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• W2080451667 abstract "The Kavli Prizes were awarded for the second time in Oslo, Norway on 7 September, 2010 to eight of the world's most prominent scientists in astrophysics, nanoscience, and neuroscience. Jerry Nelson, of the University of California, Santa Cruz, USA, Ray Wilson, formerly of Imperial College London and the European Southern Observatory, and Roger Angel, of the University of Arizona, Tucson, USA, shared the astrophysics prize for their innovative contributions in the field of telescope design. The nanoscience prize was awarded jointly to US researchers Donald Eigler, of the IBM Almaden Research Centre, San Jose, California and Nadrian Seeman, of New York University, for developing a method for moving single atoms and inventing structural DNA nanotechnology, respectively. Finally, the joint recipients of the neuroscience prize were US scientists Thomas Südhof, of Stanford University School of Medicine, Richard Scheller, of the biotech company Genentech, and James Rothman, of Yale University, for their work on the molecular basis of neurotransmitter release (See review of the laureates' work by Hussain and Davanger, 2011Hussain S. Davanger S. The discovery of the SNARE complex and the molecular regulation of synaptic vesicle transmitter release: the 2010 Kavli Prize in Neuroscience.Neuroscience. 2011; 63 (THIS ISSUE)Google Scholar, in this issue of Neuroscience). As part of the week-long Kavli Prize celebration in Oslo, The University of Oslo hosted The Kavli Prize Symposium on Neuroscience on 6 September, 2010, an event designed to celebrate excellence in Neuroscience research. At this Symposium, seven leading neuroscientists described their groundbreaking research, covering a diverse selection of problems in Neurobiology. Starting with a “public awareness” lecture by Antonio Damasio of the University of Southern California, Los Angeles, USA, the Symposium included lectures by: Richard Axel of Columbia University, New York, USA; Tobias Bonhoeffer of Max Planck Institute of Neurobiology, Martinsried, Germany; Michael E. Goldberg of Columbia University, New York, USA; Poul Nissen of Aarhus University, Denmark; Giacomo Rizzolatti of the University of Parma, Italy; and Huda Y Zoghbi of Baylor College of Medicine, Houston, Texas, USA. The seven symposium lectures described the most recent advances in understanding emotion, olfaction, visual information processing, synaptic plasticity, ion flux in neurons, perception of self and other, and the consequences of epigenetic dysregulation in the human brain. The Kavli Prize Symposium on Neuroscience was organized by Linda H. Bergersen, Edvard Moser, May-Britt Moser, and Jon Storm-Mathisen, and was made possible by the combined support of The Kavli Foundation, the Norwegian Academy of Science and Letters, and the Norwegian Ministry of Education and Research. The event was hosted by the University of Oslo, whose rector, Ole Petter Ottersen, himself a renowned neuroscientist, gave the introductory address. The Kavli Foundation is dedicated to advancing basic research for the benefit of humanity, promoting public understanding of scientific research, and supporting scientists and their work. The participants in the Symposium expressed their gratitude for the opportunity to take part in the great celebration of science, the legacy of Fred Kavli, and the achievements of the winners of the 2010 Kavli Prizes. The main points of the presentations of the 2010 Kavli Prize Symposium on Neuroscience are summarized below. Readers interested in a more detailed consideration of any of the topics discussed at the Symposium are referred to the reading list at the end of this article. Antonio Damasio University of Southern California, Los Angeles, USA The Neuroscience of Emotion and Consciousness Antonio Damasio opened the Symposium with a designated public awareness lecture, in which he elegantly described recent developments in understanding the neurological bases of emotion. Damasio emphasized the fact that multiple cortical and noncortical brain regions, including the insular cortex, the amygdala, and brain stem regions, express neural circuits that are active during human emotional experience. Early neuroscientists treated the study of emotion and feeling with deference, and consequently focused most of their research effort on other neurobiological functions and mechanisms. However, recent work, including Damasio's own studies, suggests that emotions have significant biological importance, despite early tendencies among neuroscientists to minimize their relevance to cognitive perception of the external environment. Researchers now appreciate that emotions are associated with complex and important behavioral programs and physiological responses, and that