Abiraman K.,Neuroscience Program |
Chen G.-D.,State University of New York at Buffalo |
Salvi R.J.,State University of New York at Buffalo |
Sim F.J.,Neuroscience Program
Journal of Neuroscience | Year: 2015
Therapeutic repair of myelin disorders may be limited by the relatively slow rate of human oligodendrocyte differentiation. To identify appropriate pharmacological targets with which to accelerate differentiation of human oligodendrocyte progenitors (hOPCs) directly, we used CD140a/O4-based FACS of human forebrain and microarray to hOPC specific receptors. Among these, we identified CHRM3, aM3R muscarinic acetylcholine receptor, as being restricted to oligodendrocyte-biased CD140aO4 cells. Muscarinic agonist treatment of hOPCs resulted in a specific and dose-dependent blockade of oligodendrocyte commitment. Conversely, when hOPCs were cocultured with human neurons, M3R antagonist treatment stimulated oligodendrocytic differentiation. Systemic treatment with solifenacin, an FDA-approved muscarinic receptor antagonist, increased oligodendrocyte differentiation of transplanted hOPCs in hypomyelinated shiverer/rag2 brain. Importantly, solifenacin treatment of engrafted animals reduced auditory brainstem response interpeak latency, indicative of increased conduction velocity and thereby enhanced functional repair. Therefore, solifenacin and other selective muscarinic antagonists represent new adjunct approaches to accelerate repair by engrafted human progenitors. © 2015 the authors.
Papouin T.,Tufts University |
Dunphy J.M.,Neuroscience Program |
Tolman M.,Neuroscience Program |
Dineley K.T.,University of Texas Medical Branch |
Haydon P.G.,Tufts University
Neuron | Year: 2017
The activation of the N-methyl D-aspartate receptor (NMDAR) is controlled by a glutamate-binding site and a distinct, independently regulated, co-agonist-binding site. In most brain regions, the NMDAR co-agonist is the astrocyte-derived gliotransmitter D-serine. We found that D-serine levels oscillate in mouse hippocampus as a function of wakefulness, in vitro and in vivo. This causes a full saturation of the NMDAR co-agonist site in the dark (active) phase that dissipates to sub-saturating levels during the light (sleep) phase, and influences learning performance throughout the day. We demonstrate that hippocampal astrocytes sense the wakefulness-dependent activity of septal cholinergic fibers through the α7-nicotinic acetylcholine receptor (α7nAChR), whose activation drives D-serine release. We conclude that astrocytes tune the gating of synaptic NMDARs to the vigilance state and demonstrate that this is directly relevant to schizophrenia, a disorder characterized by NMDAR and cholinergic hypofunctions. Indeed, bypassing cholinergic activity with a clinically tested α7nAChR agonist successfully enhances NMDAR activation. Video Abstract © 2017 Elsevier Inc.
Hallock R.M.,Neuroscience Program |
Taverna E.C.,Neuroscience Program
Drug and Alcohol Dependence | Year: 2013
Background: Recreational usage and attitudes toward psilocybin-containing hallucinogenic mushrooms among college students are seldom explored. Methods: We surveyed 882 randomly selected undergraduates at Skidmore College in upstate New York and quantified whether participants had ever used psilocybin mushrooms, their attitudes toward the drug, and polydrug use. Results: There were 409 responses and 29.5% of the sample reported psilocybin use. Among users, the mean number of times they reported using mushrooms was 3.4 (mode. =1). The top factors cited that influenced their decisions to try hallucinogenic mushrooms for the first time were 'curiosity', 'to achieve a mystical experience', and 'introspection'. Users and non-users had significantly different perceptions of mushrooms: non-users were more likely to say that hallucinogenic mushrooms were addictive and had the potential for abuse than users. Users did not believe that psilocybin negatively impacts their academics, mental health, or physical health, while non-users did. Both users and non-users of psilocybin reported high life-time use of alcohol (97% vs 96%, respectively), marijuana (98% vs 73%, respectively) and tobacco (82% vs 54%, respectively). Psilocybin users were significantly more likely to use other drugs such as cocaine, ecstasy, opiates, non-prescribed prescription drugs, opiates, and lysergic acid diethylamide (LSD) than non-users of psilocybin. Conclusion: This study uncovers important insights into hallucinogenic mushroom use by college students. © 2012 Elsevier Ireland Ltd.
