Neuroscience
Abstract
Chronic sympathoexcitation is implicated in ventricular arrhythmogenesis (VAs) following myocardial infarction (MI), but the critical neural pathways involved are not well understood. Cardiac adrenergic function is partly regulated by sympathetic afferent reflexes, transduced by spinal afferent fibers expressing the TRPV1 channel. The role of chronic TRPV1 afferent signaling in VAs is not known. We hypothesized that persistent TRPV1 afferent neurotransmission promotes VAs after MI. Using epicardial Resiniferatoxin (RTX) to deplete cardiac TRPV1-expressing fibers, we dissected the role of this neural circuit in VAs after chronic MI in a porcine model. We examined the underlying mechanisms using molecular approaches, immunohistochemistry, in vitro and in vivo cardiac electrophysiology, and simultaneous cardio-neural mapping. Epicardial RTX depleted cardiac TRPV1 afferent fibers and abolished functional responses to TRPV1 agonists. Ventricular tachycardia/fibrillation (VT/VF) was readily inducible in MI subjects by programmed electrical stimulation or cesium chloride administration, however, TRPV1 afferent depletion prevented VT/VF induced by either method. Mechanistically, TRPV1 afferent depletion neither altered cardiomyocyte action potentials and calcium transients; nor the expression of ion channels and calcium handling proteins. However, it attenuated fibrosis and mitigated electrical instability in the scar-border zone. In vivo recordings of cardiovascular-related stellate ganglion neurons (SGNs) revealed that MI enhances SGN function and disrupts integrated neural processing. Depleting TRPV1 afferents normalized these processes. Taken together, these data indicate that after MI, TRPV1 afferent-induced adrenergic dysfunction promotes fibrosis, adverse cardiac remodeling, and worsens border zone electrical heterogeneity, resulting in electrically unstable ventricular myocardium. We propose targeting TRPV1-expressing afferent to reduce VT/VF following MI.
Authors
Koji Yoshie, Pradeep S. Rajendran, Louis Massoud, Janki Mistry, M. Amer Swid, Xiaohui Wu, Tamer Sallam, Rui Zhang, Joshua I. Goldhaber, Siamak Salavatian, Olujimi A. Ajijola
Abstract
Vision loss in age-related macular degeneration (AMD) stems from disruption of photoreceptor cells in the macula, the central retinal area required for high-acuity vision. Mice and rats have no macula, but surgical insertion of a subretinal implant can induce localized photoreceptor degeneration due to chronic separation from retinal pigment epithelium, simulating a key aspect of AMD. We find that the implant-induced loss of photoreceptors in rat retina leads to local changes in the physiology of downstream retinal ganglion cells (RGCs), similar to changes in RGCs of rodent models of retinitis pigmentosa (RP), an inherited disease causing retina-wide photoreceptor degeneration. The local implant-induced changes in RGCs include enhanced intrinsic excitability leading to accelerated spontaneous firing, increased membrane permeability to fluorescent dyes, and enhanced photosensitization by azobenzene photoswitches. The local physiological changes are correlated with an increase in Retinoic Acid Receptor (RAR)-induced gene transcription, the key process underlying retinal remodeling in mouse models of RP. Hence the loss of photoreceptors, whether by local physical perturbation or by inherited mutation, leads to a stereotypical set of pathophysiological consequences in RGCs. These findings implicate RAR as a possible common therapeutic target for reversing the signal-corrupting effects of retinal remodeling in both RP and AMD.
