Browsing by Subject "Plasticity"

Now showing 1 - 7 of 7
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    Chemoreception and neuroplasticity in respiratory circuits
    (Elsevier, 2017-01) Barnett, William H.; Abdala, Ana P.; Paton, Julian F. R.; Rybak, Ilya A.; Zoccal, Daniel B.; Molkov, Yaroslav I.; Mathematical Sciences, School of Science
    The respiratory central pattern generator must respond to chemosensory cues to maintain oxygen (O2) and carbon dioxide (CO2) homeostasis in the blood and tissues. To do this, sensorial cells located in the periphery and central nervous system monitor the arterial partial pressure of O2 and CO2 and initiate respiratory and autonomic reflex adjustments in conditions of hypoxia and hypercapnia. In conditions of chronic intermittent hypoxia (CIH), repeated peripheral chemoreceptor input mediated by the nucleus of the solitary tract induces plastic changes in respiratory circuits that alter baseline respiratory and sympathetic motor outputs and result in chemoreflex sensitization, active expiration, and arterial hypertension. Herein, we explored the hypothesis that the CIH-induced neuroplasticity primarily consists of increased excitability of pre-inspiratory/inspiratory neurons in the pre-Bötzinger complex. To evaluate this hypothesis and elucidate neural mechanisms for the emergence of active expiration and sympathetic overactivity in CIH-treated animals, we extended a previously developed computational model of the brainstem respiratory-sympathetic network to reproduce experimental data on peripheral and central chemoreflexes post-CIH. The model incorporated neuronal connections between the 2nd-order NTS neurons and peripheral chemoreceptors afferents, the respiratory pattern generator, and sympathetic neurons in the rostral ventrolateral medulla in order to capture key features of sympathetic and respiratory responses to peripheral chemoreflex stimulation. Our model identifies the potential neuronal groups recruited during peripheral chemoreflex stimulation that may be required for the development of inspiratory, expiratory and sympathetic reflex responses. Moreover, our model predicts that pre-inspiratory neurons in the pre-Bötzinger complex experience plasticity of channel expression due to excessive excitation during peripheral chemoreflex. Simulations also show that, due to positive interactions between pre-inspiratory neurons in the pre-Bötzinger complex and expiratory neurons in the retrotrapezoid nucleus, increased excitability of the former may lead to the emergence of the active expiratory pattern at normal CO2 levels found after CIH exposure. We conclude that neuronal type specific neuroplasticity in the pre-Bötzinger complex induced by repetitive episodes of peripheral chemoreceptor activation by hypoxia may contribute to the development of sympathetic over-activity and hypertension.
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    DLK signaling in axotomized neurons triggers complement activation and loss of upstream synapses
    (Elsevier, 2024) Asghari Adib, Elham; Shadrach, Jennifer L.; Reilly-Jankowiak, Lauren; Dwivedi, Manish K.; Rogers, Abigail E.; Shahzad, Shameena; Passino, Ryan; Giger, Roman J.; Pierchala, Brian A.; Collins, Catherine A.; Anatomy, Cell Biology and Physiology, School of Medicine
    Axotomized spinal motoneurons (MNs) lose presynaptic inputs following peripheral nerve injury; however, the cellular mechanisms that lead to this form of synapse loss are currently unknown. Here, we delineate a critical role for neuronal kinase dual leucine zipper kinase (DLK)/MAP3K12, which becomes activated in axotomized neurons. Studies with conditional knockout mice indicate that DLK signaling activation in injured MNs triggers the induction of phagocytic microglia and synapse loss. Aspects of the DLK-regulated response include expression of C1q first from the axotomized MN and then later in surrounding microglia, which subsequently phagocytose presynaptic components of upstream synapses. Pharmacological ablation of microglia inhibits the loss of cholinergic C boutons from axotomized MNs. Together, the observations implicate a neuronal mechanism, governed by the DLK, in the induction of inflammation and the removal of synapses.