Moussa M.N.,Neuroscience Program
PLoS ONE | Year: 2012
At rest, spontaneous brain activity measured by fMRI is summarized by a number of distinct resting state networks (RSNs) following similar temporal time courses. Such networks have been consistently identified across subjects using spatial ICA (independent component analysis). Moreover, graph theory-based network analyses have also been applied to resting-state fMRI data, identifying similar RSNs, although typically at a coarser spatial resolution. In this work, we examined resting-state fMRI networks from 194 subjects at a voxel-level resolution, and examined the consistency of RSNs across subjects using a metric called scaled inclusivity (SI), which summarizes consistency of modular partitions across networks. Our SI analyses indicated that some RSNs are robust across subjects, comparable to the corresponding RSNs identified by ICA. We also found that some commonly reported RSNs are less consistent across subjects. This is the first direct comparison of RSNs between ICAs and graph-based network analyses at a comparable resolution. © 2012 Moussa et al.
Aston E.R.,Neuroscience Program |
Aston E.R.,Brown University |
Liguori A.,Neuroscience Program
Psychology of Addictive Behaviors | Year: 2014
The current study evaluated the relationships among trait anxiety, subjective response to alcohol, and simulated driving following a simulated alcohol binge. Sixty drinkers with a binge history completed the State Trait Anxiety Inventory (STAI), the Alcohol Use Questionnaire, and subsequently completed a driving simulation. Participants were then administered 0.2 g/kg ethanol at 30-min intervals (cumulative dose 0.8 g/kg). Following alcohol consumption, the Biphasic Alcohol Effects Scale (BAES) and visual analog scales of subjective impairment and driving confidence were administered, after which simulated driving was reassessed. Due to the emphasis on simulated driving after drinking in the current study, subjective response to alcohol (i.e., self-reported sedation, stimulation, impairment, and confidence in driving ability) was assessed once following alcohol consumption, as this is the time when drinkers tend to make decisions regarding legal driving ability. Alcohol increased driving speed, speeding tickets, and collisions. Sedation following alcohol predicted increased subjective impairment and decreased driving confidence. Subjective impairment was not predicted by sensitivity to stimulation or trait anxiety. High trait anxiety predicted low driving confidence after drinking and this relationship was mediated by sedation. Increased speed after alcohol was predicted by sedation, but not by trait anxiety or stimulation. Anxiety, combined with the sedating effects of alcohol, may indicate when consumption should cease. However, once driving is initiated, sensitivity to sedation following alcohol consumption is positively related to simulated driving speed. © 2014 American Psychological Association.
Papke D.,Neuroscience Program |
Gonzalez-Gutierrez G.,Neuroscience Program |
Gonzalez-Gutierrez G.,University of Illinois at Urbana - Champaign |
Grosman C.,Neuroscience Program |
Grosman C.,University of Illinois at Urbana - Champaign
Journal of Physiology | Year: 2011
During fast synaptic transmission, series of brief pulses of highly concentrated neurotransmitter impinge repetitively on the postsynaptic membrane. The number of neurotransmitter-gated ion channels (NGICs) that open in response to each neurotransmitter pulse may increase or decrease along such trains of stimuli to an extent that can affect the transmission of action potentials. This 'short-term' plasticity results from transient changes (lasting from milliseconds to minutes) in the properties of the presynaptic terminal, the postsynaptic terminal, or both. In this paper, we studied eight representative members of all three known superfamilies of NGICs to determine the extent to which short-term plasticity can occur at the postsynaptic-receptor level. We found that the responsiveness of all tested channels declines appreciably along trains of brief neurotransmitter pulses delivered at physiologically relevant frequencies. We suggest that the role of receptor desensitization in the synaptic control of action-potential transmission may be more general than previously thought. Abstract Changes in synaptic strength allow synapses to regulate the flow of information in the neural circuits in which they operate. In particular, changes lasting from milliseconds to minutes ('short-term changes') underlie a variety of computational operations and, ultimately, behaviours. Most studies thus far have attributed the short-term type of plasticity to activity-dependent changes in the dynamics of neurotransmitter release (a presynaptic mechanism) while largely dismissing the role of the loss of responsiveness of postsynaptic receptor channels to neurotransmitter owing to entry into desensitization. To better define the response of the different neurotransmitter-gated ion channels (NGICs) to repetitive stimulation