Authors
Bristol Denlinger, Zachary Helft, Michael Telias, Henri Lorach, Daniel Palanker, Richard H. Kramer
Abstract
BACKGROUND Bilateral loss of vestibular (inner ear inertial) sensation causes chronically blurred vision during head movement, postural instability, and increased fall risk. Individuals who fail to compensate despite rehabilitation therapy have no adequate treatment options. Analogous to hearing restoration via cochlear implants, prosthetic electrical stimulation of vestibular nerve branches to encode head motion has garnered interest as a potential treatment, but prior studies in humans have not included continuous long-term stimulation or 3D binocular vestibulo-ocular reflex (VOR) oculography, without which one cannot determine whether an implant selectively stimulates the implanted ear’s 3 semicircular canals.METHODS We report binocular 3D VOR responses of 4 human subjects with ototoxic bilateral vestibular loss unilaterally implanted with a Labyrinth Devices Multichannel Vestibular Implant System vestibular implant, which provides continuous, long-term, motion-modulated prosthetic stimulation via electrodes in 3 semicircular canals.RESULTS Initiation of prosthetic stimulation evoked nystagmus that decayed within 30 minutes. Stimulation targeting 1 canal produced 3D VOR responses approximately aligned with that canal’s anatomic axis. Targeting multiple canals yielded responses aligned with a vector sum of individual responses. Over 350–812 days of continuous 24 h/d use, modulated electrical stimulation produced stable VOR responses that grew with stimulus intensity and aligned approximately with any specified 3D head rotation axis.CONCLUSION These results demonstrate that a vestibular implant can selectively, continuously, and chronically provide artificial sensory input to all 3 implanted semicircular canals in individuals disabled by bilateral vestibular loss, driving reflexive VOR eye movements that approximately align in 3D with the head motion axis encoded by the implant.TRIAL REGISTRATION ClinicalTrials.gov: NCT02725463.FUNDING NIH/National Institute on Deafness and Other Communication Disorders: R01DC013536 and 2T32DC000023; Labyrinth Devices, LLC; and Med-El GmbH.
Authors
Peter J. Boutros, Desi P. Schoo, Mehdi Rahman, Nicolas S. Valentin, Margaret R. Chow, Andrianna I. Ayiotis, Brian J. Morris, Andreas Hofner, Aitor Morillo Rascon, Andreas Marx, Ross Deas, Gene Y. Fridman, Natan S. Davidovics, Bryan K. Ward, Carolina Treviño, Stephen P. Bowditch, Dale C. Roberts, Kelly E. Lane, Yoav Gimmon, Michael C. Schubert, John P. Carey, Andreas Jaeger, Charles C. Della Santina
Abstract
Rationale: Reflex-mediated sympathoexcitation is central to the pathogenesis of arrhythmias and heart disease; neuraxial modulation can favorably attenuate these cardiac reflexes leading to cardioprotection. Objective: The purpose of this study was to define the mechanism by which cardiac neural decentralization and spinal cord stimulation (SCS) reduces ischemia-induced ventricular fibrillation (VF) and sudden cardiac death (SCD) by utilizing direct neurotransmitter measurements in the heart. Methods and Results: Direct measurement of norepinephrine (NE) levels in the left ventricular (LV) interstitial fluid (ISF) by microdialysis in response to transient left anterior descending coronary artery occlusion (CAO: 15 min) in anesthetized canines. Responses were studied with: (i) intact neuraxis and were compared to those in which the (ii) intrathoracic component of the cardiac neuraxis (stellate ganglia),(iii) the intrinsic cardiac neuronal (ICN) system were surgically delinked from the central nervous system versus (iv) subjects with intact neuraxis subjected to pre-emptive SCS (T1-T3 spinal level). With an intact neuraxis, animals with exaggerated NE-ISF levels in response to CAO were at increased risk for VF and SCD. During CAO there was a 152% increase in NE level when the entire neuraxis was intact compared to 114% following intrathoracic neuraxial decentralization (removal of the stellates) and 16% increase following ICN decentralization, when the entire heart and ICN was delinked from the other levels of the neuraxis. During SCS, CAO increased NE levels by 59%. Risk for CAO-induced VF was 38% in controls, 8% following total decentralization and 11% following SCS. Conclusions: These data indicate that ischemia related afferent neuronal transmission engages central and intrathoracic sympathetic reflexes which amplifies sympathoexcitation and results in an increase in regional ventricular NE release that causes VF and SCD. Surgical decentralization or SCS prevents this amplification of sympathoexcitation, attenuating the resultant NE release, and reduces VF and SCD.
Authors
Jeffrey L. Ardell, Robert D. Foreman, J. Andrew Armour, Kalyanam Shivkumar
Abstract
Mitochondrial quality control (MQC) is crucial for regulating central nervous system homeostasis and its disruption has been implicated in the pathogenesis of some of the most common neurodegenerative diseases. In healthy tissues, the maintenance of MQC depends upon an exquisite balance between mitophagy (removal of damaged mitochondria by autophagy) and biogenesis (de-novo synthesis of mitochondria). Here, we show that mitophagy is disrupted in diabetic retinopathy (DR) and decoupled from mitochondrial biogenesis during the progression of the disease. Diabetic retinas from human post-mortem donors and experimental mice exhibit a net loss of mitochondrial contents during the early stages of the disease process. Using novel diabetic mitophagy-reporter mice (mitoQC-Ins2Akita) alongside pMitoTimer (a molecular clock to address mitochondrial-age dynamics), we demonstrate that mitochondrial loss arose due to an inability of mitochondrial biogenesis to compensate for diabetes-exacerbated mitophagy. However, as diabetes duration increases, Pink1-dependent mitophagy deteriorates, leading to the build-up of mitochondria primed for degradation in DR. Impairment of mitophagy during prolonged diabetes is linked with the development of retinal senescence, a phenotype that blunted hyperglycaemia-induced mitophagy in mitoQC primary Müller cells. Our findings suggest that normalizing mitochondrial turnover may preserve MQC and provide novel therapeutic options for the management of DR-associated complications.
