The Role Of The Nmda Receptor In Shaping Cortical Activity During Development

Currently, it is estimated that neuropsychiatric disorders will affect 20-25% of humans in their lifetime. These disorders are a major cause of mortality, suffering, and economic cost to society. Within this broad class, neurodevelopmental disorders (NDDs), including intellectual disability, autism spectrum disorder, and schizophrenia, are estimated to affect 2-5% percent of the world population. Devastatingly, we lack fundamental treatments for NDDs, which have proved some of the most imposing disorders to understand scientifically. The challenge is twofold: first, NDDs affect the most complex aspects of human cognition; second, pathogenesis begins early in neural circuit development, but we lack predictive biomarkers before overt behavioral deficits are apparent. Although we have identified many genes associated with these disorders, how underlying genetic disruptions lead to pathological neural network development and function remains unclear. The overarching framework of this dissertation is that all NPDs are disorders of distributed neural networks, and pathophysiology must be understood at this level to effectively intervene clinically. The cerebral cortex is necessary for complex human capacities, and cortical dysfunction is hypothesized to be central to the pathophysiology of NDDs. NMDA glutamate receptors (NMDARs) are important for the development of local circuit features in the cortex, for normal neurocognitive function, and are strongly implicated in NDDs. However, the role of NMDARs in the development of the large-scale cortical network dynamics that underly higher cognition has not been well examined. Understanding the role of NMDARs at this network level is critical because large-scale “functional connectivity” patterns are thought to be hallmarks of normal cortical function, are hypothesized to be disrupted in NDDs, and may be detectable in humans using non-invasive neuroimaging or electrophysiology. In the studies presented in this dissertation, I (in collaboration and with the support of my colleagues) tested the role of the NMDAR in shaping large-scale cortical network organization using in vivo widefield imaging of whole cortex spontaneous activity in developing mice. I found that NMDAR function in the lineage that includes cortical excitatory neurons and glia, specifically, was critical for the elaboration of normal cortical activity patterns and dynamic network organization. In the first set of experiments, NMDARs were deleted in glutamatergic excitatory neurons (Emx1-cre+/WT/Grin1f/f ; referred to as EX-NMDAR KO mice) or GABAergic inhibitory neurons (Nkx2.1+/WT/Grin1f/f; referred to as IN-NMDAR KO mice). The developing cortex normally exhibits a diverse range of spatio-temporal patterns, reflecting the emergence of functionally associated sub-networks. In EX-NMDAR KO mice, normal patterns of spontaneous activity were severely disrupted and reduced to a nearly one-dimensional dynamic space dominated by large, cortex-wide events. Interestingly, in IN-NMDAR KO mice, the structure and complexity of spontaneous activity was largely normal. In the next set of experiments, I tested the role of extrinsic thalamic neurotransmission on cortical activity during development. Deleting the vesicular glutamate transporter from thalamic neurons while leaving cortical NMDARs intact (Sert-Cre+/−,vglut1−/−,vglut2fl/fl; referred to as TH-VG KO mice) led to a shift in cortical activity patterns towards large domains of activity, reminiscent of patterns observed in EX-NMDAR KO mice. This manipulation also reduced the dimensionality of cortical activity, though not as severally as in EX-NMDAR KO mice. In a final set of experiments, I tested cortical activity in three established mouse models of mono-genetic causes of NDDs in humans: the FMR1-KO mouse based on Fragile X Syndrome, the CNTNAP2-KO mouse, and the TS2-neo mouse based on Timothy Syndrome. In all three of these mouse models, I found that large-scale cortical activity patterns were largely normal, but there was a statistically significant shift towards reduced cortex-wide synchrony and increased dimensionality of spontaneous activity, which may be consistent with the disconnectivity hypothesis of autism. In a final set of experiments, we tested our hypothesis, based on past literature and our results in EX-NMDAR KO and TH-VG KO mice, that the disruptions in cortical activity was predominantly due to the developmental loss of activity-dependent wiring of circuits. To test the developmental versus acute role of NMDAR function in shaping cortical activity, I blocked NMDAR pharmacologically in wild-type mice. I found that acute NMDAR blockade shifted cortical activity to a restricted dynamic space similar to that observed in EX-NMDAR KO mice and more extreme than that observed in TH-VG KO mice. These results strongly reinforce the critical role of NMDAR in shaping cortical activity during development, and suggest that a substantial component of that may be through NMDAR’s role in synaptic transmission and moment to moment cortex-wide circuit function. Overall, these results provide critical insight into the role of NMDARs and the glutamatergic system in cortical network functional organization during development. Specifically, they highlight the essential role of NMDARs in excitatory neurons on the functional connectivity and dynamic repertoire of the cortical network during development. These results make novel contribution to our understanding of how NMDARs may contribute to the pathophysiology of NDDs. Specifically, they contribute powerful new insight into to a critical mechanistic question about the cell-specific role of NMDARs in the pathophysiology of schizophrenia and the mechanisms of NMDAR antagonists, which have transformed psychiatry recently due to their rapid-acting anti-depressant and anti-suicidal properties. Furthermore, they identify a patterns of large-scale network dysfunction that might be detectable in humans using noninvasive functional imaging or electrophysiology