without interference from presynaptic variables, we studied eight representative members of all three known superfamilies of NGICs in fast-perfused outside-out patches of membrane. We found that the responsiveness of all tested channels (two nicotinic acetylcholine receptors, two glycine receptors, one GABA receptor, two AMPA-type glutamate receptors and one purinergic receptor) declines along trains of brief neurotransmitter pulses delivered at physiologically relevant frequencies to an extent that suggests that the role of desensitization in the synaptic control of action-potential transmission may be more general than previously thought. Furthermore, our results indicate that a sizable fraction (and, for some NGICs, most) of this desensitization occurs during the neurotransmitter-free interpulse intervals. Clearly, an incomplete clearance of neurotransmitter from the synaptic cleft between vesicle-fusion events need not be invoked to account for NGIC desensitization upon repetitive stimulation. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.
Russ J.B.,Rockefeller University |
Russ J.B.,Sloan Kettering Institute |
Kaltschmidt J.A.,Neuroscience Program |
Kaltschmidt J.A.,New York Medical College |
Kaltschmidt J.A.,Sloan Kettering Institute
Open Biology | Year: 2014
Every behaviour of an organism relies on an intricate and vastly diverse network of neurons whose identity and connectivity must be specified with extreme precision during development. Intrinsically, specification of neuronal identity depends heavily on the expression of powerful transcription factors that direct numerous features of neuronal identity, including especially properties of neuronal connectivity, such as dendritic morphology, axonal targeting or synaptic specificity, ultimately priming the neuron for incorporation into emerging circuitry. As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics. As a result, disruption of one component of the circuitry during development can have vital consequences for the proper identity specification of its synaptic partners. Recent studies have begun to harness the power of various transcription factors that control neuronal cell fate, including those that specify a neuron's subtype-specific identity, seeking insight for future therapeutic strategies that aim to reconstitute damaged circuitry through neuronal reprogramming. © 2014 The Authors. Published.
News Article | December 4, 2015
New research from Duke University helps explain the paradox of why we are quick to blame people for their actions, but slower to give them credit. We constantly read others’ intentions in what they do -- from seeing someone help an elderly person cross the street or cutting in line or committing a heinous crime. Judgments about intentionality are threaded deeply within our legal system and pervasive in our support of political candidates, and have been the focus of discussion for the past decade in the philosophical literature. Published Dec. 4 in Scientific Reports, the Duke study is “the first to use neuroscience research tools to try to explain why people are biased toward treating negative actions as intentional but positive actions as unintentional,” said the study’s lead author Lawrence Ngo, now a first-year resident in internal medicine at the Moses H. Cone Memorial Hospital in Greensboro, N.C. Take this scenario commonly used in the field of experimental philosophy: The CEO knew the plan would harm the environment, but he did not care at all about the effect the plan would have on the environment. He started the plan solely to increase profits. Did the CEO intentionally harm the environment? If you said ‘yes,’ then you align with the majority: In previously published work, 82 percent responded that the CEO was deliberate. When the researchers replaced the single word “harm” with “help” in the scenario, however, only 23 percent deemed the CEO’s actions intentional. The research team found similar results when they posed numerous similar situations to study participants. “There’s no logical reason why we would call something intentional, just because it causes a bad outcome as opposed to a good outcome,” said corresponding author Scott Huettel, professor of psychology and neuroscience and member of the Duke Institute for Brain Sciences. “Intentionality implies purpose on the part of the person, and that should be there for good as much as it is for bad. But it’s not,” Huettel added. To understand why, Huettel’s team assessed differences in personality traits and other psychological measures. Using functional magnetic resonance imaging, a type of non-invasive brain scan, the researchers also analyzed activity of individuals’ brains while they read the scenarios. The team found that people use two different mechanisms to judge how intentional an action was. If the action produced a negative effect, participants were more likely to draw on brain areas involved in processing emotion (in particular, the amygdala, a pair of almond-shaped structures deep in the brain that is well known for its role