these programs are mechanisms by which the individual being, human or animal, solves specific situational problems or life-threatening encounters. In fact, for animal species that have a lower cognitive capacity than Homo sapiens, such emotional/behavioral programs can be highly advantageous. For humans, emotional responses provide great benefit in many situations, but can conflict with social and/or cultural conventions in other situations. According to Damasio, emotions are “complex programs of actions triggered by the presence of certain stimuli”. The triggers can be perceived as external or internal phenomena, and the emotions elicited by these stimuli have been grouped into several classes, including the primary emotions (fear, anger, happiness, sadness, disgust), background emotions (enthusiasm, discouragement) and complex social emotions (compassion, shame, contempt, pride, and awe/admiration). Emotions are not learned behaviors; instead, they are genetically-encoded responses to specific objects or events that correlate with neurological activity in specific brain regions. Emotional programs are enacted in well-defined stages, including initial cognitive appraisal, triggering, execution, and finally, physiological impact or upheaval. In normal individuals, neurological activity in specific brain regions correlates with specific emotions. However, some of these specific responses are altered or absent in individuals with impaired emotional capacity. For example, Damasio and other neuroscientists have extensively studied the patient “SM,” who has the rare genetic disorder Urbach–Wiethe disease. Because of this condition, SM has focal bilateral brain damage in the subcortical brain, resulting in loss of all functional response in the amygdala. Experimental studies showed that SM completely lacks normal fear responses. Thus, when presented with fear-inducing triggers, such as spiders, snakes, or videos of violent acts, SM's reaction is characterized by excessive approach, lack of withdrawal, lack of facial, or postural reactions typical of a fear response, and lack of fear conditioning. While SM's subjective rating of fear-inducing film clips scored <1 on a scale of 1–10 (normal control score was in the range 4–7), the patient reported a normal intensity of subjective experience of sadness, anger, surprise, happiness, and disgust. Similarly, sampling over a 3-month or a 1-year period, SM reported normal frequency of emotional states other than fear, but virtually no experience of fear. Nevertheless, SM was capable of experiencing “chemo-induced” fear, when exposed to inhaled CO2. This result demonstrates that the emotion of fear is evoked by two parallel neurosensory pathways, one dependent on an external stimulus (defective in SM) and the other dependent on an internal stimulus (intact in SM). Real-time magnetoencephalographic (MEG) studies of the normal neurological response to emotionally competent visual stimuli demonstrated that emotions are activated in distinct kinetic stages involving different cortical areas (Fig. 1). A recent study showed that pleasant and unpleasant visual stimuli induce strong neurological activity in the orbitofrontal cortex, ventromedial prefrontal cortex, anterior cingulate, and somatosensory cortices 350–500 ms after stimulation. Less strong responses were noted in the visual cortex in the 70–200 ms time frame, and in the ventral visual stream, temporopolar and orbitofrontal regions in the 200–350 ms time frame. Stronger activity correlated with more emotionally competent stimuli. These data suggest complex dynamics in neurological processing of emotionally competent visual stimuli. Interestingly, studies of patients with congenital hydroencephaly or herpes virus-induced cortical brain damage reveal that emotional responses (and associated neurological activity) are retained in individuals with significant loss of normal cortical structures and functions. Furthermore, in these individuals, emotional responses can be activated by both internal and external stimuli. Recent studies show distinct involvement of noncortical structures including the hypothalamus and multiple brain stem nuclei (including the nucleus of the tractus solitarius and the parabrachial nucleus), all of which are tightly and recursively interconnected in the normal brain. These and other data support the conclusion that emotional responses require and are dependent on neurological activity in multiple cortical and noncortical brain regions. Richard Axel Columbia University, New York, USA A Molecular Logic of Olfactory Perception The neurobiology of olfactory perception has been elucidated in great detail, revealing striking complexity and features that strongly distinguish olfactory perception from other sensoryneural systems. Richard Axel, whose