Browsing by Author "Huang, Shuo"

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    Cav3.2 calcium channel interactions with the epithelial sodium channel ENaC
    (2019-02-08) Garcia-Caballero, Agustin; Gandini, Maria A; Huang, Shuo; Chen, Lina; Souza, Ivana A; Dang, Yan L; Stutts, M. J; Zamponi, Gerald W
    Abstract This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β-ENaC subunits showed overlapping expression with endogenous Cav3.2 calcium channels in the thalamus and hypothalamus as detected by immunostaining. Moreover, β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Mutation of a cluster of lysines present in the intracellular N-terminus region of β-ENaC (K4R/ K5R/ K9R/ K16R/ K23R) reduced interactions with Cav3.2 calcium channels. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. T-type current density was increased when fully assembled αβγ-ENaC channels were transiently expressed in CAD cells, a neuronal derived cell line. Altogether, these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues.
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    Peripheral nerve injury-induced alterations in VTA neuron firing properties
    (2019-11-04) Huang, Shuo; Borgland, Stephanie L; Zamponi, Gerald W
    Abstract The ventral tegmental area (VTA) is one of the main brain regions harboring dopaminergic (DA) neurons, and plays important roles in reinforcement and motivation. Recent studies have indicated that DA neurons not only respond to rewarding stimuli, but also to noxious stimuli. Furthermore, VTA DA neurons undergo plasticity during chronic pain. Lateral and medial VTA neurons project to different brain areas, and have been characterized via their distinct electrophysiological properties. In this study, we characterized electrophysiological properties of lateral and medial VTA DA neurons using DAT-cre reporter mice, and examined their plasticity during neuropathic pain states. We observed various DA subpopulations in both the lateral and medial VTA, as defined by action potential firing patterns, independently of synaptic inputs. Our results demonstrated that lateral and medial VTA DA neurons undergo differential plasticity after peripheral nerve injury that leads to neuropathic pain. However, these changes only reside in specific DA subpopulations. This study suggests that lateral and medial VTA DA neurons are differentially affected during neuropathic pain conditions, and emphasizes the importance of subpopulation specificity when targeting VTA DA neurons for treatment of neuropathic pain.
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    The role of the mesocortical dopaminergic pathway in the processing of chronic pain signals
    (2020-04-27) Huang, Shuo; Zamponi, Gerald W.; Borgland, Stephanie Laureen; Bains, Jaideep Singh; Trang, Tuan; Gordon, Grant Robert J.; Smith, Peter A.
    Chronic pain is a debilitating condition which is prevalent in terminal diseases and aged populations. Pain medications are frequently ineffective for chronic use due to resistance to treatment. This is because the pathophysiology, especially cerebral mechanisms of chronic pain is not fully understood. The processing of chronic pain signals is mainly through the cortical areas, the limbic system, and the nucleus accumbens in the brain, which outputs affect downstream targets exerting top-down control. These brain areas mediate emotional and salience-related processing of pain signals, forming the ‘pain matrix’. The ‘pain matrix’ refers to the brain regions mediating different functions such as valance, salience, emotion, and memory that are able to interact with each other to allow pain perception to emerge. The ‘pain matrix’ also process reward information. Signals from pain and reward converge in the ‘pain matrix’and dopamine modulates the emotional and salience aspects of both. The medial prefrontal cortex (mPFC) is a cortical region that controls many executive functions such as attention, working memory, and learning. The mPFC is involved in pain perception, and undergoes plasticity during development of chronic pain. The PFC receives dopaminergic inputs from the ventral tegmental area (VTA), forming the mecoscortical pathway. The mesocortical circuit modulates neuronal plasticity in the mPFC. This modulation has been shown to affect working memory and aversion; however, whether and how the VTA-mPFC dopaminergic inputs are involved in chronic pain remains incompletely understood. This PhD dissertation examines the hypothesis that VTA dopaminergic neurons undergo plasticity during chronic pain states, and projections from these neurons to the mPFC modulate chronic pain-associated behaviours. Dopaminergic subpopulations of both the lateral and medial VTA were defined by action potential firing patterns. However, plasticity induced by neuropathic chronic pain only resides in specific dopaminergic subpopulations. In addition, dopaminergic subpopulations of lateral and medial VTA are differentially altered after induction of neuropathic pain. Using optogenetic approaches to selectively target dopaminergic inputs to the mPFC, we found that phasic activation of VTA-mPFC dopaminergic inputs reduced mechanical hypersensitivity during neuropathic pain states. Photostimulation of dopamine input to the mPFC also induced a preference for photostimulation-paired context only in mice with neuropathic pain. Fiber photometry imaging of calcium signals demonstrated that dopamine enhances the activity of mPFC neurons projecting to the ventrolateral periaquductal gray, a crucial downstream target for top-down regulation of pain states. Altogether, this study indicates an important modulatory role of mesocortical dopamine in cerebral chronic pain signaling.