in processing negative emotions). The greater the emotional reaction the participant reported having to a particular story, the stronger it activated their amygdala. But if an action produced a positive effect, it was less likely to set off the amygdala. On the other hand, for positive outcomes people relied less on emotion and more on statistics. That is, they thought about how often people in a particular situation would behave in a similar way. In the example of the CEO who makes a profit and also helps the environment, participants were more likely to say that because CEOs commonly aim to make money, helping the environment was an unintentional side-effect. How intentional a crime was often affects the final ruling, and our broader moral judgments. But the new study, Huettel said, shows that the arrow can go in both directions: Moral judgments about whether an action harmed others can influence judgments about how intentional that action was in the first place. More generally, “the most rewarding part of the work was how seeing how the intersection between philosophy and neuroscience gave us new insights about both fields,” Ngo said. Duke researchers are already making strides toward bridging these disparate fields. Huettel and his collaborators are planning new studies on trust, deception and altruism. This research was supported by the Duke University School of Medicine Medical Scientist Training Program , the Wakeman Fellowship, the Kenan Institute for Ethics Graduate Fellowship, Duke University’s Neuroscience Program of Research, the National Institutes of Mental Health and the Duke Institute for Brain Sciences.
News Article | December 5, 2016
A preclinical study by investigators at the Medical University of South Carolina provides strong evidence that pericytes are the primary locus of matrix-mellaproteinase-9-dependent (MMP-9) capillary damage and blood leakage during ischemia Pericytes are the primary locus of matrix-mellaproteinase-9-dependent (MMP-9) capillary damage and blood leakage during ischemia, according to preclinical findings reported by Medical University of South Carolina (MUSC) investigators in an article published online on November 14, 2016 by The Journal of Neuroscience. In vivo two-photon microscopy revealed MMP-9 activity and plasma leakage disproportionately occurred at locations where pericyte somata were attached to the endothelium. These results suggest that pericytes, normally essential for blood-brain barrier (BBB) function, contribute to capillary damage during stroke. The BBB--a highly specialized vascular structure--prevents the entry of blood-borne substances that can harm the brain (e.g., neurotransmitters such as glutamate, clotting factors such as fibrin, and free radical-generating substances such as iron). During ischemic stroke and related cerebrovascular diseases, the BBB is damaged, allowing incursion of blood plasma that injures neurons and other structures essential for normal cerebral function. The role of pericytes as builders and custodians of the BBB is well recognized, but how pericytes respond to blood flow loss in the adult brain has largely been a mystery, until now. MUSC researchers recently harnessed cutting-edge technology to image pericytes in the intact brains of live mice and to spatially and temporally track the proteolytic enzyme, MMP-9, as the BBB degraded and blood began leaking into the brain. Findings from this novel study not only provide critical new information about pericytes as a potent source of MMP-9 during BBB leakage but also open new discovery pathways for future therapies in neurological conditions involving ischemia. It all began when Robert Underly, a Ph.D .candidate in the MUSC College of Graduate Studies Neuroscience Program and first author on the article, noticed that, when a laser was used to induce ischemic strokes in the laboratory, BBB leakage occurred at very specific sites along the capillaries. "I'd assumed that blood leakage occurred along the entire capillary length," said Underly. "But it wasn't like that. There were hot spots that leaked first and more than the rest of the capillary bed. That was really unexpected." Andy Y. Shih, Ph.D., Assistant Professor of Neurosciences and senior author on the article, and his team followed up on Underly's observation. "We found a very close association between where the round cell bodies of pericytes were located and where the leaks occurred," said Shih. "So that was our first clue that the pericytes were possibly doing something harmful in the early stages of an ischemic stroke." It is well known that the BBB becomes dysfunctional when genetic defects disrupt pericyte-endothelial signaling from birth. However, very little is known about how normally developed pericytes in the adult brain respond during acute ischemia, and only one or two studies have investigated this in vivo. "Pericytes have a lot of potential functions--they seem to be a sort of a jack-of-all-trades," said Shih. "We've had an idea of what these cells do, but we haven't been able to visualize and