groundbreaking research in olfactory neurobiology earned him the 2004 Nobel Prize together with Linda Buck, opened his talk by posing the question “How does the brain know what the nose knows?” This question has now been answered in great detail, aided in part by powerful imaging technology that selectively identified odor- and odorant receptor-specific activity in subsets of neurons in odor-responsive brain regions. Although there are approximately 1000 odorant receptor genes and corresponding proteins, each olfactory sensory neuron in the sensory epithelium expresses a single receptor, and in a single olfactory glomerulus, all afferent olfactory axons are from sensory neurons that express the same odorant receptor; thus, olfactory information encoded in the olfactory bulb is spatially segregated. The olfactory bulb, the first neurological relay station in odor perception and recognition, sends information mainly to five higher brain regions, including the anterior olfactory nucleus, olfactory tubercle, amygdala, entorhinal cortex, and the piriform cortex. Remarkably, the projections from neurons in a single glomerulus do not converge on a single region of the piriform cortex; in contrast, axonal projections from glomerulus neurons connect in a highly dispersed and apparently random manner to cortical neurons in the piriform cortex. Thus, the paradigm of spatial segregation, observed in the olfactory bulb, is replaced with a paradigm of spatial dispersion in the piriform cortex. Odor-specific neurological responses were visualized by injecting and imaging odor-dependent fluorescence of a calcium-activated dye in the piriform cortex of anaesthetized but odor-responsive mice. These studies revealed that every odor activates 3–15% of the neurons in the piriform cortex, that cortical neurons respond to multiple odors, and that cells responsive to one odor are interspersed with cells responsive to different odors (Fig. 2A ). Furthermore, specific odors activate an ensemble of spatially-dispersed neurons, none of which are continuously tuned to a specific trigger. Thus, unlike visual and sensory cognition, in which a two-dimensional map unifies sensory experience in the external world and sensory experience in its corresponding cognitive space in the brain, olfactory information is perceived at the cognitive level in a spatially dispersed manner, that does not correlate to a physical space in the external world. Axel hypothesized that axonal projections from the olfactory bulb to the piriform cortex are random, and that olfactory perception in this brain region is entirely associative, implying that it is defined strictly through experience. To test this idea, approximately 1000 neurons in the piriform cortex were infected with a lentiviral construct expressing light-responsive Chlamydomonas reinhardtii channel rhodopsin (ChR2) and appropriate markers. Importantly, the virus infected cells on a random basis, with no a priori selection or targeting. Infected mice were then subjected to either light-induced appetitive or light-induced aversive behavioral training. The results validate Axel's hypothesis, clearly demonstrating that a random group of piriform cortical neurons can acquire cognitive function through an experience-direction associative learning process (i.e. odor recognition as a learned behavior). Nevertheless, some olfactory responses are innate (i.e. genetically-encoded behaviors), implying that the brain perceives a select group of odors by a different mechanism, possibly involving one of the other four higher brain regions that are innervated by axons from the olfactory bulb. To explain this phenomenon, Axel hypothesized that odors that trigger an innate response are perceived by a mechanism involving a distinct group of spatially segregated glomerular projections to the posterior lateral amygdala (Fig. 2B). What might be the significance of the existence of two such divergent mechanisms for olfactory perception? In closing his talk, Axel suggested that responses to some odors, such as pheromones, have significant adaptive value, in that they contribute to survival and/or reproductive fitness, and it is likely that these odors trigger innate responses mediated by neurons in the amygdala. Tobias Bonhoeffer Max Planck Institute of Neurobiology, Martinsried, Germany How Experience Changes the Circuitry of the Brain Humans and other animal species demonstrate remarkable innate and learned behaviors. Many neurobiologists are attempting to determine the biological mechanisms underlying these behaviors, to understand how individuals adapt and modify their behavior based on experience, and how the brain stores information at the cellular level. One of the first hypotheses concerning the cellular basis of learning was advanced in 1949 by Donald O. Hebb (The