scholarly journals A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

2020 ◽  
Author(s):  
Krishnakanth Kondabolu ◽  
Natalie M. Doig ◽  
Olaoluwa Ayeko ◽  
Bakhtawer Khan ◽  
Alexandra Torres ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Subthalamic Nucleus ◽  
Ex Vivo ◽  
Cell Types ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Primary Input ◽  
Cholinergic Interneurons ◽  
Axonal Connections ◽  
Excitatory Responses

AbstractThe striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four-to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

scholarly journals The cryptic gonadotropin-releasing hormone neuronal system of human basal ganglia

2021 ◽  
Author(s):  
Katalin Skrapits ◽  
Miklós Sárvári ◽  
Imre Farkas ◽  
Balázs Göcz ◽  
Szabolcs Takács ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Basal Forebrain ◽  
Cell Types ◽  
Gonadotropin Releasing Hormone ◽  
Human Reproduction ◽  
Projection Neurons ◽  
Neuronal System ◽  
Releasing Hormone ◽  
Cholinergic Interneurons ◽  
Gnrh Neurons

Human reproduction is controlled by ~2,000 hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Here we report the discovery and characterization of additional 150-200,000 GnRH-synthesizing cells in the human basal ganglia and basal forebrain. Extrahypothalamic GnRH neurons were cholinergic. Though undetectable in adult rodents, the GnRH-GFP transgene was expressed transiently by caudate-putamen cholinergic interneurons in newborn transgenic mice. In slice electrophysiological studies, GnRH inhibited these interneurons via GnRHR1 autoreceptors. Whole-transcriptome analysis of cholinergic interneurons and medium spiny projection neurons laser-microdissected from the human putamen confirmed selective expression of GnRH and GnRHR1 autoreceptors in cholinergic cells and uncovered the detailed transcriptome profile and molecular connectome of these two cell types. Higher-order non-reproductive functions regulated by GnRH under physiological conditions in the human basal ganglia and basal forebrain require clarification. GnRH/GnRHR1 signaling as a potential therapeutic target in the treatment of neurodegenerative disorders affecting cholinergic neurocircuitries, including Parkinson’s and Alzheimer’s diseases, needs to be explored.

scholarly journals The cryptic gonadotropin-releasing hormone neuronal system of human basal ganglia

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Katalin Skrapits ◽  
Miklós Sárvári ◽  
Imre Farkas ◽  
Balázs Göcz ◽  
Szabolcs Takács ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Basal Forebrain ◽  
Gonadotropin Releasing Hormone ◽  
Human Reproduction ◽  
Projection Neurons ◽  
Marker Enzyme ◽  
Neuronal System ◽  
Releasing Hormone ◽  
Cholinergic Interneurons ◽  
Gnrh Neurons

Human reproduction is controlled by ~2,000 hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Here we report the discovery and characterization of additional ~150,000-200,000 GnRH-synthesizing cells in the human basal ganglia and basal forebrain. Nearly all extrahypothalamic GnRH neurons expressed the cholinergic marker enzyme choline acetyltransferase. Similarly, hypothalamic GnRH neurons were also cholinergic both in embryonic and adult human brains. Whole-transcriptome analysis of cholinergic interneurons and medium spiny projection neurons laser-microdissected from the human putamen showed selective expression of GNRH1 and GNRHR1 autoreceptors in the cholinergic cell population and uncovered the detailed transcriptome profile and molecular connectome of these two cell types. Higher-order non-reproductive functions regulated by GnRH under physiological conditions in the human basal ganglia and basal forebrain require clarification. The role and changes of GnRH/GnRHR1 signaling in neurodegenerative disorders affecting cholinergic neurocircuitries, including Parkinson's and Alzheimer's diseases, need to be explored.

