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• W2015779946 abstract "A thought-provoking new study has found that symptom-free carriers of the neurodegenerative Huntington's disease present a dramatic two-fold acceleration in perceptual learning. A thought-provoking new study has found that symptom-free carriers of the neurodegenerative Huntington's disease present a dramatic two-fold acceleration in perceptual learning. The remarkable ease of learning seen in children seems only a distant memory to most of our adult brains. Understanding the factors that might renew such learning in older brains is a main goal of brain plasticity studies. A study published in this issue of Current Biology [1Beste C. Wascher E. Dinse H.R. Saft C. Faster perceptual learning through excitotoxic neurodegeneration.Curr. Biol. 2012; 22: 1914-1917Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] has opened new possibilities by showing dramatically improved learning in pre-symptomatic Huntington's disease carriers. Brain systems are shaped by a complex interplay between genes and experience, a process that begins early in development and extends throughout the life span. A major determinant of such brain sculpting is the balance between excitation and inhibition in neural networks [2Morishita H. Hensch T.K. Critical period revisited: impact on vision.Curr. Opin. Neurobiol. 2008; 18: 101-107Crossref PubMed Scopus (244) Google Scholar]. Excitatory-inhibitory co-tuning driven by consistent and reliable patterned sensory stimulation leads to the progressive remodeling of the receptive fields. Such sculpting of connectivity through synaptic activity eventually become associated with a number of structural changes, which in turn ultimately put a brake on further exposure-based modifications [3Dorrn A.L. Yuan K. Barker A.J. Schreiner C.E. Froemke R.C. Developmental sensory experience balances cortical excitation and inhibition.Nature. 2010; 465: 932-936Crossref PubMed Scopus (215) Google Scholar]. By adulthood, many of these brakes are in place, limiting the potential brain plasticity. This is why children typically recover more gracefully from brain insults than adults. The recent work of Beste et al. [1Beste C. Wascher E. Dinse H.R. Saft C. Faster perceptual learning through excitotoxic neurodegeneration.Curr. Biol. 2012; 22: 1914-1917Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] aims to link increased excitation and enhanced learning by focusing on a special population of human patients, those who carry the Huntington disease (HD) gene, but are not yet affected by its severe dysregulation (termed pre-HD thereafter). HD is a progressive neurodegenerative disorder caused by mutations of the Huntingtin gene that confer toxic properties to the protein it codes for. This results, among other effects, in massive neural cell death with up to 95% loss of GABAergic medium spiny projection neurons in the striatum, as well as atrophy in the cerebral cortex and white matter. Key symptoms include severe motor, cognitive and psychiatric dysfunctions that lead patients to lose their autonomy at advanced stages of the illness. Despite intense research, HD remains poorly understood and incurable [4Ha A.D. Fung V.S.C. Huntington's disease.Curr. Opin. Neurol. 2012; 25: 491-498Crossref PubMed Scopus (73) Google Scholar]. HD onset is declared based on severe motor deficits. This does not, however, imply that pre-HD patients are unaffected by the disease. In fact, pre-HD patients show significant deficits in a broad range of cognitive and emotional tasks when carefully tested in a laboratory setting, with deficiencies detectable as early as 15 years before disease onset [5Stout J.C. Paulsen J.S. Queller S. Solomon A.C. Whitlock K.B. Campbell J.C. Carlozzi N. Duff K. Beglinger L.J. Langbehn D.R. et al.Neurocognitive signs in prodromal Huntington disease.Neuropsychology. 2011; 25: 1-14Crossref PubMed Scopus (282) Google Scholar]. These more subtle changes suggest a dysregulation of the balance between excitation and inhibition well before the disease fully sets in. To test the idea that pre-HD patients may have enhanced learning capabilities, Beste et al. [1Beste C. Wascher E. Dinse H.R. Saft C. Faster perceptual learning through excitotoxic neurodegeneration.Curr. Biol. 2012; 22: 1914-1917Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] exploited a new learning design they have pioneered [6Beste C. Wascher E. Güntürkün O. Dinse H.R. Improvement and impairment of visually guided behavior through LTP- and LTD-like exposure-based visual learning.Curr. Biol. 2011; 21: 876-882Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar], testing perceptual performance (Figure 1) before and after a plasticity-inducing repetitive visual stimulation ‘treatment’. The efficiency of this ‘treatment’ is measured by changes in perceptual performance from pre- to post-treatment. To induce plasticity, Beste et al. [1Beste C. Wascher E. Dinse H.R. Saft C. Faster perceptual