Organization of Behavior, p 62), who proposed the following idea: “When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased”. Hebb's concept is considered the basis of the modern concept of synaptic plasticity, which suggests that the strength of a synaptic connection is determined by the activity patterns occurring at that specific synapse. Recent studies by Tobias Bonhoeffer and colleagues revealed experience-based changes in synaptic structures in the visual cortex of mice, thus providing a structural/morphological correlate of synaptic plasticity. Initial in vitro studies using hippocampal slices from mouse brain demonstrated that the number of tiny dendritic protrusions, so-called spines, increase during long-term potentiation (LTP) in specific brain regions. To extend this observation to an in vivo model, Bonhoeffer exploited the well-characterized paradigm of ocular dominance in the visual cortex. For this purpose, the mouse visual cortical region was imaged through a chronic cranial window, which allowed monitoring experience-induced changes in dendritic spine density as well as neuronal activity and connectivity by two-photon microscopy. Perturbations to the system included monocular deprivation (MD), with or without prior MD during the critical developmental stage for binocular vision, or with or without prior MD in the same eye (i.e. contralateral MD followed by contralateral MD vs. contralateral MD followed by ipsilateral MD). Bonhoeffer's studies showed that MD during the critical developmental period enhanced activity in the visual cortex induced by the opposite eye, both in the critical period and during repeat MD in the same eye, but had no effect on neuron firing in the visual cortex during repeat MD in the opposite eye. Two photon microscopic analysis of neural synapses in these mice showed that MD was specifically associated with a net increase in spine density as well as an increase in spine turnover in the visual cortex (Fig. 3A ). Although repeat MD in the same eye did not further increase spine density, newly added spines persisted after the end of the first MD (Fig. 3B). These data suggest that persistent spines added in the mouse visual cortex during MD may be directly related to the enhanced visual capacity and synaptic plasticity demonstrated by these mice during subsequent MD events. Thus, these data support the hypothesis that newly added or strengthened spines between communicating neurons are a structural/morphological correlate of synaptic plasticity and that changes in synaptic connectivity correlate with acquired information and learned behaviors. Future studies will explore whether changes in synaptic connectivity are also associated with more complex behavioral conditioning. Michael E Goldberg Columbia University, New York, USA The Neurophysiology of Visual Attention Visual attention is the mechanism by which the brain focuses on one object and ignores other objects. There are two types of attention: exogenous (bottom-up/involuntary) attention, which is directed towards objects with unusual or salient visual characteristics, and endogenous (top-down/voluntary) attention, directed towards objects that are perceived as behaviorally important or that are only visually important through context or association. Visual information is processed in the lateral intraparietal area (LIP) of the parietal lobe. The LIP makes extensive connections with brain areas involved in oculomotor activity (frontal eye field, superior colliculus) and visual perception (V1, V3A, V4, middle temporal area, inferior temporal area TE/TEO, parahippocampal gyrus). Michael Goldberg's recent studies analyzed processing of visual information in the LIP of monkeys trained to perform visual tasks, such as a probe-directed saccade to a visual target within or outside of a neuron's receptive field, with or without a distractor, within or outside of the receptive field. In some tasks the monkeys were rewarded by a hand movement, reporting a visual search target, and made eye movements as a natural component of visual search without reward per se. Activities of specific neurons in the LIP were measured and correlated with performance of the selected tasks. The perceptual threshold was measured by varying contrast within the visual field, or the interval between appearance of the probe and target in the visual field. Goldberg's studies established that a saccade goal has a privileged perceptual threshold during and within a short window (1.8 s) after a probe is presented to a trained monkey, and that the average neuronal activity in the monkey's LIP correlates with the animal's attentional spotlight in the visual field. Successful performance of visual tasks was predicted by average LIP activity in the receptive field 100 ms before a probe was