Bourassa M.W.,Burke Cornell Medical Research Institute |
Ratan R.R.,Burke Cornell Medical Research Institute |
Ratan R.R.,Cornell University
Neurochemistry International | Year: 2014
Neurological conditions, such as Alzheimer's disease and stroke, represent a prevalent group of devastating illnesses with few treatments. Each of these diseases or conditions is in part characterized by the dysregulation of many genes, including those that code for microRNAs (miRNAs) and histone deacetylases (HDACs). Recently, a complex relationship has been uncovered linking miRNAs and HDACs and their ability to regulate one another. This provides a new avenue for potential therapeutics as the ability to reinstate a careful balance between miRNA and HDACs has lead to improved outcomes in a number of in vitro and in vivo models of neurological conditions. In this review, we will discuss recent findings on the interplay between miRNAs and HDACs and its implications for pathogenesis and treatment of neurological conditions, including amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease and stroke. © 2014 Elsevier Ltd. All rights reserved.
Deconinck F.J.A.,Ghent University |
Deconinck F.J.A.,Manchester Metropolitan University |
Smorenburg A.R.P.,Burke Cornell Medical Research Institute |
Benham A.,Bradford Institute for Health Research |
And 3 more authors.
Neurorehabilitation and Neural Repair | Year: 2015
Background. Mirror visual feedback (MVF), a phenomenon where movement of one limb is perceived as movement of the other limb, has the capacity to alleviate phantom limb pain or promote motor recovery of the upper limbs after stroke. The tool has received great interest from health professionals; however, a clear understanding of the mechanisms underlying the neural recovery owing to MVF is lacking. Objective. We performed a systematic review to assess the effect of MVF on brain activation during a motor task. Methods. We searched PubMed, CINAHL, and EMBASE databases for neuroimaging studies investigating the effect of MVF on the brain. Key details for each study regarding participants, imaging methods, and results were extracted. Results. The database search yielded 347 article, of which we identified 33 suitable for inclusion. Compared with a control condition, MVF increases neural activity in areas involved with allocation of attention and cognitive control (dorsolateral prefrontal cortex, posterior cingulate cortex, S1 and S2, precuneus). Apart from activation in the superior temporal gyrus and premotor cortex, there is little evidence that MVF activates the mirror neuron system. MVF increases the excitability of the ipsilateral primary motor cortex (M1) that projects to the "untrained" hand/arm. There is also evidence for ipsilateral projections from the contralateral M1 to the untrained/affected hand as a consequence of training with MVF. Conclusion. MVF can exert a strong influence on the motor network, mainly through increased cognitive penetration in action control, though the variance in methodology and the lack of studies that shed light on the functional connectivity between areas still limit insight into the actual underlying mechanisms. © The Author(s) 2014.
Ma T.C.,Columbia University |
Willis D.E.,New York Medical College |
Willis D.E.,Burke Cornell Medical Research Institute
Frontiers in Molecular Neuroscience | Year: 2015
Regenerative failure remains a significant barrier for functional recovery after central nervous system (CNS) injury. As such, understanding the physiological processes that regulate axon regeneration is a central focus of regenerative medicine. Studying the gene transcription responses to axon injury of regeneration competent neurons, such as those of the peripheral nervous system (PNS), has provided insight into the genes associated with regeneration. Though several individual “regeneration-associated genes” (RAGs) have been identified from these studies, the response to injury likely regulates the expression of functionally coordinated and complementary gene groups. For instance, successful regeneration would require the induction of genes that drive the intrinsic growth capacity of neurons, while simultaneously downregulating the genes that convey environmental inhibitory cues. Thus, this view emphasizes the transcriptional regulation of gene “programs” that contribute to the overall goal of axonal regeneration. Here, we review the known RAGs, focusing on how their transcriptional regulation can reveal the underlying gene programs that drive a regenerative phenotype. Finally, we will discuss paradigms under which we can determine whether these genes are injury-associated, or indeed necessary for regeneration. © 2015 Ma and Willis.