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    Finite Element Analysis of and Multiscale Skeletal Tissue Mechanics Concerning a Single Dental Implant Site
    (2016) Sego, Timothy James; Tovar, Andres; Chu, Tien-Min Gabriel; Anwar, Sohel
    Finite element analysis (FEA) in implantology is performed in design applications concerning the complex topology of an implant, according to theoretical assumptions about and clinical data concerning the biomechanical nature of skeletal tissue. Implants are placed in topologically and physiologically complex sites, and major disagreement exists in literature about various aspects concerning their modeling and analysis. Current research seeks to improve the implementation of an implant by the use of short implants, which negate the necessity of additional surgical procedures in regions of limited bone height. However, short implants with large crown heights introduce biomechanical complications associated with increased stress and strain distributions in skeletal tissue, which may cause bone loss and implant failure. The short implant is characterized by the geometric ratio of the crown height to the implant length, called the crown-to-implant (C/I) ratio. In this work nonlinear FEA was performed to investigate the effects and significance of the C/I ratio on long-term implant stability. A finite element model was developed according to literature, and emulation of previous research and comparison of reported results were performed. Comparison of results demonstrated significant sources of error in previous research, which are argued to be caused by mesh-dependency from common model idealizations in literature. A convergence test was then performed, which verified the mesh-dependency of results and challenged the reliability of some common model assumptions and methods of analysis in literature. A 16-point design of experiments was then performed to evaluate the significance and influence of the C/I ratio, considering a proposed novel method for evaluating results and predicting long-term stability. Analysis of results demonstrated that the C/I ratio augments the inherent biomechanical effects of an implant design, particularly overloading strain concentrations at implant interface features. The use of short implants with high C/I ratios is determined to be inadvisable, considering the physiological response of tissue to strain distributions and biological context. A novel, multiscale material model is then proposed to describe the short-term accumulation of damage and biomechanical remodeling response in orthotropic skeletal tissue, as a potential solution to the mesh-dependency of results.
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    Prenatal Opioid Exposure Impairs Endocannabinoid and Glutamate Transmission in the Dorsal Striatum
    (Society for Neuroscience, 2022-04-20) Grecco, Gregory G.; Muñoz, Braulio; Di Prisco, Gonzalo Viana; Doud, Emma H.; Fritz, Brandon M.; Maulucci, Danielle; Gao, Yong; Mosley, Amber L.; Baucum, Anthony J.; Atwood, Brady K.; Pharmacology and Toxicology, School of Medicine
    The opioid crisis has contributed to a growing population of children exposed to opioids during fetal development; however, many of the long-term effects of opioid exposure on development are unknown. We previously demonstrated that opioids have deleterious effects on endocannabinoid plasticity at glutamate synapses in the dorsal striatum of adolescent rodents, but it is unclear whether prenatal opioid exposure produces similar neuroadaptations. Using a mouse model of prenatal methadone exposure (PME), we performed proteomics, phosphoproteomics, and patch-clamp electrophysiology in the dorsolateral striatum (DLS) and dorsomedial striatum (DMS) to examine synaptic functioning in adolescent PME offspring. PME impacted the proteome and phosphoproteome in a region- and sex-dependent manner. Many proteins and phosphorylated proteins associated with glutamate transmission were differentially abundant in PME offspring, which was associated with reduced glutamate release in the DLS and altered the rise time of excitatory events in the DMS. Similarly, the intrinsic excitability properties of DMS neurons were significantly affected by PME. Last, pathway analyses revealed an enrichment in retrograde endocannabinoid signaling in the DLS, but not in the DMS, of males. Electrophysiology studies confirmed that endocannabinoid-mediated synaptic depression was impaired in the DLS, but not DMS, of PME-males. These results indicate that PME induces persistent neuroadaptations in the dorsal striatum and could contribute to the aberrant behavioral development described in offspring with prenatal opioid exposure.
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    Role of Postsynaptic Density Protein 95 (PSD95) and Neuronal Nitric Oxide Synthase (NNOS) Interaction in the Regulation of Conditioned Fear
    (2019-10) Li, Liangping; Johnson, Philip L.; Lahiri, Debomoy K.; Shekhar, Anantha; Truitt, William A.; Xu, Xiao-Ming
    Stimulation of N-­methyl-­D-­aspartic acid receptors (NMDARs) and the resulting activation of neuronal nitric oxide synthase (nNOS) are critical for fear memory formation. A variety of previously studied NMDAR antagonists and NOS inhibitors can disrupt fear memory, but they also affect many other CNS functions. Following NMDAR stimulation, efficient activation of nNOS requires linking nNOS to a scaffolding protein, the postsynaptic density protein 95 (PSD95). We hypothesized that PSD95-­nNOS interaction in critical limbic regions (such as amygdala and hippocampus) during fear conditioning is important in regulating fear memory formation, and disruption of this protein-­protein binding may cause impairments in conditioned fear memory. Utilizing co-­immunoprecipitation, electrophysiology and behavioral paradigms, we first showed that fear conditioning results in significant increases in PSD95-­nNOS binding within the basolateral amygdala (BLA) and the ventral hippocampus (vHP) in a time-­dependent manner, but not in the medial prefrontal cortex (mPFC). Secondly, by using ZL006, a small molecule disruptor of PSD95-­ nNOS interaction, it was found that systemic and intra-­BLA disruption of PSD95-­ nNOS interaction by ZL006 impaired the consolidation of cue-­induced fear. In contrast, disruption of PSD95-­nNOS interaction within the vHP did not affect the consolidation of cue-­induced fear, but significantly impaired the consolidation of context-­induced fear. At the cellular level, disruption of PSD95-­nNOS interaction with ZL006 was found to impair long-­term potentiation (LTP) in the BLA neurons. Finally, unlike NMDAR antagonist MK-­801, ZL006 is devoid of adverse effects on many other CNS functions, such as motor function, social activity, cognitive functions in tasks of object recognition memory and spatial memory. These findings collectively demonstrated that PSD95-­nNOS interaction within the conditioned fear network appears to be a key molecular step in regulating synaptic plasticity and the consolidation of conditioned fear. Disruption of PSD95-­nNOS interaction holds promise as a novel treatment strategy for fear-­ motivated disorders, such as post-­traumatic stress disorder and phobias.
