Browsing by Author "Zhang, Zizhen"

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    Analgesic effects of optogenetic inhibition of basolateral amygdala inputs into the prefrontal cortex in nerve injured female mice
    (2019-12-04) Gadotti, Vinicius M; Zhang, Zizhen; Huang, Junting; Zamponi, Gerald W
    Abstract Peripheral nerve injury can lead to remodeling of brain circuits, and this can cause chronification of pain. We have recently reported that male mice subjected to spared injury of the sciatic nerve undergo changes in the function of the medial prefrontal cortex (mPFC) that culminate in reduced output of layer 5 pyramidal cells. More recently, we have shown that this is mediated by alterations in synaptic inputs from the basolateral amygdala (BLA) into GABAergic interneurons in the mPFC. Optogenetic inhibition of these inputs reversed mechanical allodynia and thermal hyperalgesia in male mice. It is known that the processing of pain signals can exhibit marked sex differences. We therefore tested whether the dysregulation of BLA to mPFC signaling is equally altered in female mice. Injection of AAV-Arch3.0 constructs into the BLA followed by implantation of a fiberoptic cannula into the mPFC in sham and SNI operated female mice was carried out, and pain behavioral responses were measured in response to yellow light mediated activation of this inhibitory opsin. Our data reveal that Arch3.0 activation leads to a marked increase in paw withdrawal thresholds and latencies in response to mechanical and thermal stimuli, respectively. However, we did not observe nerve injury-induced changes in mPFC layer 5 pyramidal cell output in female mice. Hence, the observed light-induced analgesic effects may be due to compensation for dysregulated neuronal circuits downstream of the mPFC.
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    Corticofugal postsynaptic potentials and their frequency specific impact on auditory midbrain neurons
    (2018-07-04) Qi, Jiyao; Yan, Jun; Stell, William K.; Thompson, Roger J.; Zhang, Zizhen; Eggermont, Jos Jan
    Neuroanatomical studies reveal a great amount of descending (corticofugal) projections from the primary auditory cortex (AI) to all subcortical regions such as the central nucleus of the inferior colliculus (ICc). In the past 20 years, physiological studies have shown that the corticofugal system implements a highly frequency-specific modulation of sound information processing in the ascending auditory system. Specifically, focal electrical stimulation of the AI (ESAI) facilitates subcortical neurons when the best frequency (BF) of subcortical neurons is identical to the BF of cortical neurons (physiologically matched). In contrast, ESAI inhibits subcortical neurons when their BFs are different (unmatched). ESAI also shifts the BFs of unmatched subcortical neurons towards the BF of cortical neurons. While previous physiological findings have been achieved using extracellular recordings, to date, little is known about the cellular mechanism(s) underlying such highly, frequency-specific corticofugal modulation. An immediate question this raises is: what corticofugal postsynaptic potentials may be found in matched and unmatched subcortical neurons? A subsequent, critical question to ask is how the corticofugal postsynaptic potentials interplay with ascending (tone-evoked) postsynaptic potentials. This thesis sets out to answer these two questions by examining the corticocolliculuar (AI-to-ICc) synaptic activities in a mouse model. The membrane potential of ICc neurons was recorded by in vivo whole-cell patch current-clamp. I found that ESAI primarily evoked excitatory postsynaptic potential (EPSP) in ICc neurons. ESAI-evoked ICc EPSPs were larger in matched than in unmatched neurons. I further examined how ESAI-evoked EPSPs influence the tone-evoked EPSPs of ICc neurons. My data show that ESAI-evoked EPSPs facilitated tone-evoked EPSPs of matched neurons, but inhibited tone-evoked EPSPs of unmatched neurons. My findings reveal for the first time that corticofugal postsynaptic potentials are excitatory and frequency-dependent, and they interact with the ascending synaptic inputs in a frequency-specific manner.
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    Inhibitory insula-ACC projections modulate affective but not sensory aspects of neuropathic pain
    (2023-08-21) Alonso-Matielo, Heloísa; Zhang, Zizhen; Gambeta, Eder; Huang, Junting; Chen, Lina; de Melo, Gabriel O.; Dale, Camila S.; Zamponi, Gerald W.
    Abstract The insula and anterior cingulate cortex (ACC) are brain regions that undergo structural and functional reorganization in neuropathic pain states. Here, we aimed to study inhibitory parvalbumin positive (PV+) posterior insula (pIC) to posterior ACC (pACC) projections, and to evaluate the effects of direct optogenetic manipulation of such projections on mechanical nociception and spontaneous ongoing pain in mice with Spared Nerve Injury (SNI). CTB488 tract-tracing in male PVCrexAi9 mice revealed a small proportion of PV+ projections from the pIC to the pACC. Electrophysiological analysis confirmed the existence of synaptic inputs into the pACC by pIC GABAergic cells. Optogenetic stimulation of these pathways did not change mechanical nociception, but induced conditioned place preference behavior responses. Our results suggest the presence of inhibitory projections between the pIC and the pACC which are able to selectively modulate affective aspects of neuropathic pain.
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    Spared nerve injury leads to reduced activity of neurons projecting from the ventrolateral periaqueductal gray to the locus coeruleus
    (2024-07-24) Yu, Wing L.; Zhang, Zizhen; Zamponi, Gerald W.
    Abstract The ventrolateral periaqueductal gray (vlPAG) serves as a central hub for descending pain modulation. It receives upstream projections from the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (vlOFC), and projects downstream to the locus coeruleus (LC) and the rostroventral medulla (RVM). While much research has focused on upstream circuits and the LC-RVM connection, less is known about the PAG-LC circuit and its involvement in neuropathic pain. Here we examined the intrinsic electrophysiological properties of vlPAG-LC projecting neurons in Sham and spared nerve injury (SNI) operated mice. Injection of the retrotracer Cholera Toxin Subunit B (CTB-488) into the LC allowed the identification of LC-projecting neurons in the vlPAG. Electrophysiological recordings from CTB-488 positive cells revealed that both GABAergic and glutamatergic cells that project to the LC exhibited reduced intrinsic excitability after peripheral nerve injury. By contrast, CTB-488 negative cells did not exhibit alterations in firing properties after SNI surgery. An SNI-induced reduction of LC projecting cells was confirmed with c-fos labeling. Hence, SNI induces plasticity changes in the vlPAG that are consistent with a reduction in the descending modulation of pain signals.
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    The IL33 receptor ST2 contributes to mechanical hypersensitivity in mice with neuropathic pain
    (2021-02-17) Huang, Junting; Gadotti, Vinicius M; Zhang, Zizhen; Zamponi, Gerald W
    Abstract Pathogen infection triggers pain via activation of the innate immune system. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are the main components of innate immunity and have been implicated in pain signaling. We previously revealed that the TLR2-NLRP3-IL33 pathway mediates inflammatory pain responses during hyperactivity of innate immunity. However, their roles in neuropathic pain had remained unclear. Here we report that although knockout of TLR2 or NLRP3 does not affect spared nerve injury (SNI)-induced neuropathic pain, intrathecal inhibition of IL33/ST2 signaling with ST2 neutralizing antibodies reverses mechanical thresholds in SNI mice compared to PBS vehicle treated animals. This effect indicates a universal role of IL33 in both inflammatory and neuropathic pain states, and that targeting the IL33/ST2 axis could be a potential therapeutic approach for pain treatment.