Sindhurakar A.,Burke Cornell Medical Research Institute |
Bradley N.S.,University of Southern California
PLoS ONE | Year: 2012
Chicks are bipedal precocious vertebrates that achieve adaptive locomotor skill within hours after hatching. Development of limb movement has been extensively studied in the chicken embryo, but few studies have focused on the preparations leading to precocious locomotor skill. Chicks typically hatch after 21 days of incubation, and recent studies provided evidence that the neural circuits for intralimb control of stepping are established between embryonic days (E) 18-20. It has also been shown that variations in light exposure during embryogenesis can accelerate or delay the onset of hatching and walking by 1 to 2 days. Our earlier work revealed that despite these differences in time to hatch, chicks incubated in different light conditions achieved similar locomotor skill on the day of hatching. Results suggested to us that light exposure during incubation may have accelerated development of locomotor circuits in register with earlier hatching. Thus, in this study, embryos were incubated in 1 of 3 light conditions to determine if development of interlimb coordination at a common time point, 19 days of incubation, varied with light exposure during embryogenesis. Leg muscle activity was recorded bilaterally and burst analyses were performed for sequences of spontaneous locomotor-related activity in one or more ankle muscles to quantify the extent of interlimb coordination in ovo. We report findings indicating that the extent of interlimb coordination varied with light exposure, and left-right alternating steps were a more reliable attribute of interlimb coordination for embryos incubated in constant bright light. We provide evidence that morphological development of the leg varied with light exposure. Based on these findings, we propose that light can accelerate the development of interlimb coordination in register with earlier hatching. Our results lead us to further propose that alternating left-right stepping is the default pattern of interlimb coordination produced by locomotor circuits during embryogenesis. © 2012 Sindhurakar, Bradley.
Kim E.,Burke Cornell Medical Research Institute |
Kim E.,Cornell College |
Tolhurst A.T.,Burke Cornell Medical Research Institute |
Cho S.,Burke Cornell Medical Research Institute |
Cho S.,Cornell College
Journal of Neuroinflammation | Year: 2014
Background: Although elicited inflammation contributes to tissue injury, a certain level of inflammation is necessary for subsequent tissue repair/remodeling. Diabetes, a chronic low-grade inflammatory state, is a predisposing risk factor for stroke. The condition is associated with delayed wound healing, presumably due to disrupted inflammatory responses. With inclusion of the diabetic condition in an experimental animal model of stroke, this study investigates whether the condition alters inflammatory response and influences stroke-induced brain injury. Methods: C57BL/6 mice were fed a diabetic diet (DD) for 8 weeks to induce an experimental diabetic condition or a normal diet (ND) for the same duration. Gene expression of inflammatory factors including monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), CCR2, and CD36 was assessed in the peripheral immune cells and brains of normal and diabetic mice before and after focal cerebral ischemia. The expression of these factors was also determined in lipopolysaccharide (LPS)-treated cultured normal and diabetic macrophages. Ischemic outcome was assessed in these mice at 3 days post-ischemia. Results: DD intervention in mice resulted in obesity and elevated insulin and glucose level in the blood. The peritoneal immune cells from the diabetic mice showed higher MCP-1 mRNA levels before and after stroke. Compared to normal mice, diabetic mice showed reduced MCP-1, IL-6, and CCR2 gene expression in the brain at 6 h post-ischemia. LPS-stimulated inflammatory responses were also reduced in the diabetic macrophages. The diabetic mice showed larger infarct size and percent swelling.Conclusions: These results showed that diabetic conditions deregulate acute inflammatory response and that the condition is associated with increased stroke-induced injury. The study suggests that interventions aimed at restoring appropriate inflammatory response in peripheral immune cells/macrophages may be beneficial in reducing stroke-induced brain injury in subjects with chronic inflammatory conditions. © 2014 Kim et al.; licensee BioMed Central Ltd.
