scholarly journals Chemogenetic restoration of autonomous subthalamic nucleus activity ameliorates Parkinsonian motor dysfunction

2018 ◽  
Author(s):  
Eileen L. McIver ◽  
Hong-Yuan Chu ◽  
Jeremy F. Atherton ◽  
Kathleen E. Cosgrove ◽  
Jyothisri Kondapalli ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Subthalamic Nucleus ◽  
Projection Neuron ◽  
Motor Dysfunction ◽  
Projection Neurons ◽  
List Type ◽  
Oxygen Species ◽  
Striatal Projection Neurons ◽  
Autonomous Activity ◽  
Genetic Mouse Models

Highlightsdecorrelating autonomous STN activity was downregulated in both toxin and genetic models of PDelevation of D2-striatal projection neuron transmission was sufficient for downregulationdownregulation was dependent on activation of STN NMDA receptors and KATP channelschemogenetic restoration of autonomous spiking reduced synaptic patterning of STN neurons and PD motor dysfunctioneToCExcessive synaptic synchronization of STN activity is linked to the symptomatic expression of PD.McIver and colleagues describe the cellular and circuit mechanisms responsible for the loss of decorrelating autonomous STN activity in PD models and demonstrate that chemogenetic rescue of autonomous spiking reduces synaptically patterned STN activity and ameliorates Parkinsonian motor dysfunction.SUMMARYExcessive, synaptically-driven synchronization of subthalamic nucleus (STN) neurons is widely thought to contribute to akinesia, bradykinesia, and rigidity in Parkinson’s disease (PD). Electrophysiological, optogenetic, chemogenetic, genetic, 2-photon imaging, and pharmacological approaches revealed that the autonomous activity of STN neurons, which opposes synaptic synchronization, was downregulated in both toxin and genetic mouse models of PD.Loss of autonomous spiking was due to increased transmission of D2-striatal projection neurons, leading in the STN to elevated activation of NMDA receptors and generation of reactive oxygen species that promoted KATP channel opening.Chemogenetic restoration of autonomous firing in STN neurons reduced synaptic patterning and ameliorated Parkinsonian motor dysfunction, arguing that elevating intrinsic STN activity is an effective therapeutic intervention in PD.

scholarly journals Dysregulation of external globus pallidus-subthalamic nucleus network dynamics in Parkinsonian mice

2019 ◽  
Author(s):  
Ryan F. Kovaleski ◽  
Joshua W. Callahan ◽  
Marine Chazalon ◽  
Jérôme Baufreton ◽  
Mark D. Bevan
Keyword(s):  
Globus Pallidus ◽  
Subthalamic Nucleus ◽  
Wave Activity ◽  
Motor Dysfunction ◽  
Network Activity ◽  
Projection Neurons ◽  
D2 Dopamine Receptor ◽  
Striatal Projection Neurons ◽  
Cell Class ◽  
Compensatory Plasticity

AbstractReciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key, centrally-positioned network within the basal ganglia, a group of subcortical brain nuclei critical for voluntary movement. In Parkinson’s disease (PD) and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Using cell class-specific optogenetic identification and inhibition approaches during cortical slow-wave activity and activation, we report that in dopamine-depleted mice 1) D2 dopamine receptor expressing striatal projection neurons (D2-SPNs) are hyperactive 2) prototypic parvalbumin (PV)-expressing GPe neurons are excessively patterned by D2-SPNs 3) despite being disinhibited, STN neurons are not hyperactive 4) the STN opposes rather than facilitates abnormal striatopallidal patterning. Together with recent studies, these data argue that in Parkinsonian mice abnormal, temporally offset PV GPe neuron and STN activity results from increased striatopallidal transmission and that compensatory plasticity within the STN prevents its hyperactivity.

scholarly journals Complete connectomic reconstruction of olfactory projection neurons in the fly brain

2020 ◽  
Author(s):  
A.S. Bates ◽  
P. Schlegel ◽  
R.J.V. Roberts ◽  
N. Drummond ◽  
I.F.M. Tamimi ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Olfactory System ◽  
Neuronal Cell ◽  
Building Blocks ◽  
Cell Types ◽  
Projection Neuron ◽  
Brain Regions ◽  
Projection Neurons ◽  
List Type ◽  
Lateral Horn