Authors
Jose R. Hombrebueno, Lauren Cairns, Louise R. Dutton, Timothy J. Lyons, Derek P. Brazil, Paul Moynagh, Tim M. Curtis, Heping Xu
Abstract
The choroid plexus (ChP) is a highly vascularized tissue found in the brain ventricles, with an apical epithelial cell layer surrounding fenestrated capillaries. It is responsible for the production of most of the cerebrospinal fluid (CSF) in the ventricular system, subarachnoid space, and central canal of the spinal cord, while also constituting the blood-CSF barrier (BCSFB). In addition, epithelial cells of the choroid plexus (EChP) synthesize neurotrophic factors and other signaling molecules that are released into the CSF. Here we show that insulin is produced in EChP of mice and humans, and its expression and release are regulated by serotonin. Insulin mRNA and immune-reactive protein, including C-peptide, are present in EChP, as detected by several experimental approaches, and in much higher levels than any other brain region and non-pancreatic peripheral tissues. Moreover, insulin is produced in primary cultured mouse EChP, and its release, albeit Ca2+-sensitive, is not regulated by glucose. Instead, activation of the 5HT2C receptor by serotonin treatment led to activation of IP3-sensitive channels and Ca2+ mobilization from intracellular storage, leading to insulin secretion. In vivo depletion of brain serotonin in the dorsal raphe nucleus negatively affected insulin expression in the ChP, suggesting an endogenous modulation of ChP insulin by serotonin. Therefore, for the first time to our knowledge, here we show that insulin is produced by EChP in the brain, and its release is modulated at least by serotonin, and not glucose.
Authors
Caio Henrique Mazucanti, Qing-Rong Liu, Doyle Lang, Nicholas Huang, Jennifer F. O’Connell, Simonetta Camandola, Josephine M. Egan
Abstract
Intrathecal (IT) delivery and pharmacology of antisense oligonucleotides (ASOs) for the CNS have been successfully developed to treat spinal muscular atrophy. However, ASO pharmacokinetic (PK) and pharmacodynamic (PD) properties remain poorly understood in the IT compartment. We applied multimodal imaging techniques to elucidate the IT PK and PD of unlabeled, radioactively labeled, or fluorescently labeled ASOs targeting ubiquitously expressed or neuron-specific RNAs. Following lumbar IT bolus injection in rats, all ASOs spread rostrally along the neuraxis, adhered to meninges, and were partially cleared to peripheral lymph nodes and kidneys. Rapid association with the pia and arterial walls preceded passage of ASOs across the glia limitans, along arterial intramural basement membranes, and along white-matter axonal bundles. Several neuronal and glial cell types accumulated ASOs over time, with evidence of probable glial accumulation preceding neuronal uptake. IT doses of anti-GluR1 and anti-Gabra1 ASOs markedly reduced the mRNA and protein levels of their respective neurotransmitter receptor protein targets by 2 weeks and anti-Gabra1 ASOs also reduced binding of the GABAA receptor PET ligand 18F-flumazenil in the brain over 4 weeks. Our multimodal imaging approaches elucidate multiple transport routes underlying the CNS distribution, clearance, and efficacy of IT-dosed ASOs.