presented. Furthermore, LIP activity correlated strongly with the visual locus of attention on a moment-by-moment and monkey-by-monkey basis. Goldberg conceptualized the results from these studies, stating that the activity in the LIP is equivalent to a real-time priority map of the visual world. Extending this concept to the search task, Goldberg showed that LIP neurons build the priority map by acting as summing junctions for three independent signals: first, a visual signal whose activity is unrelated to either the nature of the stimulus in the receptive field or the direction of the impending saccade; second, a saccadic signal that predicts the goal and latency of the impending saccade; and third, a cognitive signal that reported the nature of the object in the receptive field (target or distractor) even when the monkey made a saccade away from the object (Fig. 4A ). To evaluate this concept, neurological activity (i.e. the waveform) was calculated and compared during saccades when: (1) the monkey made a saccade to or away from a search target in the receptive field; and (2) the monkey made a saccade to or away from a distractor in the receptive field. Notably, the calculated and measured waveform was similar when saccades were made to a target in the receptive field (Fig. 4B). Activity in the priority map is modulated by a nonspecific arousal signal. In a more difficult version of the search task, the monkey had to find the target without making an eye movement. This so-called “fixation” version of the task was more difficult—the monkeys succeeded only 70% of the time on an average. Each trial began with a 500 ms epoch during which the monkey had to fixate, but did not know if the impending trial was going to be a fixation trial or a saccade trial. The baseline activity during this epoch, when the monkey could not predict the trial type or the target location correlated both with the monkey's probability of success in the task and the intensity of the neuron's response to the appearance of the search array, suggesting that the sensorimotor processing of the priority map is modulated by a signal which is more related to the monkey's state of arousal or motivation than to the specifics of the current behavior. Poul Nissen Aarhus University, Denmark The Structure and Function of Ion Pumps in Cells and Changes in Disease (or Why YY?) Brain tissue is characterized by a high metabolic rate and high rate of consumption of ATP. A significant fraction of the energy released from ATP hydrolysis in the brain is stored in the form of steep electrochemical gradients across cell membranes. This stored energy drives normal neuronal processes, including synaptic firing. The Na+K+ATPase (NKA) is a P-type ATPase that plays a critical role in establishing and maintaining membrane potentials in brain cells, increasing extracellular Na+ and decreasing extracellular K+ by pumping three Na+ ions out and two K+ ions into the cell for every ATP hydrolyzed. The enzymatic mechanism of P-type ATPases, revealed through X-ray crystallographic and extensive mutagenesis studies, involves formation and breakdown of a phosphoenzyme intermediate, which is linked to large protein domain movements and protein conformational changes. The essential neurobiological role of NKA is reflected by the fact that mutations in the catalytic alpha subunit (NKAα) are tightly linked to two neurological diseases: Familial hemiplegic migraine 2 (FHM2) and Rapid-onset dystonia Parkinsonism (RDP). Crystal structures of NKAα and the closely related plasma membrane sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) revealed considerable structural similarity between the two enzymes, including analogous ion binding sites, suggesting super-imposable sites for calcium and two of the three sodium ion binding sites in SERCA and NKA, respectively. It has been proposed that residues in transmembrane helices TM5, TM8, and TM9 of NKAα bind a third sodium ion and interact indirectly with the NKAα C-terminal region. However, the NKAα C-terminus lies 13 Å away from the proposed site, and the exact location of the third sodium ion binding site in NKAα remains unconfirmed. To address this question and to better understand the mechanism of NKA-catalyzed ion transport, Poul Nissen and colleagues conducted structural and biochemical studies on a series of NKAα variants with amino acid substitutions in the conserved C-terminal domain. The importance of the C-terminal region of NKAα was suspected, because of its highly conserved amino acid sequence, and because multiple mutations in this region cause FHM2 and RDP. In particular, NKAα2, R937P, and R1002Q variants cause FHM2, and R937 and R1002 form hydrogen bonds and cation–π interactions with conserved C-terminal residues Y1019 and Y1020. Structural studies also indicated the