AbstractNervous systems contain sensory neurons, local neurons, projection neurons and motor neurons. To understand how these building blocks form whole circuits, we must distil these broad classes into neuronal cell types and describe their network connectivity. Using an electron micrograph dataset for an entire Drosophila melanogaster brain, we reconstruct the first complete inventory of olfactory projections connecting the antennal lobe, the insect analogue of the mammalian olfactory bulb, to higher-order brain regions in an adult animal brain. We then connect this inventory to extant data in the literature, providing synaptic-resolution ‘holotypes’ both for heavily investigated and previously unknown cell types. Projection neurons are approximately twice as numerous as reported by light level studies; cell types are stereotyped, but not identical, in cell and synapse numbers between brain hemispheres. The lateral horn, the insect analogue of the mammalian cortical amygdala, is the main target for this olfactory information and has been shown to guide innate behaviour. Here, we find new connectivity motifs, including: axo-axonic connectivity between projection neurons; feedback and lateral inhibition of these axons by local neurons; and the convergence of different inputs, including non-olfactory inputs and memory-related feedback onto lateral horn neurons. This differs from the configuration of the second most prominent target for olfactory projection neurons: the mushroom body calyx, the insect analogue of the mammalian piriform cortex and a centre for associative memory. Our work provides a complete neuroanatomical platform for future studies of the adult Drosophila olfactory system.HighlightsFirst complete parts list for second-order neurons of an adult olfactory systemQuantification of left-right stereotypy in cell and synapse numberAxo-axonic connections form hierarchical communities in the lateral hornLocal neurons and memory-related feedback target projection neuron axons

scholarly journals Inhibition of Phosphodiesterase 10A Increases the Responsiveness of Striatal Projection Neurons to Cortical Stimulation

2008 ◽  
Vol 328 (3) ◽  
pp. 785-795 ◽  
Author(s):  
Sarah Threlfell ◽  
Stephen Sammut ◽  
Frank S. Menniti ◽  
Christopher J. Schmidt ◽  
Anthony R. West
Keyword(s):  
Cortical Stimulation ◽  
Projection Neurons ◽  
Striatal Projection Neurons ◽  
Phosphodiesterase 10A

Differential Involvement of Projection Neurons During Emergence of Spontaneous Activity in the Developing Avian Hindbrain

2009 ◽  
Vol 101 (2) ◽  
pp. 591-602 ◽  
Author(s):  
Hiraku Mochida ◽  
Gilles Fortin ◽  
Jean Champagnat ◽  
Joel C. Glover
Keyword(s):  
Spontaneous Activity ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Charge Coupled Device ◽  
Neuron Populations ◽  
Motor Nerves ◽  
Differential Involvement ◽  
A Charge ◽  
The Brain ◽  
Calcium Green

To better characterize the emergence of spontaneous neuronal activity in the developing hindbrain, spontaneous activity was recorded optically from defined projection neuron populations in isolated preparations of the brain stem of the chicken embryo. Ipsilaterally projecting reticulospinal (RS) neurons and several groups of vestibuloocular (VO) neurons were labeled retrogradely with Calcium Green-1 dextran amine and spontaneous calcium transients were recorded using a charge-coupled-device camera mounted on a fluorescence microscope. Simultaneous extracellular recordings were made from one of the trigeminal motor nerves (nV) to register the occurrence of spontaneous synchronous bursts of activity. Two types of spontaneous activity were observed: synchronous events (SEs), which occurred in register with spontaneous bursts in nV once every few minutes and were tetrodotoxin (TTX) dependent, and asynchronous events (AEs), which occurred in the intervals between SEs and were TTX resistant. AEs occurred developmentally before SEs and were in general smaller and more variable in amplitude than SEs. SEs appeared at the same stage as nV bursts early on embryonic day 4, first in RS neurons and then in VO neurons. All RS neurons participated equally in SEs from the outset, whereas different subpopulations of VO neurons participated differentially, both in terms of the proportion of neurons that exhibited SEs, the fidelity with which the SEs in individual neurons followed the nV bursts, and the developmental stage at which SEs appeared and matured. The results show that spontaneous activity is expressed heterogeneously among hindbrain projection neuron populations, suggesting its differential involvement in the formation of different functional neuronal circuits.

Differences in synaptic integration between direct and indirect striatal projection neurons: Role of CaV 3 channels

Synapse ◽  
2018 ◽  
Vol 73 (4) ◽  
pp. e22079 ◽  
Author(s):  
Brisa García-Vilchis ◽  
Paola Suárez ◽  
Miguel Serrano-Reyes ◽  
Mario Arias-García ◽  
Dagoberto Tapia ◽  
...  
Keyword(s):  
Synaptic Integration ◽  
Projection Neurons ◽  
Striatal Projection Neurons

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.

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