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    Spinophilin Limits Metabotropic Glutamate Receptor 5 Scaffolding to the Postsynaptic Density and Cell Type Specifically Mediates Excessive Grooming
    (Elsevier, 2023) Morris, Cameron W.; Watkins, Darryl S.; Shah, Nikhil R.; Pennington, Taylor; Hens, Basant; Qi, Guihong; Doud, Emma H.; Mosley, Amber L.; Atwood, Brady K.; Baucum, Anthony J., II; Pharmacology and Toxicology, School of Medicine
    Background: Grooming dysfunction is a hallmark of the obsessive-compulsive spectrum disorder trichotillomania. Numerous preclinical studies have utilized SAPAP3-deficient mice for understanding the neurobiology of repetitive grooming, suggesting that excessive grooming is caused by increased metabotropic glutamate receptor 5 (mGluR5) activity in striatal direct- and indirect-pathway medium spiny neurons (MSNs). However, the MSN subtype-specific signaling mechanisms that mediate mGluR5-dependent adaptations underlying excessive grooming are not fully understood. Here, we investigated the MSN subtype-specific roles of the striatal signaling hub protein spinophilin in mediating repetitive motor dysfunction associated with mGluR5 function. Methods: Quantitative proteomics and immunoblotting were utilized to identify how spinophilin impacts mGluR5 phosphorylation and protein interaction changes. Plasticity and repetitive motor dysfunction associated with mGluR5 action were measured using our novel conditional spinophilin mouse model in which spinophilin was knocked out from striatal direct-pathway MSNs and/or indirect-pathway MSNs. Results: Loss of spinophilin only in indirect-pathway MSNs decreased performance of a novel motor repertoire, but loss of spinophilin in either MSN subtype abrogated striatal plasticity associated with mGluR5 function and prevented excessive grooming caused by SAPAP3 knockout mice or treatment with the mGluR5-specific positive allosteric modulator VU0360172 without impacting locomotion-relevant behavior. Biochemically, we determined that the spinophilin-mGluR5 interaction correlates with grooming behavior and that loss of spinophilin shifts mGluR5 interactions from lipid raft-associated proteins toward postsynaptic density proteins implicated in psychiatric disorders. Conclusions: These results identify spinophilin as a novel striatal signaling hub molecule in MSNs that cell subtype specifically mediates behavioral, functional, and molecular adaptations associated with repetitive motor dysfunction in psychiatric disorders.
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    Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium
    (Elsevier, 2018-05-03) Lynch, Thomas J.; Anderson, Preston J.; Rotti, Pavana G.; Tyler, Scott R.; Crooke, Adrianne K.; Choi, Soon H.; Montoro, Daniel T.; Silverman, Carolyn L.; Shahin, Weam; Zhao, Rui; Jensen-Cody, Chandler; Adamcakova-Dodd, Andrea; Evans, T. Idil Apak; Xie, Weiliang; Zhang, Yulong; Mou, Hongmei; Herring, B. Paul; Thorne, Peter S.; Rajagopal, Jayaraj; Yeaman, Charles; Parekh, Kalpaj R.; Engelhardt, John F.; Cellular and Integrative Physiology, School of Medicine
    The mouse trachea is thought to contain two distinct stem cell compartments that contribute to airway repair-basal cells in the surface airway epithelium (SAE) and an unknown submucosal gland (SMG) cell type. Whether a lineage relationship exists between these two stem cell compartments remains unclear. Using lineage tracing of glandular myoepithelial cells (MECs), we demonstrate that MECs can give rise to seven cell types of the SAE and SMGs following severe airway injury. MECs progressively adopted a basal cell phenotype on the SAE and established lasting progenitors capable of further regeneration following reinjury. MECs activate Wnt-regulated transcription factors (Lef-1/TCF7) following injury and Lef-1 induction in cultured MECs promoted transition to a basal cell phenotype. Surprisingly, dose-dependent MEC conditional activation of Lef-1 in vivo promoted self-limited airway regeneration in the absence of injury. Thus, modulating the Lef-1 transcriptional program in MEC-derived progenitors may have regenerative medicine applications for lung diseases.