presence of a cavity lined by several polar and charged residues (K999, D930, N927, N858, and T778) in between the C-terminal region and the previously proposed third sodium binding site, suggesting that this cavity could play a critical structural role in a cytoplasmic ion pathway. Therefore, biochemical studies were performed to explore whether and how FHM2-linked NKA residues R937 and R1002, the C-terminal KETYY motif, and RDP-linked residue D930 modulate sodium binding and release by NKAα in vitro. For this purpose, wild type and mutant NKAα2 variants were expressed at a high level in Xenopus oocytes, and transient sodium currents were measured in vitro in the absence of potassium. Using this system, the kinetics of sodium binding and release were determined and compared for wild-type and mutant variants of NKAα2. The results showed that mutations altering proposed Site IIIa (E958A, Y775F) and proposed Site IIIb (D930A/L/E, T778V) had similar profound effects on transient sodium currents. In addition, R937P, R1002Q, Y1019A/Y2010A NKAα variants caused similar profound effects on transient NKA-mediated sodium currents, but had different/reverse effects on the kinetics of sodium binding and release. For the C-terminal mutants, the midpoint potential of the transient sodium current was strongly left-shifted (100–185 mV), and relative to wild-type NKAα, the rate constants for sodium release were much lower at negative potentials and five- to 10-fold higher at positive membrane potentials (Fig. 5A ). The inverse shape of the rate constant curves of the C-terminal mutants indicates that sodium binding is weakened and sodium release is greatly accelerated. One interpretation of these data is that the C-terminal tail occludes the third sodium binding site in wild-type NKA, and that the rate limiting step for sodium release requires a conformational shift that involves movement of the C-terminal tail and opening of the occluded sodium-binding channel. Molecular dynamic simulations confirmed this proposal, demonstrating that the C-terminal tail regulates solvent and ion access to the cavity proposed by Nissen and colleagues to play a critical role in this cytoplasmic ion binding pathway. In addition, NKAα2 variant D390N supported no transient sodium currents in vitro, and was characterized by extremely low sodium affinity and high potassium affinity (Fig. 5B). Together, these data suggest a novel unifying model for ion transport by NKA, as proposed by Nissen and colleagues and summarized as follows (Fig. 5C): starting with the sodium-bound pump, release of sodium to the extracellular space is coupled to disengagement of the C terminus from the C-terminal ion channel, after which D930 is protonated by a proton entering through the C-terminal pathway; two potassium ions bind; after occlusion, both potassium ions and one proton are released into the cytoplasm, and three sodium ions bind to complete the cycle. Importantly, this model is consistent with and postulates a plausible mechanism for the overall asymmetric stoichiometry of ion transport by NKA. Giacomo Rizzolatti University of Parma, Italy Mirror Neurons: Interpretations and Misinterpretations One of the most exciting discoveries in neurosciences over the last years has been a mechanism that unifies action perception and action execution. Giacomo Rizzolatti and coworkers propose that the essence of this mechanism—called the mirror mechanism—is the following: each time an individual observes an action performed by another person, a set of motor system mirror neurons are activated in brain areas that encode movement. Considering hand movement as an example, what is the functional role of the mirror neurons? One way to solve this problem is to examine what the mirror neurons encode when they discharge during voluntary motor behavior. Compelling evidence shows that most of these neurons encode motor acts (defined as movements with a goal, e.g. grasping), rather than movements (defined as body-part displacements without a specific goal, e.g. finger flexion). Thus, when an individual observes another person acting on an object, there is a motor copy in his/her brain similar to that underlying the goal of the action agent. This copy allows an immediate understanding of goals of others' without any cognitive inference. This understanding does not depend on some “magic” property of mirror neurons, but on the fact that mirror neurons in area F5 are connected with other cortical areas and subcortical centers. Thus, the neural pattern is similar when an individual observes a motor act and when the same individual prepares to perform that motor act. Recent data suggest that the activation of mirror neurons might also play an important role, besides goal understanding, in the perception of the visual aspects of the