Disturbed network activities of GABAergic basal ganglia projection neurons in Parkinsonism

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.

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Control of Basal Ganglia Output by Direct and Indirect Pathway Projection Neurons

Journal of Neuroscience ◽

10.1523/jneurosci.1278-13.2013 ◽

2013 ◽

Vol 33 (47) ◽

pp. 18531-18539 ◽

Cited By ~ 200

Author(s):

B. S. Freeze ◽

A. V. Kravitz ◽

N. Hammack ◽

J. D. Berke ◽

A. C. Kreitzer

Keyword(s):

Basal Ganglia ◽

Projection Neurons ◽

Indirect Pathway

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

eLife ◽

10.7554/elife.67714 ◽

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.

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The inhibitory microcircuit of the substantia nigra provides feedback gain control of the basal ganglia output

eLife ◽

10.7554/elife.02397 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 23

Author(s):

Jennifer Brown ◽

Wei-Xing Pan ◽

Joshua Tate Dudman

Keyword(s):

Basal Ganglia ◽

Substantia Nigra ◽

Feedback Inhibition ◽

Gain Control ◽

Feedback Gain ◽

Projection Neurons ◽

Tonic Firing ◽

Canonical Models ◽

Firing Rates ◽

Engineered Systems

Dysfunction of the basal ganglia produces severe deficits in the timing, initiation, and vigor of movement. These diverse impairments suggest a control system gone awry. In engineered systems, feedback is critical for control. By contrast, models of the basal ganglia highlight feedforward circuitry and ignore intrinsic feedback circuits. In this study, we show that feedback via axon collaterals of substantia nigra projection neurons control the gain of the basal ganglia output. Through a combination of physiology, optogenetics, anatomy, and circuit mapping, we elaborate a general circuit mechanism for gain control in a microcircuit lacking interneurons. Our data suggest that diverse tonic firing rates, weak unitary connections and a spatially diffuse collateral circuit with distinct topography and kinetics from feedforward input is sufficient to implement divisive feedback inhibition. The importance of feedback for engineered systems implies that the intranigral microcircuit, despite its absence from canonical models, could be essential to basal ganglia function.

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Environment-based object values learned by local network in the striatum tail

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2013623118 ◽

2021 ◽

Vol 118 (4) ◽

pp. e2013623118

Author(s):

Jun Kunimatsu ◽

Shinya Yamamoto ◽

Kazutaka Maeda ◽

Okihide Hikosaka

Keyword(s):

Basal Ganglia ◽

Selective Inhibition ◽

Switching Behavior ◽

Local Network ◽

Projection Neurons ◽

Inhibitory Input ◽

Neuronal Mechanism ◽

Fast Spiking ◽

Value Learning

Basal ganglia contribute to object-value learning, which is critical for survival. The underlying neuronal mechanism is the association of each object with its rewarding outcome. However, object values may change in different environments and we then need to choose different objects accordingly. The mechanism of this environment-based value learning is unknown. To address this question, we created an environment-based value task in which the value of each object was reversed depending on the two scene-environments (X and Y). After experiencing this task repeatedly, the monkeys became able to switch the choice of object when the scene-environment changed unexpectedly. When we blocked the inhibitory input from fast-spiking interneurons (FSIs) to medium spiny projection neurons (MSNs) in the striatum tail by locally injecting IEM-1460, the monkeys became unable to learn scene-selective object values. We then studied the mechanism of the FSI-MSN connection. Before and during this learning, FSIs responded to the scenes selectively, but were insensitive to object values. In contrast, MSNs became able to discriminate the objects (i.e., stronger response to good objects), but this occurred clearly in one of the two scenes (X or Y). This was caused by the scene-selective inhibition by FSI. As a whole, MSNs were divided into two groups that were sensitive to object values in scene X or in scene Y. These data indicate that the local network of striatum tail controls the learning of object values that are selective to the scene-environment. This mechanism may support our flexible switching behavior in various environments.

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A Computational Model of Thalamic Tonic-burst Motor Projection Neurons and Their Regulation by Pallidal GABAergic Neurons

10.1101/806653 ◽

2019 ◽

Author(s):

Md Ali Azam ◽

Deepak Kumbhare ◽

Ravi Hadimani ◽

Jamie Toms ◽

Mark S. Baron ◽

...

Keyword(s):

Basal Ganglia ◽

Computational Model ◽

Gabaergic Neurons ◽

Neuronal Firing ◽

Projection Neurons ◽

Thalamic Neurons ◽

Firing Patterns ◽

Firing Mode ◽

Low Threshold

AbstractA modified computational model of pallidal receiving ventral oral posterior (Vop) thalamocortical motor relay neurons was adapted based on in vivo observations in our rodent model. The model accounts for different input neuronal firing patterns in the primary motor output nucleus of basal ganglia, the globus pallidus interna (GPi) and subsequently generate Vop outputs as observed in vivo under different conditions. Hyperpolarizing input de-inactivates its T-type calcium channel and sets the thalamic neurons in the preferable burst firing mode over a tonic mode and induces low threshold spikes (LTS). In the hyperpolarized state, both spontaneously and in response to excitatory (e.g. corticothalamic) inputs, burst spiking occurs on the crest of the LTS. By selecting and determining the timing and extent of opening of thalamic T-type calcium channels via GABAergic hyperpolarizing input, the GPi precisely regulates Vop-cortical burst motor signaling. Different combinations of tonic, burst, irregular tonic and irregular burst inputs from GPi were used to verify our model. In vivo data obtained from recordings in the entopedunucular nucleus (EP; rodent equivalent of GPi) from resting head restrained healthy and dystonic rats were used to simulate the influences of different inputs from GPi. In all cases, GPi neuronal firing patterns are demonstrated to act as a firing mode selector for thalamic Vop neurons.