Kim E.,Burke Cornell Medical Research Institute |
Kim E.,New York Medical College |
Yang J.,Burke Cornell Medical Research Institute |
D Beltran C.,Burke Cornell Medical Research Institute |
And 2 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2014
Monocytes/macrophages (MMs), mononuclear phagocytes, have been implicated in stroke-induced inflammation and injury. However, the presence of pro-inflammatory Ly-6Chigh and antiinflammatory Ly-6Clow monocyte subsets raises uncertainty regarding their role in stroke pathologic assessment. With recent identification of the spleen as an immediate reservoir of MMs, this current study addresses whether the spleen-derived MMs are required for stroke pathologic assessment. We observed that the spleen was contracted in poststroke animals and the contraction was accompanied by decreased number of Ly-6Chigh and Ly-6Clow subsets in the spleen. The deployment of these subsets from the spleen temporally coincided with respective increases in the ischemic brain. Compared to mice with the spleen, mice receiving a splenectomy just before the stroke displayed less accumulation of Ly-6Chigh and Ly-6Clow MMs in the brain. Despite the reduced accumulation of both subsets, infarct size and swelling were not reduced in the asplenic mice. The dissociative findings of infarct size and extent of MM infiltration in the postischemic brain indicate minimal involvement of spleen-derived total MMs in acute infarct development. Selective Ly-6C high or Ly-6Clow MM targeting is suggested to address the contribution of the individual subset to acute stroke pathologic assessment. © 2014 ISCBFM.
Basso M.,Burke Cornell Medical Research Institute |
Basso M.,Cornell University |
Ratan R.R.,Burke Cornell Medical Research Institute |
Ratan R.R.,Cornell University
Journal of Cerebral Blood Flow and Metabolism | Year: 2013
Transglutaminases (TGs) are multifunctional, calcium-dependent enzymes that have been recently implicated in stroke pathophysiology. Classically, these enzymes are thought to participate in cell injury and death in chronic neurodegenerative conditions via their ability to catalyze covalent, nondegradable crosslinks between proteins or to incorporate polyamines into protein substrates. Accumulating lines of inquiry indicate that specific TG isoforms can shuttle into the nucleus when they sense pathologic changes in calcium or oxidative stress, bind to chromatin and thereby transduce these changes into transcriptional repression of genes involved in metabolic or oxidant adaptation. Here, we review the evidence that supports principally a role for one isoform of this family, TG2, in cell injury and death associated with hemorrhagic or ischemic stroke. We also outline an evolving model in which TG2 is a critical mediator between pathologic signaling and epigenetic modifications that lead to gene repression. Accordingly, the salutary effects of TG inhibitors in stroke may derive from their ability to restore homeostasis by removing inappropriate deactivation of adaptive genetic programs by oxidative stress or extrasynaptic glutamate receptor signaling. © 2013 ISCBFM All rights reserved.
Bashir S.,Harvard University |
Edwards D.,Harvard University |
Edwards D.,Burke Cornell Medical Research Institute |
Edwards D.,University of Western Australia |
And 2 more authors.
Brain Topography | Year: 2011
Low-frequency repetitive transcranial magnetic stimulation (rTMS) can exert local and inter-hemispheric neuromodulatory effects on cortical excitability. These physiologic effects can translate into changes in motor behavior, and may offer valuable therapeutic interventions in recovery from stroke. Neuronavigated TMS can maximize accurate and consistent targeting of a given cortical region, but is a lot more involved that conventional TMS. We aimed to assess whether neuronavigation enhances the physiologic and behavioral effects of low-frequency rTMS. Ten healthy subjects underwent two experimental sessions during which they received 1600 pulses of either navigated or non-navigated 1 Hz rTMS at 90% of the resting motor threshold (RMT) intensity over the motor cortical representation for left first dorsal interosseous (FDI) muscle. We compared the effects of navigated and non-navigated rTMS on motor-evoked potentials (MEPs) to single-pulse TMS, intracortical inhibition (ICI) and intracortical facilitation (ICF) by paired-pulse TMS, and performance in various behavioral tasks (index finger tapping, simple reaction time and grip strength tasks). Following navigated rTMS, the amplitude of MEPs elicited from the contralateral (unstimulated) motor cortex was significantly increased, and was associated with an increase in ICF and a trend to decrease in ICI. In contrast, non-navigated rTMS elicited nonsignificant changes, most prominently ipsilateral to rTMS. Behaviorally, navigated rTMS significantly improved reaction time RT and pinch force with the hand ipsilateral to stimulation. Non-navigated rTMS lead to similar behavioral trends, although the effects did not reach significance. In summary, navigated rTMS leads to more robust modulation of the contralateral (unstimulated) hemisphere resulting in physiologic and behavioral effects. Our findings highlight the spatial specificity of inter-hemispheric TMS effects, illustrate the superiority of navigated rTMS for certain applications, and have implications for therapeutic applications of rTMS. © 2010 Springer Science+Business Media, LLC.
