Rabies screen reveals GPe control of cocaine-triggered plasticity

Beier, Kevin T.; Kim, Christina K.; Hoerbelt, Paul; Hung, Lin W.; Heifets, Boris D.; DeLoach, Katherine E.; Mosca, Timothy J.; Neuner, Sophie; Deisseroth, Karl; Luo, Liqun; Malenka, Robert C.

doi:10.1038/nature23888

Cited by 107 publications

(143 citation statements)

References 44 publications

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“…(4) Rabies virus spreads polysynaptically among helper‐expressing graft neurons, and may therefore bias the starter population toward more highly interconnected neuronal subtypes. (5) For two identical presynaptic host neurons, one may be more likely to be labeled with rabies due to higher neuronal activity…”

Section: Rabies Tracing Is Useful But Care Should Be Taken To Avoid Omentioning

confidence: 99%

Transsynaptic tracing and its emerging use to assess graft-reconstructed neural circuits

2020

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Fetal neural progenitor grafts have been evaluated in preclinical animal models of spinal cord injury and Parkinson's disease for decades, but the initial reliance on primary tissue as a cell source limited the scale of their clinical translatability. With the development of robust methods to differentiate human pluripotent stem cells to specific neural subtypes, cell replacement therapy holds renewed promise to treat a variety of neurodegenerative diseases and injuries at scale. As these cell sources are evaluated in preclinical models, new transsynaptic tracing methods are making it possible to study the connectivity between host and graft neurons with greater speed and detail than was previously possible. To date, these studies have revealed that widespread, long-lasting, and anatomically appropriate synaptic contacts are established between host and graft neurons, as well as new aspects of host-graft connectivity which may be relevant to clinical cell replacement therapy.It is not yet clear, however, whether the synaptic connectivity between graft and host neurons is as cell-type specific as it is in the endogenous nervous system, or whether that connectivity is responsible for the functional efficacy of cell replacement therapy. Here, we review evidence suggesting that the new contacts established between host and graft neurons may indeed be cell-type specific, and how transsynaptic tracing can be used in the future to further elucidate the mechanisms of graft-mediated functional recovery in spinal cord injury and Parkinson's disease.

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Section: Rabies Tracing Is Useful But Care Should Be Taken To Avoid Omentioning

confidence: 99%

Transsynaptic tracing and its emerging use to assess graft-reconstructed neural circuits

2020

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“…To investigate the behavioral functions of DR Sert →OFC and DR Sert →CeA neurons, we employed two complementary approaches. In the first (gain-of-function) approach, we expressed the hM3Dq chemogenetic activator (Armbruster et al, 2007) in DR Sert →OFC or DR Sert →CeA neurons by unilaterally injecting AAV retro -FLEx-Flp into the OFC or CeA of Sert-Cre mice, and Flp-dependent hM3Dq (Beier et al, 2017) into the DR in the experimental group. In the two control groups for each experimental group, we replaced either hM3Dq with GFP or Sert-Cre mice with wild-type mice ( Figure 5A 1 , B 1 ).…”

Section: Both Ofc-and Cea-projecting Dr Serotonin Neurons Suppress Lomentioning

confidence: 99%

Anatomical, Physiological, and Functional Heterogeneity of the Dorsal Raphe Serotonin System

Ren

Friedmann

Xiong

et al. 2018

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SummaryThe dorsal raphe (DR) constitutes a major serotonergic input to the forebrain, and modulates diverse functions and brain states including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single, homogeneous population. Using viral-genetic methods, we found that subcortical-vs. cortical-projecting serotonin neurons have distinct cell body distributions within the DR and different degrees of coexpressing a vesicular glutamate transporter. Further, the amygdala-and frontal cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gainand loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal cortex-projecting neurons promote active coping in face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.

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“…The basal ganglia (BG) are a collection of subcortical nuclei implicated in motor planning, action selection (Albin et al, 1989), and habit formation (Yin and Knowlton, 2006), and they are also the major site of pathology and dysfunction in PD following the progressive loss of substantia nigra dopamine-synthesizing neurons (Hammond et al, 2007). The external globus pallidus (GP) is a GABAergic nucleus composed of several subtypes of projection neurons (Abdi et al, 2015;Dodson et al, 2015;Herná ndez et al, 2015;Mastro et al, 2014) that holds a pivotal position in the circuit through its widespread projections to all BG nuclei (Beier et al, 2017;Kita, 2007;Saunders et al, 2016) and the cortex (Saunders et al, 2015). The activity of GP neurons is controlled by extrinsic GABAergic inputs from striatal indirect-pathway medium spiny neurons (iSPNs) and intrinsic pallidal local collaterals (Miguelez et al, 2012;Rav-Acha et al, 2005;Sims et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents

et al. 2018

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The external globus pallidus (GP) is a key GABAergic hub in the basal ganglia (BG) circuitry, a neuronal network involved in motor control. In Parkinson's disease (PD), the rate and pattern of activity of GP neurons are profoundly altered and contribute to the motor symptoms of the disease. In rodent models of PD, the striato-pallidal pathway is hyperactive, and extracellular GABA concentrations are abnormally elevated in the GP, supporting the hypothesis of an alteration of neuronal and/or glial clearance of GABA. Here, we discovered the existence of persistent GABAergic tonic inhibition in GP neurons of dopamine-depleted (DD) rodent models. We showed that glial GAT-3 transporters are downregulated while neuronal GAT-1 function remains normal in DD rodents. Finally, we showed that blocking GAT-3 activity in vivo alters the motor coordination of control rodents, suggesting that GABAergic tonic inhibition in the GP contributes to the pathophysiology of PD.

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Rabies screen reveals GPe control of cocaine-triggered plasticity

Cited by 107 publications

References 44 publications

Transsynaptic tracing and its emerging use to assess graft-reconstructed neural circuits

Transsynaptic tracing and its emerging use to assess graft-reconstructed neural circuits

Anatomical, Physiological, and Functional Heterogeneity of the Dorsal Raphe Serotonin System

GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents

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