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  • What Is a Cognitive Map? Organizing Knowledge for Flexible Behavior.

    22 November 2018

    It is proposed that a cognitive map encoding the relationships between entities in the world supports flexible behavior, but the majority of the neural evidence for such a system comes from studies of spatial navigation. Recent work describing neuronal parallels between spatial and non-spatial behaviors has rekindled the notion of a systematic organization of knowledge across multiple domains. We review experimental evidence and theoretical frameworks that point to principles unifying these apparently disparate functions. These principles describe how to learn and use abstract, generalizable knowledge and suggest that map-like representations observed in a spatial context may be an instance of general coding mechanisms capable of organizing knowledge of all kinds. We highlight how artificial agents endowed with such principles exhibit flexible behavior and learn map-like representations observed in the brain. Finally, we speculate on how these principles may offer insight into the extreme generalizations, abstractions, and inferences that characterize human cognition.

  • Time-Dependent, HIV-Tat-Induced Perturbation of Human Neurons In Vitro: Towards a Model for the Molecular Pathology of HIV-Associated Neurocognitive Disorders.

    5 November 2018

    A significant proportion of human immunodeficiency virus type 1 (HIV)-positive individuals are affected by the cognitive, motor and behavioral dysfunction that characterizes HIV-associated neurocognitive disorders (HAND). While the molecular etiology of HAND remains largely uncharacterized, HIV transactivator of transcription (HIV-Tat) is thought to be an important etiological cause. Here we have used mass spectrometry (MS)-based discovery proteomics to identify the quantitative, cell-wide changes that occur when non-transformed, differentiated human neurons are treated with HIV-Tat over time. We identified over 4000 protein groups (false discovery rate <0.01) in this system with 131, 118 and 45 protein groups differentially expressed at 6, 24 and 48 h post treatment, respectively. Alterations in the expression of proteins involved in gene expression and cytoskeletal maintenance were particularly evident. In tandem with proteomic evidence of cytoskeletal dysregulation we observed HIV-Tat induced functional alterations, including a reduction of neuronal intrinsic excitability as assessed by patch-clamp electrophysiology. Our findings may be relevant for understanding in vivo molecular mechanisms in HAND.

  • Ion dynamics during seizures.

    5 November 2018

    Changes in membrane voltage brought about by ion fluxes through voltage and transmitter-gated channels represent the basis of neural activity. As such, electrochemical gradients across the membrane determine the direction and driving force for the flow of ions and are therefore crucial in setting the properties of synaptic transmission and signal propagation. Ion concentration gradients are established by a variety of mechanisms, including specialized transporter proteins. However, transmembrane gradients can be affected by ionic fluxes through channels during periods of elevated neural activity, which in turn are predicted to influence the properties of on-going synaptic transmission. Such activity-induced changes to ion concentration gradients are a feature of both physiological and pathological neural processes. An epileptic seizure is an example of severely perturbed neural activity, which is accompanied by pronounced changes in intracellular and extracellular ion concentrations. Appreciating the factors that contribute to these ion dynamics is critical if we are to understand how a seizure event evolves and is sustained and terminated by neural tissue. Indeed, this issue is of significant clinical importance as status epilepticus-a type of seizure that does not stop of its own accord-is a life-threatening medical emergency. In this review we explore how the transmembrane concentration gradient of the six major ions (K(+), Na(+), Cl(-), Ca(2+), H(+)and [Formula: see text]) is altered during an epileptic seizure. We will first examine each ion individually, before describing how multiple interacting mechanisms between ions might contribute to concentration changes and whether these act to prolong or terminate epileptic activity. In doing so, we will consider how the availability of experimental techniques has both advanced and restricted our ability to study these phenomena.

  • Treatment of infants with epilepsy: Common practices around the world.

    5 November 2018

    OBJECTIVES: High quality data to guide recommendations for infants with epilepsy are lacking. This study aimed to develop an understanding of common practice and regional variations in the treatment interventions of infants with epilepsy, and also to identify areas for further study and to highlight where common practice occurs without sound evidence. METHOD: A survey addressed clinical treatment practice for infants with epilepsy. Alternative interventions were included. RESULTS: The survey found that most regions had similar practice for first-line interventions, except for North America, where more levetiracetam was prescribed. There was a preference for valproate as first-line therapy for generalized seizures, myoclonic seizures, and Dravet syndrome; only Oceania differed for generalized and myoclonic seizures. Phenobarbital was used for generalized and focal seizures in resource-poor and resource-equipped regions. Carbamazepine and oxcarbazepine were the preferred agents for focal seizures from all regions except North America, which uses more levetiracetam. For second- and third-line interventions, the range of choices was diverse, often with little correlation across regions. The ketogenic diet, vagus nerve stimulation, and epilepsy surgery were considered viable choices in most settings, but usually only once seizures were considered medically refractory. The survey highlighted the marked discrepancy in Africa, the one region that consistently confirmed a lack of access to these alternative interventions and to the newer antiepileptic drugs. SIGNIFICANCE: More randomized controlled trials in infants with seizures are needed to permit useful recommendations. The survey identified widespread use of levetiracetam in North America, which may be the result of effective marketing or based on good clinical practice. The widespread use of valproate may have safety implications. The lack of access to care in the African region highlighted the need for more sustained resources. Although the survey was not evidence based, the findings could be useful to support additional well-designed studies.

  • Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis.

    5 November 2018

    Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl- ions based on the neuronal Cl- driving force. Established theories regarding the determinants of Cl- driving force have recently been questioned. Here, we present biophysical models of Cl- homeostasis using the pump-leak model. Using numerical and novel analytic solutions, we demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl- driving force. Our models, together with experimental validation, show that while impermeant anions can contribute to setting [Cl-]i in neurons, they have a negligible effect on the driving force for Cl- locally and cell-wide. In contrast, we demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signaling in neurons. Our findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.

  • Openspritzer: an open hardware pressure ejection system for reliably delivering picolitre volumes.

    5 November 2018

    The ability to reliably and precisely deliver picolitre volumes is an important component of biological research. Here we describe a high-performance, low-cost, open hardware pressure ejection system (Openspritzer), which can be constructed from off the shelf components. When connected to a standard micro-pipette via suitable pneumatic tubing, the device is capable of delivering minute doses of reagents to a wide range of biological and chemical systems. In this work, we characterise the performance of the device and compare it to a popular commercial system using two-photon fluorescence microscopy. We found that Openspritzer provides the same level of control over delivered reagent dose as the commercial system. Next, we demonstrate the utility of Openspritzer in a series of standard neurobiological applications. First, we used Openspritzer to deliver precise amounts of the neurotransmitters glutamate and GABA to hippocampal neurons to elicit time- and dose-precise excitatory and inhibitory responses, respectively. Second, we used Openspritzer to deliver infectious viral and bacterial agents to living tissue. Viral transfection of hippocampal interneurons with channelrhodopsin allowed for the optogenetic manipulation of hippocampal circuitry with light. Finally, we successfully used Openspritzer to infect organotypic hippocampal slice cultures with fluorescent Mycobacterium bovis bacilli. We anticipate that due to its high performance and low cost Openspritzer will be of interest to a broad range of researchers working in the life and physical sciences.

  • The attitudes of medical students to research.

    5 November 2018

    BACKGROUND: The workforce of 'physician--scientists' is ageing and decreasing in numbers. The responsibility to combat this trend rests on future generations of healthcare professionals and it is therefore valuable to evaluate medical students' attitudes towards research. OBJECTIVE: To establish the attitudes of University of Cape Town (UCT) medical students towards research and to investigate the factors influencing these attitudes. METHODS: An anonymous, cross--sectional, self--administered questionnaire was administered to medical students from years 1 to 6 studying medicine at UCT in 2011. Questions were primarily closed--ended and consisted of Likert scales. RESULTS: Out of a population of 1 195 medical students, 733 were sampled (63%); 65% were female, 53% were preclinical students (years 1 -- 3) and 47% were in their clinical years (year 4 -- 6). Overall, 61% of students had a positive attitude towards research and 74% felt that participation in research was important to their medical school education; 22% had been involved in voluntarily extracurricular research, 4% had presented at a scientific meeting and 3% had published in peer--reviewed journals. A number of perceived barriers to student research were identified including a lack of adequate training, time and research opportunities. CONCLUSION: Students believed that research was important and had a positive attitude towards it. However, few had been involved in voluntary research and produced work worthy of presentation and/or publication. Addressing identified barriers and improving students' attitudes may begin to reverse the trend in declining numbers of physician--scientists.

  • Genome-wide association studies of brain imaging phenotypes in UK Biobank.

    5 November 2018

    The genetic architecture of brain structure and function is largely unknown. To investigate this, we carried out genome-wide association studies of 3,144 functional and structural brain imaging phenotypes from UK Biobank (discovery dataset 8,428 subjects). Here we show that many of these phenotypes are heritable. We identify 148 clusters of associations between single nucleotide polymorphisms and imaging phenotypes that replicate at P < 0.05, when we would expect 21 to replicate by chance. Notable significant, interpretable associations include: iron transport and storage genes, related to magnetic susceptibility of subcortical brain tissue; extracellular matrix and epidermal growth factor genes, associated with white matter micro-structure and lesions; genes that regulate mid-line axon development, associated with organization of the pontine crossing tract; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide insights into the genetic architecture of the brain that are relevant to neurological and psychiatric disorders, brain development and ageing.

  • Collaborators

    10 January 2018

    Information and links to our collaborators (both internal and external)