learning through excitotoxic neurodegeneration.Curr. Biol. 2012; 22: 1914-1917Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] used an exposure-based learning protocol, during which subjects are presented sequences of rapidly (20 Hz) alternating light and dark bars on the computer screen for an extended period of time. The temporal properties of exposure-based learning resemble those used to induce long-term potentiation (LTP) and in this perspective exposure-based learning has been shown to produce plausible behavioral learning effects [6Beste C. Wascher E. Güntürkün O. Dinse H.R. Improvement and impairment of visually guided behavior through LTP- and LTD-like exposure-based visual learning.Curr. Biol. 2011; 21: 876-882Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]. The results of the experiments were clear-cut. Before exposure-based learning, pre-HD and control subjects' perceptual performances were identical. After 20 minutes of exposure-based learning, pre-HD patients largely outperformed control subjects, for whom improvement is absent after 20 minutes of exposure-based learning but progressively reaches pre-HD performance level after 40 minutes of exposure-based learning. The comparison of specific groups systematically yields suspicions of sampling biases and the possibility of confounding factors. Subjects who are genetically tested for HD are more likely to take antidepressants [7Rowe K.C. Paulsen J.S. Langbehn D.R. Wang C. Mills J. Beglinger L.J. Smith M.M. Epping E.A. Fiedorowicz J.G. Duff K. et al.Patterns of serotonergic antidepressant usage in prodromal Huntington disease.Psychiatr. Res. 2012; 196: 309-314Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar], some of which might boost learning [8Maya Vetencourt J.F. Sale A. Viegi A. Baroncelli L. De Pasquale R. O'Leary O.F. Castrén E. Maffei L. The antidepressant fluoxetine restores plasticity in the adult visual cortex.Science. 2008; 320: 385-388Crossref PubMed Scopus (694) Google Scholar]. Pre-HD subjects might be more motivated to perform well and higher levels of attention improve exposure-based learning [9Gutnisky D.A. Hansen B.J. Iliescu B.F. Dragoi V. Attention alters visual plasticity during exposure-based learning.Curr. Biol. 2009; 19: 555-560Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. The presence of these confounds, however, is unlikely. For each pre-HD patient Beste et al. [1Beste C. Wascher E. Dinse H.R. Saft C. Faster perceptual learning through excitotoxic neurodegeneration.Curr. Biol. 2012; 22: 1914-1917Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] collected the ‘disease burden score’ — an index of the Huntingtin mutation strength — and found that it correlated with learning-induced performance improvement; pre-HD patients with the highest disease burden scores showed greater learning. These results are spectacular in the face of the massive literature showing subtle cognitive impairments in pre-HD patients [5Stout J.C. Paulsen J.S. Queller S. Solomon A.C. Whitlock K.B. Campbell J.C. Carlozzi N. Duff K. Beglinger L.J. Langbehn D.R. et al.Neurocognitive signs in prodromal Huntington disease.Neuropsychology. 2011; 25: 1-14Crossref PubMed Scopus (282) Google Scholar]. Their strength is such that it may be worth considering the inclusion of this experimental setup — a fast, efficient and cheap diagnostic tool — in the battery of tests used to predict HD onset. It has been repeatedly shown that glutamate receptors, and in particular NMDA receptors are involved in both LTP and learning [10Barria A. Malinow R. NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII.Neuron. 2005; 48: 289-301Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar, 11Foster K.A. McLaughlin N. Edbauer D. Phillips M. Bolton A. Constantine-Paton M. Sheng M. Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation.J. Neurosci. 2010; 30: 2676-2685Crossref PubMed Scopus (169) Google Scholar, 12Zhou Y. Takahashi E. Li W. Halt A. Wiltgen B. Ehninger D. Li G. Hell J.W. Kennedy M.B. Silva A.J. Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning.J. Neurosci. 2007; 27: 13843-13853Crossref PubMed Scopus (144) Google Scholar, 13Tang Y.P. Shimizu E. Dube G.R. Rampon C. Kerchner G.A. Zhuo M. Liu G. Tsien J.Z. Genetic enhancement of learning and memory in mice.Nature. 1999; 401: 63-69Crossref PubMed Scopus (1564) Google Scholar] as well as in Huntington's disease [14Milnerwood A.J. Raymond L.A. Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease.Trends Neurosci. 2010; 33: 513-523Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 15Okamoto S. Pouladi M.A. Talantova M. Yao D. Xia P. Ehrnhoefer D.E. Zaidi R. Clemente A. Kaul M. Graham R.K. et al.Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin.Nat. Med. 2009; 15: 1407-1413Crossref PubMed Scopus (338) Google Scholar, 16Milnerwood A.J. Gladding C.M. Pouladi M.A. Kaufman A.M. Hines R.M. Boyd J.D. Ko R.W.Y. Vasuta O.C. Graham R.K. Hayden M.R. et al.Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice.Neuron. 