Authors
Curt Mazur, Berit Powers, Kenneth Zasadny, Jenna M. Sullivan, Hemi Dimant, Fredrik Kamme, Jacob Hesterman, John Matson, Michael Oestergaard, Marc Seaman, Robert W. Holt, Mohammed Qutaish, Ildiko Polyak, Richard Coelho, Vijay Gottumukkala, Carolynn M. Gaut, Marc Berridge, Nazira J. Albargothy, Louise Kelly, Roxana O. Carare, Jack Hoppin, Holly Kordasiewicz, Eric E. Swayze, Ajay Verma
Abstract
Efferocytosis, or phagocytic clearance of dead/dying cells by brain-resident microglia and/or infiltrating macrophages, is instrumental for inflammation resolution and restoration of brain homeostasis after stroke. Here, we identify the signal transducer and activator of transcription 6/arginase1 (STAT6/Arg1) signaling axis as a potentially novel mechanism that orchestrates microglia/macrophage responses in the ischemic brain. Activation of STAT6 was observed in microglia/macrophages in the ischemic territory in a mouse model of stroke and in stroke patients. STAT6 deficiency resulted in reduced clearance of dead/dying neurons, increased inflammatory gene signature in microglia/macrophages, and enlarged infarct volume early after experimental stroke. All of these pathological changes culminated in an increased brain tissue loss and exacerbated long-term functional deficits. Combined in vivo analyses using BM chimeras and in vitro experiments using microglia/macrophage-neuron cocultures confirmed that STAT6 activation in both microglia and macrophages was essential for neuroprotection. Adoptive transfer of WT macrophages into STAT6-KO mice reduced accumulation of dead neurons in the ischemic territory and ameliorated brain infarction. Furthermore, decreased expression of Arg1 in STAT6–/– microglia/macrophages was responsible for impairments in efferocytosis and loss of antiinflammatory modality. Our study suggests that efferocytosis via STAT6/Arg1 modulates microglia/macrophage phenotype, accelerates inflammation resolution, and improves stroke outcomes.
Authors
Wei Cai, Xuejiao Dai, Jie Chen, Jingyan Zhao, Mingyue Xu, Lili Zhang, Boyu Yang, Wenting Zhang, Marcelo Rocha, Toshimasa Nakao, Julia Kofler, Yejie Shi, R. Anne Stetler, Xiaoming Hu, Jun Chen
Abstract
Alcohol withdrawal (AW) after chronic alcohol exposure produces a series of symptoms, with AW-associated seizures being among the most serious and dangerous. However, the mechanism underlying AW seizures has yet to be established. In our mouse model, a sudden AW produced 2 waves of seizures: the first wave includes a surge of multiple seizures that occurs within hours to days of AW, and the second wave consists of sustained expression of epileptiform spikes and wave discharges (SWDs) during a protracted period of abstinence. We revealed that the structural and functional adaptations in newborn dentate granule cells (DGCs) in the hippocampus underlie the second wave of seizures but not the first wave. While the general morphology of newborn DGCs remained unchanged, AW increased the dendritic spine density of newborn DGCs, suggesting that AW induced synaptic connectivity of newborn DGCs with excitatory afferent neurons and enhanced excitability of newborn DGCs. Indeed, specific activation and suppression of newborn DGCs by the chemogenetic DREADD method increased and decreased the expression of epileptiform SWDs, respectively, during abstinence. Thus, our study unveiled that the pathological plasticity of hippocampal newborn DGCs underlies AW seizures during a protracted period of abstinence, providing critical insight into hippocampal neural circuits as a foundation to understand and treat AW seizures.
Authors
Daehoon Lee, Balu Krishnan, Hai Zhang, Hee Ra Park, Eun Jeoung Ro, Yu-Na Jung, Hoonkyo Suh
Abstract
Accumulation of lysosomal storage material and late-stage neurodegeneration are hallmarks of lysosomal storage disorders (LSDs) affecting the brain. Yet, for most LSDs, including CLN3 disease, the most common form of childhood dementia, it is unclear what mechanisms drive neurologic symptoms. Do deficits arise from loss of function of the mutated protein or toxicity from storage accumulation? Here, using in vitro voltage sensitive dye imaging and in vivo electrophysiology, we find progressive hippocampal dysfunction occurs prior to notable lysosomal storage and neuronal loss in two CLN3 disease mouse models. Pharmacologic reversal of lysosomal storage deposition in young mice does not rescue this circuit dysfunction. Additionally, we find that CLN3 disease mice lose an electrophysiologic marker of new memory encoding – hippocampal sharp wave ripples. This discovery, which is also seen in Alzheimer’s disease, suggests the possibility of a shared electrophysiologic signature of dementia. Overall, our data describes new insights into previously unknown network-level changes occurring in LSDs affecting the central nervous system, and highlight the need for new therapeutic interventions targeting early circuit defects.
Authors
Rebecca C. Ahrens-Nicklas, Luis Tecedor, Arron Hall, Elena Lysenko, Akiva S. Cohen, Beverly L. Davidson, Eric D. Marsh
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