track them in vivo until recently." The team was also intrigued by a handful of published studies showing that various inflammatory signaling cascades can induce pericyte MMP-9 expression. "The problem is that, like pericytes, MMPs are hard to study in vivo--most of what we know about them is from studies on cultured cells or extracted brains," said Underly. "We wanted to probe this process in live animals so we could see the spatiotemporal relationship between pericytes and MMP activation in vivo--in the acute stroke time frame." To do this, the team combined several novel tools to create a unique study protocol using transgenic mice, two-photon fluorescent microscopy, and a fluorescent gelatin-based reporter of MMPs that only one other research group had ever used to study the intact brain. The researchers also used photothrombosis to block blood flow in a small area of the capillary bed and imaged transgenic mouse lines expressing bright fluorescent reporters specifically in the pericytes to clearly identify them. "The successful combination of technologies is certainly one of the innovations of this project," said Shih. "It's the first study to combine these tools to look at the relationship among pericytes, MMP activity, and BBB leakage in ischemia." Their findings revealed that ischemia resulted in extremely rapid (within tens of minutes), localized activation of MMP-9 and plasma leakage. Furthermore, plasma leakage occurred preferentially where the pericyte somata adjoined the capillary wall--not homogeneously along the length of the capillaries as previously imagined by the group. These results provide strong evidence that pericytes--normally protectors of the BBB--contribute to early BBB degradation during ischemic stroke. Using the new technology, the team did not have to extract and cut the brain and so did not lose the structure of the vasculature and blood flow. "We had an intact system and could see where things were coming from and we were very surprised," said Shih. "I thought, 'I've been looking at this for years and I never knew that there was this beautiful co-localization.' It told us we were looking at something really interesting. The pericytes seem to nurture or damage the BBB depending on the conditions they're put in." This discovery opens many directions for further study and could eventually lead to new therapeutic options for patients experiencing an acute stroke. "The very rapid reaction we saw to ischemia is really important and provides clues to potential mechanisms by which MMPs may be up-regulated," explained Underly. "This is a future direction for our research--to define upstream regulators of this process that can be therapeutically targeted." "The findings raise so many new research questions," said Shih. "For example, why do pericytes have so much MMP? What are they doing with it? What happens to pericytes days to weeks after an ischemic event? There's so much still to be understood about the acute phenomena--we're focused on that for now. In the future, we could look at later, post-injury, events to see what happens next in the life of the pericyte." Indeed, in vivo cellular-level imaging research has a bright future. "There's a renaissance happening with the development of new molecular tools to image and modify cell function in vivo," said Shih. "We're going to see a lot more integration between tool-makers and in vivo imaging groups in the next decade or two. There are going to be many more studies looking at the intact brain." "It's important to fund projects like this because with in vivo imaging we're able to track exactly what happens when brain function breaks down," said Underly. "The disease state occurs in front of our eyes." Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.
Aston E.R.,Neuroscience Program |
Liguori A.,Neuroscience Program
Addictive Behaviors | Year: 2013
This article reviews the history of blood alcohol concentration (BAC) estimation training, which trains drinkers to discriminate distinct BAC levels and thus avoid excessive alcohol consumption. BAC estimation training typically combines education concerning alcohol metabolism with attention to subjective internal cues associated with specific concentrations. Estimation training was originally conceived as a component of controlled drinking programs. However, dependent drinkers were unsuccessful in BAC estimation, likely due to extreme tolerance. In contrast, moderate drinkers successfully acquired this ability. A subsequent line of research translated laboratory estimation studies to naturalistic settings by studying large samples of drinkers in their preferred drinking environments. Thus far, naturalistic studies have provided mixed results regarding the most effective form of BAC feedback. BAC estimation training is important because it imparts an ability to perceive individualized impairment that may be present below the legal limit for driving. Consequently, the training can be a useful component for moderate drinkers in drunk driving prevention programs. © 2013 Elsevier Ltd.