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Parallel Movement-suppressing Striatal Output Pathways

10.1101/2020.09.02.273615 ◽

2020 ◽

Author(s):

Qiaoling Cui ◽

Xixun Du ◽

Isaac Y. M. Chang ◽

Arin Pamukcu ◽

Varoth Lilascharoen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Basal Ganglia ◽

Body Movement ◽

Disease Model ◽

Projection Neurons ◽

Indirect Pathway ◽

Direct Pathway ◽

Striatal Projection Neurons ◽

6 Hydroxydopamine

AbstractThe classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and how they are involved in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting role of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson’s disease that has not been previously considered.Significance statementIn the classic basal ganglia model, the striatum is described as a divergent structure—it controls motor and adaptive functions through two segregated, opponent output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal sub-pathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this sub-pathway undergoes plastic changes in a Parkinson’s disease model. In particular, our results suggest that the increase in strength of this sub-pathway contributes to the slowness or reduced movements observed in Parkinson’s disease.

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

10.1101/2021.03.04.433872 ◽

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.

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Interaction between cognitive and motor cortico-basal ganglia loops during decision making: a computational study

Journal of Neurophysiology ◽

10.1152/jn.00026.2013 ◽

2013 ◽

Vol 109 (12) ◽

pp. 3025-3040 ◽

Cited By ~ 39

Author(s):

M. Guthrie ◽

A. Leblois ◽

A. Garenne ◽

T. Boraud

Keyword(s):

Decision Making ◽

Basal Ganglia ◽

Computational Study ◽

Selection Process ◽

Action Selection ◽

External Input ◽

Projection Neurons ◽

Cognitive Level ◽

Striatal Projection Neurons ◽

Previous Modeling Study

In a previous modeling study, Leblois et al. (2006) demonstrated an action selection mechanism in cortico-basal ganglia loops based on competition between the positive feedback, direct pathway through the striatum and the negative feedback, hyperdirect pathway through the subthalamic nucleus. The present study investigates how multiple level action selection could be performed by the basal ganglia. To do this, the model is extended in a manner consistent with known anatomy and electrophysiology in three main areas. First, two-level decision making has been incorporated, with a cognitive level selecting based on cue shape and a motor level selecting based on cue position. We show that the decision made at the cognitive level can be used to bias the decision at the motor level. We then demonstrate that, for accurate transmission of information between decision-making levels, low excitability of striatal projection neurons is necessary, a generally observed electrophysiological finding. Second, instead of providing a biasing signal between cue choices as an external input to the network, we show that the action selection process can be driven by reasonable levels of noise. Finally, we incorporate dopamine modulated learning at corticostriatal synapses. As learning progresses, the action selection becomes based on learned visual cue values and is not interfered with by the noise that was necessary before learning.

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Opposite Functions of Histamine H1 and H2 Receptors and H3 Receptor in Substantia Nigra Pars Reticulata

Journal of Neurophysiology ◽

10.1152/jn.00148.2006 ◽

2006 ◽

Vol 96 (3) ◽

pp. 1581-1591 ◽

Cited By ~ 43

Author(s):

Fu-Wen Zhou ◽

Jian-Jun Xu ◽

Yu Zhao ◽

Mark S. LeDoux ◽

Fu-Ming Zhou

Keyword(s):

Basal Ganglia ◽

Substantia Nigra ◽

Inhibitory Neuron ◽

Projection Neuron ◽

Receptor Activation ◽

Histamine Receptors ◽

Receptor Expression ◽

Substantia Nigra Pars Reticulata ◽

Projection Neurons ◽

Neuron Firing

The substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus. Inhibitory outputs from SNr are encoded in spike frequency and pattern of the inhibitory SNr projection neurons. SNr output intensity and pattern are often abnormal in movement disorders of basal ganglia origin. In Parkinson’s disease, histamine innervation and histamine H3 receptor expression in SNr may be increased. However, the functional consequences of these alterations are not known. In this study, whole cell patch-clamp recordings were used to elucidate the function of different histamine receptors in SNr. Histamine increased SNr inhibitory projection neuron firing frequency and thus inhibitory output. This effect was mediated by activation of histamine H1 and H2 receptors that induced inward currents and depolarization. In contrast, histamine H3 receptor activation hyperpolarized and inhibited SNr inhibitory projection neurons, thus decreasing the intensity of basal ganglia output. By the hyperpolarization, H3 receptor activation also increased the irregularity of the interspike intervals or changed the pattern of SNr inhibitory neuron firing. H3 receptor–mediated effects were normally dominated by those mediated by H1 and H2 receptors. Furthermore, endogenously released histamine provided a tonic, H1 and H2 receptor–mediated excitation that helped keep SNr inhibitory projection neurons sufficiently depolarized and spiking regularly. These results suggest that H1 and H2 receptors and H3 receptor exert opposite effects on SNr inhibitory projection neurons. Functional balance of these different histamine receptors may contribute to the proper intensity and pattern of basal ganglia output and, as a consequence, exert important effects on motor control.

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