observed motor acts. In particular, Rizzolatti and coworkers analyzed the visual responses of mirror neurons in area F5, when monkeys were presented with videos of hand grasping motor acts from different visual perspectives (Fig. 6). Remarkably, the majority (75%) of tested neurons were activated in a specific point-of-view-dependent manner, with a smaller subset (approximately 25%) activated in a point-of-view-independent manner. The presence of view-invariant mirror neurons in area F5 is consistent with the idea that these mirror neurons encode the goal of observed motor acts. It is more difficult to interpret the significance of view-dependent mirror neurons. A fascinating possibility is that view-dependent mirror neurons, in spite of their motor nature, actually encode the visual perspective of the observed actions. This could be explained by the neural connectivity of area F5, which sends output toward motor centers and the inferior parietal lobule, which further projects to the superior temporal sulcus (STS). Such a network seems ideally suited to transfer information from premotor cortex, coding the goal of the motor act, to visual representations of the observed actions encoded in the STS. The association of motor goal understanding with the visual aspects of the presented action allows the full perception of the observed motor acts. Huda Y Zoghbi Baylor College of Medicine, Houston, USA The Story of Rett Syndrome: Where Epigenetics Meets Neurobiology Classic Rett syndrome is a postnatal developmental disorder characterized by disruption of normal development, loss of acquired language and motor skills, and onset of autistic regression, ataxia, seizures, stereotyped repetitive hand movements, and autonomic dysfunction in 12–18-month old children. The vast majority of Rett syndrome cases are caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). However, less severe and/or partial phenotypes, such as autism or mild learning disability can be associated with partial loss of MeCP2 function or favorable patterns of X chromosome inactivation in females. Mouse models for loss of function MeCP2 alleles demonstrate remarkably complete recapitulation of the human disease phenotype. Even more remarkably, transgenic mice that overexpress MeCP2, two-fold are phenotypically similar to mice that express a subnormal level or dysfunctional MeCP2. To investigate the molecular basis of this observation, Huda Zoghbi and colleagues measured the magnitude of evoked EPSCs (excitatory postsynaptic currents) in individual hippocampal glutamatergic neurons of MeCP2 null and MeCP2 transgenic mice, and discovered strong correlation between MeCP2 expression and both EPSCs and number of hippocampal glutamatergic synapses (Fig. 7A ). These data suggest that MeCP2 plays a critical role in regulating excitatory synapses. Zoghbi and colleagues also carried out gene expression studies in the cerebellum and hypothalamus of mice expressing reduced or increased number of functional copies of MeCP2. These studies demonstrated that MeCP2 differentially up- or down-regulates >1000 genes in the hypothalamus and cerebellum, and in general, the same gene showed opposite effects in the null and transgenic mice. One explanation for the phenotypic variation associated with MeCP2 mutations is that it reflects stochastic X-inactivation in subsets of neurons in which loss of MeCP2 function has different neurological consequences (Fig. 7B). To test this idea, Zoghbi and colleagues have constructed and characterized mouse models for conditional neuron-selective knockout of Mecp2. In one such model, loss of MeCP2 in Sim1 hypothalamic neurons produced a phenotype characterized by hyperphagia, obesity, and stress-induced aggression. Strikingly, a similar cluster of phenotypes has also been reported in two young male siblings with an A140V mutation in MECP2. In contrast to this partial recapitulation of Rett-associated symptoms, mice engineered for specific loss of MeCP2 in all GABAergic neurons recapitulated all symptoms of classic Rett syndrome, except tremors and anxiety. These studies are providing insight into the molecular basis of Rett syndrome and Rett-syndrome-like neurological disease and reveal the neuropathological consequences associated with neuron-selective MeCP2 dysfunction. The findings also have wide implications for understanding how a specific gene mutation can cause varied phenotypes." @default.
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• W2080451667 title "What the nose knows, what the eyes see, how we feel, how we learn, how we understand motor acts, why “YY” is essential for ion transport, how epigenetics meet neurobiology in Rett syndrome: seven topics at the 2010 Kavli Prize Symposium on Neuroscience" @default.
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