A human factors evaluation of an electronic display system for an aircraft flight deck

This thesis describes a two and a half year study of the human factors associated with the introduction of electronic displays, i.e. cathode ray tubes, and their associated controls onto a civil transport aircraft flight deck. A simulator was constructed for the evaluation which was managed jointly by the British Aircraft Corporation Ltd. and Hawker Siddeley Aviation Ltd. (now British Aerospace) under a Ministry of Defence contract.[Continues.

Time-lapse capacitive resistivity imaging: a new technology concept for the monitoring of permafrost

The British Geological Survey, in partnership with the Universities of Sussex and Bonn, is investigating and seeking to prove a new technology concept for the non-invasive volumetric imaging and routine temporal monitoring of the thermal state of permafrost (Figure 1), a key indicator of global climate change. Capacitive Resistivity Imaging (CRI), a technique based upon a low-frequency, capacitively-coupled measurement approach (Kuras et al., 2006) is applied in order to emulate Electrical Resistivity Tomography (ERT) methodology, but without the need for galvanic contact on frozen soils or rocks. Recent work has shown that temperature-calibrated ERT using galvanic sensors (Figure 2) is capable of imaging recession and re-advance of rock permafrost in response to the ambient temperature regime. However, the use of galvanic sensors can lead to significant practical limitations on field measurements due to high levels of and large variations in contact resistances between sensors and the host material as it freezes and thaws Figure 3). The capacitive technology developed here overcomes this problem and provides a more robust means of making high-quality resistance measurements with permanently installed sensors over time. Reducing the uncertainty associated with uncontrolled noise from galvanic sensors increases the value of time-lapse ERT datasets in the context of monitoring permafrost

Analisa Aktivitas Antibakteri dari Ekstrak Metanol Buah Andaliman terhadap Pseudomonas Aeruginosa Secara In Vitro

Andaliman (Zanthoxylum acanthopodium DC) tergolong rempah-rempah dengan ciri khas tersendiri, terutama tumbuh di Sumatera Utara. Penelitian ini diklasifikasikan sebagai penelitian eksperimental dengan menerapkan desain kelompok kontrol post-test-only in vitro. Tujuan dari penelitian ini adalah untuk menganalisis efek antibakteri ekstrak metanol buah Andaliman terhadap Pseudomonas aeruginosa. Aktivitas antibakteri ekstrak metanol buah andaliman tidak hanya disebabkan oleh senyawa aktif yang dikandungnya, tetapi dapat juga disebabkan oleh jenis bakterinya. Pseudomonas aeruginosa merupakan bakteri gram negatif yang lebih resisten terhadap senyawa antimikroba

Implications of sampling design and sample size for national carbon accounting systems