2010; 65: 178-190Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]. Mice in which NR2B (a subtype of NMDA receptor subunit) was overexpressed in the forebrain show a stronger LTP and perform better in some learning tasks [13Tang Y.P. Shimizu E. Dube G.R. Rampon C. Kerchner G.A. Zhuo M. Liu G. Tsien J.Z. Genetic enhancement of learning and memory in mice.Nature. 1999; 401: 63-69Crossref PubMed Scopus (1564) Google Scholar]. Interestingly, these same NR2B-containing receptors seem to be responsible for altered NMDA receptor function in various mouse models of HD and overexpressing the NR2B subunit in an HD model mouse exacerbates selective striatal neuron degeneration [14Milnerwood A.J. Raymond L.A. Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease.Trends Neurosci. 2010; 33: 513-523Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. Overactivation of NMDA receptors in HD could also be increased by defective glutamate uptake by astrocytes [17Maragakis N.J. Rothstein J.D. Mechanisms of Disease: astrocytes in neurodegenerative disease.Nat. Clin. Pract. Neurol. 2006; 2: 679-689Crossref PubMed Scopus (655) Google Scholar]. Finally, memantine (a NMDA receptor blocker) was shown in HD model mice to reverse motor learning deficits, confirming a role for NMDA receptor [16Milnerwood A.J. Gladding C.M. Pouladi M.A. Kaufman A.M. Hines R.M. Boyd J.D. Ko R.W.Y. Vasuta O.C. Graham R.K. Hayden M.R. et al.Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice.Neuron. 2010; 65: 178-190Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]. Crucially, the exposure-based learning treatment used here also relies on NMDA receptors as illustrated by the fact that memantine impedes such learning in healthy humans [18Dinse H.R. Ragert P. Pleger B. Schwenkreis P. Tegenthoff M. Pharmacological modulation of perceptual learning and associated cortical reorganization.Science. 2003; 301: 91-94Crossref PubMed Scopus (235) Google Scholar]. The evidence thus suggests that an increased activation of NMDA receptors in early HD might enhance the degenerative process, increase LTP and speed learning. This does not, however, imply that in early HD excitotoxicity is the cause of faster learning, as hinted by the title of the Beste et al. [1Beste C. Wascher E. Dinse H.R. Saft C. Faster perceptual learning through excitotoxic neurodegeneration.Curr. Biol. 2012; 22: 1914-1917Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] paper. It is more likely that increased NMDA receptor activation is the common cause of excitotoxicity and faster learning. That NMDA receptors play an ‘ambivalent’ role with ‘good’ and ‘bad’ effects is well documented. Early attempts to block excitotoxicity in stroke with NMDA receptor antagonists quickly revealed its risks for learning and memory [19Creeley C. Wozniak D.F. Labruyere J. Taylor G.T. Olney J.W. Low doses of memantine disrupt memory in adult rats.J. Neurosci. 2006; 26: 3923-3932Crossref PubMed Scopus (118) Google Scholar]. This ambivalence was also found when studying the ‘pro-death’ and ‘pro-survival’ signals mediated by NMDA receptors in what has been termed the “NMDA receptor paradox” [20Hardingham G.E. Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders.Nat. Rev. Neurosci. 2010; 11: 682-696Crossref PubMed Scopus (1135) Google Scholar]. Similarly, when HD develops, overexpression or overactivation of various forms of NMDA receptors may lead to faster learning and to neurodegeneration. But the fact that these two effects are likely to occur in parallel, rather than in sequence, leaves some hope that the bad effects may be selectively blocked. Adapting the exposure-based learning procedure pioneered in the present study to animal models in future research could be a productive way to characterize the respective mechanisms subtending enhanced learning and excitotoxicity in Huntington's disease. Faster Perceptual Learning through Excitotoxic NeurodegenerationBeste et al.Current BiologySeptember 13, 2012In BriefGlutamatergic neural transmission is involved in both neural plasticity [1–3] and neurodegeneration [4–6]. This combination of roles could result in ambivalent effects in which excitotoxic neurodegeneration augments neural plasticity in parallel. Neural plasticity can be induced by exposure-based learning (EBL) that resembles timing properties of long-term potentiation (LTP) protocols (i.e., LTP-like learning) [7, 8]. Even though it has not been demonstrated so far in animal models that perceptual effects of such stimulation protocols are mediated by typical LTP mechanisms, it has been shown that exposure-based learning exerts strong effects on cognitive brain functioning [9] and is modulated by glutamatergic neural transmission [1]. Full-Text PDF Open Archive" @default.
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• W2015779946 title "Brain Plasticity: Paradoxical Case of a Neurodegenerative Disease?" @default.
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