

scholarly journals Asymmetrical choice-related ensemble activity in direct and indirect-pathway striatal neurons drives perceptual decisions

2021 ◽  
Author(s):  
Lele Cui ◽  
Shunhang Tang ◽  
Kai Zhao ◽  
Jingwei Pan ◽  
Zhaoran Zhang ◽  
...  
Keyword(s):  
Decision Making ◽  
Action Selection ◽  
Behavioral Effects ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Indirect Pathway ◽  
Two Photon ◽  
Decision Making Behavior ◽  
Ensemble Activity ◽  
Deep Brain

Action selection during decision-making depends on the basal ganglia circuits that comprise the direct and indirect pathways known to oppositely control movement. However, the mechanism for coordinating these opponent pathways during decision-making remains unclear. We address this by employing deep-brain two-photon imaging and optogenetic manipulations of the direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) in the posterior striatum during an auditory decision-making behavior. We show that while dSPNs and iSPNs play opposite causal roles during decision-making, each subtype contains divergent ensembles preferring different choices. The ensembles in dSPNs show stronger contralateral dominance than those in iSPNs manifested by higher-level activation and synchronization. Consistent with this asymmetrical contralateral dominance, optogenetic disinhibition of both pathways promoted contralateral choices. A computational model incorporating the striatal ensemble asymmetry recapitulated the causal behavioral effects. Our results uncover the asymmetry between opponent SPN ensembles as a circuit mechanism for action selection during decision-making.

scholarly journals Striatal Control of Movement: A Role for New Neuronal (Sub-) Populations?

2021 ◽  
Vol 15 ◽  
Author(s):  
Tim Fieblinger
Keyword(s):  
Brain Area ◽  
Projection Neurons ◽  
Anatomical Location ◽  
Striatal Neurons ◽  
Indirect Pathway ◽  
Transcriptional Profiles ◽  
Transcriptional Signature ◽  
Neuronal Populations ◽  
Abnormal Movements ◽  
Two Populations

The striatum is a very heterogenous brain area, composed of different domains and compartments, albeit lacking visible anatomical demarcations. Two populations of striatal spiny projection neurons (SPNs) build the so-called direct and indirect pathway of the basal ganglia, whose coordinated activity is essential to control locomotion. Dysfunction of striatal SPNs is part of many movement disorders, such as Parkinson’s disease (PD) and L-DOPA-induced dyskinesia. In this mini review article, I will highlight recent studies utilizing single-cell RNA sequencing to investigate the transcriptional profiles of striatal neurons. These studies discover that SPNs carry a transcriptional signature, indicating both their anatomical location and compartmental identity. Furthermore, the transcriptional profiles reveal the existence of additional distinct neuronal populations and previously unknown SPN sub-populations. In a parallel development, studies in rodent models of PD and L-DOPA-induced dyskinesia (LID) report that direct pathway SPNs do not react uniformly to L-DOPA therapy, and that only a subset of these neurons is underlying the development of abnormal movements. Together, these studies demonstrate a new level of cellular complexity for striatal (dys-) function and locomotor control.

scholarly journals Dopamine D2L Receptor Deficiency Alters Neuronal Excitability and Spine Formation in Mouse Striatum

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 101
Author(s):  
Gubbi Govindaiah ◽  
Rong-Jian Liu ◽  
Yanyan Wang
Keyword(s):  
Neuronal Excitability ◽  
Dopamine D2 Receptor ◽  
Synaptic Function ◽  
Projection Neurons ◽  
Spine Density ◽  
Striatal Neurons ◽  
Cellular Mechanisms ◽  
Drug Induced ◽  
Cholinergic Interneurons ◽  
Spike Firing

The striatum contains several types of neurons including medium spiny projection neurons (MSNs), cholinergic interneurons (ChIs), and fast-spiking interneurons (FSIs). Modulating the activity of these neurons by the dopamine D2 receptor (D2R) can greatly impact motor control and movement disorders. D2R exists in two isoforms: D2L and D2S. Here, we assessed whether alterations in the D2L and D2S expression levels affect neuronal excitability and synaptic function in striatal neurons. We observed that quinpirole inhibited the firing rate of all three types of striatal neurons in wild-type (WT) mice. However, in D2L knockout (KO) mice, quinpirole enhanced the excitability of ChIs, lost influence on spike firing of MSNs, and remained inhibitory effect on spike firing of FSIs. Additionally, we showed mIPSC frequency (but not mIPSC amplitude) was reduced in ChIs from D2L KO mice compared with WT mice, suggesting spontaneous GABA release is reduced at GABAergic terminals onto ChIs in D2L KO mice. Furthermore, we found D2L deficiency resulted in reduced dendritic spine density in ChIs, suggesting D2L activation plays a role in the formation/maintenance of dendritic spines of ChIs. These findings suggest new molecular and cellular mechanisms for causing ChIs abnormality seen in Parkinson’s disease or drug-induced dyskinesias.

scholarly journals Mutant huntingtin enhances activation of dendritic Kv4 K+ channels in striatal spiny projection neurons

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Luis Carrillo-Reid ◽  
Michelle Day ◽  
Zhong Xie ◽  
Alexandria E Melendez ◽  
Jyothisri Kondapalli ◽  
...  
Keyword(s):  
Zinc Finger Protein ◽  
Ex Vivo ◽  
Brain Slices ◽  
Projection Neurons ◽  
Receptor Signaling ◽  
Striatal Neurons ◽  
Indirect Pathway ◽  
Trkb Receptor ◽  
Dendritic Excitability ◽  
Kv4 Channels

Huntington’s disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD.

scholarly journals Duplex optogenetic stimulation system modulates compulsive behaviors bidirectionally

2021 ◽  
Vol 2 (3) ◽  
Author(s):  
Edenia Menezes ◽  
◽  
David Ashurov ◽  
Catarina Sousa Cunha ◽  
◽  
...  
Keyword(s):  
Mental Illnesses ◽  
Projection Neurons ◽  
Spine Density ◽  
Indirect Pathway ◽  
Obsessive Compulsive ◽  
Optogenetic Stimulation ◽  
Compulsive Behaviors ◽  
Stimulation System ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders

Decisions enable us to consider our actions while adjusting behaviors to a relentlessly changing environment. Since conscious decision making requires our full attention and is therefore expensive, we use a cheaper system for everyday and repetitive tasks that run automatically without conscious evaluations, commonly described as habits. The combination of these two systems is highly adaptive. However, if there is a disruption in these systems’ balance, mental illnesses such as Obsessive-Compulsive Disorders (OCD) or addiction may arise. Now, how does a newly acquired memory or behavior transition to a habit? We know that the striatum’s dorsolateral region (DLS) plays a significant role in sustaining successful behaviors and habits manifestation. Furthermore, it has been shown that the micro-circuitry of the DLS is organized into two functional opposing pathways that consist of the direct pathway striatal spiny projection neurons (dSPNs), which facilitate movement, and the indirect pathway SPNs, which inhibit actions. Already Freud wrote in the letters to his friend Fliess that memory and motive are inseparable, and its recollection would have no force or meaning unless it would be coupled to a motive or emotion. Therefore, we hypothesize that emotional-associated cues would directly prime the DLS through the amygdala to turn newly acquired behaviors into habits. We are adding new supporting insight for this hypothesis by using a duplex optogenetic stimulation system of the amygdala input in the DLS, modulating specific compulsive behaviors bidirectionally. These behavior modulations were accompanied by spine density modulations and intrinsic excitability changes in the SPNs of the DLS. Keywords: Compulsions; Habits; Optogenetics; Neuromodulation; Dorsolateral striatum; Amygdala.

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.

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