<p>Abstract</p> <p>Background</p> <p>Countries willing to adopt a REDD regime need to establish a national Measurement, Reporting and Verification (MRV) system that provides information on forest carbon stocks and carbon stock changes. Due to the extensive areas covered by forests the information is generally obtained by sample based surveys. Most operational sampling approaches utilize a combination of earth-observation data and in-situ field assessments as data sources.</p> <p>Results</p> <p>We compared the cost-efficiency of four different sampling design alternatives (simple random sampling, regression estimators, stratified sampling, 2-phase sampling with regression estimators) that have been proposed in the scope of REDD. Three of the design alternatives provide for a combination of in-situ and earth-observation data. Under different settings of remote sensing coverage, cost per field plot, cost of remote sensing imagery, correlation between attributes quantified in remote sensing and field data, as well as population variability and the percent standard error over total survey cost was calculated. The cost-efficiency of forest carbon stock assessments is driven by the sampling design chosen. Our results indicate that the cost of remote sensing imagery is decisive for the cost-efficiency of a sampling design. The variability of the sample population impairs cost-efficiency, but does not reverse the pattern of cost-efficiency of the individual design alternatives.</p> <p>Conclusions, brief summary and potential implications</p> <p>Our results clearly indicate that it is important to consider cost-efficiency in the development of forest carbon stock assessments and the selection of remote sensing techniques. The development of MRV-systems for REDD need to be based on a sound optimization process that compares different data sources and sampling designs with respect to their cost-efficiency. This helps to reduce the uncertainties related with the quantification of carbon stocks and to increase the financial benefits from adopting a REDD regime.</p

Anti-Terrorism, Citizenship and Security

This book explores how different publics make sense of and evaluate anti-terrorism powers within the UK, and the implications of this for citizenship and security. Drawing on primary empirical research, the book argues that whilst white individuals are not unconcerned about the effects of anti-terrorism, ethnic minority citizens (including, but not only those identifying as Muslim) believe that anti-terrorism powers have impacted negatively on their citizenship and security. This book thus offers the first systematic engagement with 'vernacular' or 'everyday' understandings of anti-terrorism policy, citizenship and security. It argues that while transformations in anti-terrorism frameworks impact on public experiences of security and citizenship, they do not do so in a uniform, homogeneous, or predictable manner. At the same time, public understandings and expectations of security and citizenship themselves shape how developments in anti-terrorism frameworks are discussed and evaluated. This important new book will be of interest to researchers and students working in a wide range of disciplines including Political Science, International Relations, Security Studies and Sociology

From Precaution to Prejudice: Mistakes in Counter Terrorism

This chapter disaggregates the mistakes, errors and miscalculations around counter-terrorism policy. We note the difficulties in assessing when ‘something goes wrong’ in counter-terrorism which centre around the issue of uncertainty. We reflect on how to calculate the impacts of counter-terrorism in objective and subjective terms, before considering specific aspects of counter-terrorism in examples from British counter-terrorism policing and measures. We distinguish three types of ‘mistakes’: ‘genuine’ errors, misapplication of policy and unintended consequences. We consider the effects of such mistakes, in the form of ‘suspect communities’ and the ways in which high-profile mistakes come to shape perceptions of counter-terrorism practices. Given the inherent uncertainty and the seeming decision to prioritise precautionary logics, ‘mistakes’ in counter-terrorism are inevitable

THE YIN-AND-YANG OF COLLABORATIVE CONSUMPTION DEVELOPMENT: THE ROLE OF AMBIDEXTROUS IS CAPABILITIES AT GOGET CARSHARE

In this paper, we present a model of how ambidextrous IS capabilities enact the development and management of collaborative consumption platforms. Collaborative consumption in an increasingly digital economy is emergent, and fosters hyper-connections among human actors, organizations, and processes in the negotiating and sharing of goods and services. Despite this, existing literature does not provide actionable process models, nor does it meaningfully engage with the role of IS in understanding how collaborative consumption platforms create value. We present a study of GoGet, a car-sharing platform, service and community that has experienced significant growth over the past decade. Based on preliminary findings and drawing on IS capabilities as theoretical lens, we reveal a four-stage process model − minimizing, attaining, extending and optimizing − central to achieving a balance between growth and control objectives in a collaborative consumption ecosystem. Our ongoing study, which seeks to reveal a roadmap as to how IS capabilities facilitate this new mode of consumption, has implications for both theory and practice