Gumy L.F.,University of Cambridge |
Yeo G.S.H.,University of Cambridge |
Tung Y.-C.L.,University of Cambridge |
Zivraj K.H.,University of Cambridge |
And 6 more authors.
RNA | Year: 2011
mRNAs are transported, localized, and translated in axons of sensory neurons. However, little is known about the full repertoire of transcripts present in embryonic and adult sensory axons and how this pool of mRNAs dynamically changes during development. Here, we used a compartmentalized chamber to isolate mRNA from pure embryonic and adult sensory axons devoid of non-neuronal or cell body contamination. Genome-wide microarray analysis reveals that a previously unappreciated number of transcripts are localized in sensory axons and that this repertoire changes during development toward adulthood. Embryonic axons are enriched in transcripts encoding cytoskeletal-related proteins with a role in axonal outgrowth. Surprisingly, adult axons are enriched in mRNAs encoding immune molecules with a role in nociception. Additionally, we show Tubulin-beta3 (Tubb3) mRNA is present only in embryonic axons, with Tubb3 locally synthesized in axons of embryonic, but not adult neurons where it is transported, thus validating our experimental approach. In summary, we provide the first complete catalog of embryonic and adult sensory axonal mRNAs. In addition we show that this pool of axonal mRNAs dynamically changes during development. These data provide an important resource for studies on the role of local protein synthesis in axon regeneration and nociception during neuronal development. Copyright © 2011 RNA Society.
Ferre C.,Columbia University |
Bleyenheuft Y.,University for Professionals for Pediatric Physical Therapy |
Hung Y.-C.,Catholic University of Leuven |
Friel K.,Queens College, City University of New York |
Gordon A.M.,Burke Cornell Medical Research Institute
Neurorehabilitation and Neural Repair | Year: 2014
Background. High-intensity training aims to improve hand function in children with unilateral spastic cerebral palsy (USCP). However, the extent to which skill training is required is not known. Objectives. To compare the effects of intensive bimanual training with and without structured progression of skill difficulty, on manual dexterity, bimanual hand use, daily functioning, and functional goals in children with USCP. Method. Twenty-two children were randomized to structured practice group (SPG) or unstructured practice group (UPG), and received 6 h/d training during 15 days. Children from the SPG were engaged in fine and gross motor bimanual activities, with skill progression and goal training. Children from UPG performed the same activities without skill progression or goal training. Participants were evaluated before, immediately and 6 months after training by a physical therapist blinded to group allocation. The primary outcomes were the Jebsen-Taylor Test of Hand Function (JTTHF) and Assisting Hand Assessment (AHA). Secondary outcomes included the Canadian Occupational Performance Measure (COPM), Pediatric Evaluation of Disability Inventory (PEDI), and ABILHAND-Kids. Results. Both groups showed similar improvements in the JTTHF, AHA, ABILHAND-Kids, COPM-satisfaction, and PEDI (P < .05). A significant interaction in the COPM-performance scale (P = .03) showed superior improvements of the SPG immediately, but not 6 months, after the intervention. Conclusions: Children from both groups demonstrated improvements in dexterity and functional hand use. This suggests that for intensive bimanual approaches, intensive training at such high doses may not require structured practice to elicit improvements. However, there may be immediate added benefit of including goal training. © The Author(s) 2013.