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 Enhanced GABAergic Inhibition of Cholinergic Interneurons in the zQ175+/− Mouse Model of Huntington's Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Sean Austin O. Lim ◽  
D. James Surmeier
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Ex Vivo ◽  
Brain Slices ◽  
Projection Neurons ◽  
Gabaergic Inhibition ◽  
Indirect Pathway ◽  
Cholinergic Interneurons ◽  
Specific Alteration

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that initially manifests itself in the striatum. How intrastriatal circuitry is altered by the disease is poorly understood. To help fill this gap, the circuitry linking spiny projection neurons (SPNs) to cholinergic interneurons (ChIs) was examined using electrophysiological and optogenetic approaches in ex vivo brain slices from wildtype mice and zQ175+/− models of HD. These studies revealed a severalfold enhancement of GABAergic inhibition of ChIs mediated by collaterals of indirect pathway SPNs (iSPNs), but not direct pathway SPNs (dSPNs). This cell-specific alteration in synaptic transmission appeared in parallel with the emergence of motor symptoms in the zQ175+/− model. The adaptation had a presynaptic locus, as it was accompanied by a reduction in paired-pulse ratio but not in the postsynaptic response to GABA. The alterations in striatal GABAergic signaling disrupted spontaneous ChI activity, potentially contributing to the network dysfunction underlying the hyperkinetic phase of HD.

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.

Microcircuits of the Striatum

2017 ◽  
pp. 121-132
Author(s):  
Natalie M. Doig ◽  
J. Paul Bolam
Keyword(s):  
Basal Ganglia ◽  
Caudate Nucleus ◽  
Internal Capsule ◽  
Projection Neurons ◽  
Gabaergic Interneurons ◽  
Cholinergic Interneurons ◽  
Spiny Neurons ◽  
Output Neurons ◽  
Major Division ◽  
Selection Of

The striatum (or caudate-putamen, or caudate nucleus and putamen in those species in which they are divided by the internal capsule) is the major division of the basal ganglia, a group of structures involved in a variety of processes, including movement and cognitive and mnemonic functions. The striatum consists of a population of principal neurons, the medium-sized, densely spiny neurons (MSNs)—accounting for up to 97% of all neurons depending on species—which are the projection neurons of the striatum, several populations of GABAergic interneurons, and a population of cholinergic interneurons. The principal afferents of the striatum are glutamatergic, are derived from the cortex and thalamus, and mainly innervate the spines of MSNs. The essential computation performed by the striatum is the decision about which MSNs will fire, the consequence of which is altered firing of basal ganglia output neurons, and hence the selection of the basal ganglia–associated behavior.

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 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 Cholinergic Midbrain Afferents Modulate Striatal Circuits and Shape Encoding of Action Control

2018 ◽  
Author(s):  
Daniel Dautan ◽  
Icnelia Huerta-Ocampo ◽  
Miguel Valencia ◽  
Krishnakanth Kondabolu ◽  
Todor V. Gerdjikov ◽  
...  
Keyword(s):  
Cognitive Flexibility ◽  
Acetylcholine Release ◽  
Cholinergic Neurons ◽  
Behavioral Adaptation ◽  
Projection Neurons ◽  
Cholinergic Transmission ◽  
Cholinergic Interneurons ◽  
Shape Encoding ◽  
Tegmental Nuclei ◽  
Excitatory Responses

SummaryAssimilation of novel strategies into a consolidated action repertoire is a crucial function for behavioral adaptation and cognitive flexibility. Acetylcholine in the striatum plays a pivotal role in such adaptation and its release has been causally associated with the activity of cholinergic interneurons. Here we show that the midbrain, a previously unknown source of acetylcholine in the striatum, is a major contributor to cholinergic transmission in the striatal complex. Neurons of the pedunculopontine and laterodorsal tegmental nuclei synapse with striatal cholinergic interneurons and give rise to excitatory responses that, in turn, mediate inhibition of spiny projection neurons. Inhibition of acetylcholine release from midbrain terminals in the striatum impairs action shifting and mimics the effects observed following inhibition of acetylcholine release from striatal cholinergic interneurons. These results suggest the existence of two hierarchically-organized modes of cholinergic transmission in the striatum where cholinergic interneurons are modulated by cholinergic neurons of the midbrain.

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