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Results

Systems neuroscience: From networks to behaviour - Modulation of prefrontal cortex circuits in vivo and in vitro in normal animals and rodent models of schizophrenia. 27 Jan 2012

The prefrontal cortex (PFC) is involved in many higher cognitive functions including working memory, attention and planning. Neuromodulators, such as the monoamines dopamine and serotonin play a key role in regulating these functions and are also central to many diseases associated with PFC dysfunction, including addiction and schizophrenia. In addition, the neuromodulator systems are also the targets of treatment for these conditions. Despite this key role the mechanisms of how the different neuromodulator systems alter PFC circuit function are still unclear and this proposal aims to further our understanding of the role of these key neuromodulators in the PFC.

Amount: £10,172
Funder: The Wellcome Trust
Recipient: Newcastle University

Mechanisms and plasticity of dendritic temporal sequence processing. 13 Feb 2012

The mechanism by which neurons detect, organize and process numerous chemical and electrical signals is a fundamental problem in modern neuroscience. For example, the ability to discriminate spatiotemporal sequences of synaptic input has been suggested to be important for generating efficient coding schemes, and input sequence detection in general is a computation essential for animal behaviour. Previous work showed that dendrites could be responsive to the "direction" of temporally spaced inputs due to their cable filtering properties, suggesting that single neurons could act as basic sequence detectors. This "passive" direction selectivity was confirmed experimentally by Branco and colleagues, who also discovered that "active" NMDA receptor conductance recruitment dramatically enhances the direction sensitivity of somatic responses. In addition, Branco et al. 3 found that dendrites could discriminate not only directional sequences, bu1 also a wide range of spatiotemporal patterns. However, the role and impact of dendritic sequence processing is unknown for computation in different cortical areas and under different conditions. I plan to concentrate on two broad questions addressing how dendritic mechanisms can optimally discriminate sequences and potentially store selected input patterns. First, I will concentrate on the types of spatiotemporal patterns that can be distinguished from each other. Second, I will investigate whether specific input sequences can be stored, by probing plasticity processes triggered by different input patterns. Optimal conditions for dendritic pattern recognition. What is the optimal spatial distribution of inputs? What is the "optimal dendrite"? Interaction of patterns on the dendrite. The interaction of backpropagating action potential and patterned inputs. Influence of background noise. Sources of calcium ? pharmacology. Tthe effects of neuromodulation. Plasticity triggered.by patterned input. Plasticity induction readouts. Plasticity induction protocols - repetition of the same input pattern and pattern and action-potential combination Effect of neuromodulation in regulating of pattern-induced plasticity.

Amount: £14,356
Funder: The Wellcome Trust
Recipient: University College London

Olig2 and the regulation of neural stem cell fate. 27 Jan 2012

During development of the central nervous system (CNS), neuroepithelial stem cells (NSCs), residing in the ventricular zones (VZ) of the embryonic brain and spinal cord, divide and differentiate to generate all the neurons and glial cells (astrocytes and oligodendrocytes) of the mature CNS. Typically, neurons form before glia. In the ventral spinal cord, for example, embryonic NSCs of the pMN progenitor domain generate several subtypes of motor neurons (MNs) before switching abruptly (at E12.5 in mouse) to production of oligodendrocyte precursors (OLPs). The OLPs then migrate away from the VZ into all parts of the spinal cord before associating with axons, differentiating into post-mitotic oligodendrocytes (OLs) and synthesizing myelin. We aim to address how NSCs switch at a predetermined time from neuron to glial production ? specifically, the mechanism of the MN-OLP fate switch in the ventral spinal cord. Broadly, the proposed project aims to characterize the role and regulation of the basic helix-loophelix transcription factor Olig2 in the MN-OLP fate-switch. Recent work from the Richardson lab showed that a specific serine residue (S147) in Olig2 is phosphorylated during MN specification and de-phosphorylated at the switch to OLP production. What triggers de-phosphorylation of Olig2 at the time of the MN-OLP switch? The sequence surrounding S147 conforms to a protein kinase-A target site, but the identity of the putative phosphatase responsible for dephosphorylation has not been established. What are the targets and co-factors of Olig2 in its different phosphorylated states that coordinate the temporally-defined switch in NSC fate? And what are the functions of the other predicted Olig2 phosphorylation states? This project will involve three distinct lines of investigation. 1: Characterizing the expression of candidate phosphatases/phosphatase inhibitors in the ventral spinal cord at the time of the MNOLP fate-switch. 2: Identifying target genes of Olig2 in its phosphorylated and de-phosphorylated states. 3: Characterizing the developmental function of another Olig2 phosphorylation site, S263, a potential target of p38 mitogen-activated protein kinase (MAPK).

Amount: £31,882
Funder: The Wellcome Trust
Recipient: University College London

Identifying mechanisms of mechanosensation in the Drosophila notum that contribute to the control of epithelial junction remodelling. 27 Jan 2012

When two epithelial cells make contact they form a stable cell adhesion complex that finally results in the formation of an epithelium. However when two mesenchymal cells make contact the outcome is completely different: they do not form a permanent adhesion complex and very frequently they move away from each other in a behavior called contact inhibition of locomotion [1]. Intriguingly, cell adhesion molecules such as cadherins are known to be involved in both kinds of cell interaction. The formation and dynamics of the adhesion complex in epithelial cells has been extensively studied [2], but the study of cell-cell interactions and cell adhesion in mesenchymal cells has been rather neglected. The aim of this project is to compare cell adhesion complex formation between epithelial cells and between mesenchymal cells, in order to understand the different outcomes of these two cell interactions. This knowledge would help us to better understand important processes such as epithelial-to-mesenchymal transition and contact inhibition of locomotion; two cell behaviors that are central to both cancer metastasis and cell migration during embryo development. We will use two embryonic cell populations whose behavior has been very well characterized in our lab: neural crest (as a mesenchymal cell type) and placode cells (as an epithelial cell type). Most of the experiments will be performed using Xenopus cells cultured in vitro, but we will also analyze cell behavior in vivo, using zebrafish and Xenopus embryos. The cell adhesion complex has been well characterized in epithelial cells, and several key molecules have been described, such as cadherins, catenins, and elements of the cytoskeleton like actin and myosin. In addition, the regulation of small GTPases, such as RhoA and Rac, has been shown to be essential for the formation and maintenance of epithelial junctions. In this project, we will study in placode (epithelial) and neural crest (mesenchymal) cells: i) the dynamic localization of molecules of the cell adhesion complex during cell contact ii) the dynamics of small GTPases during cell contact and their regulation by elements of the adhesion complex. iii) From the above experiments we expect to find the key elements that regulate the different outcome of epithelial and mesenchymal cell-cell contacts. Based on these results, we will perform functional studies with these molecules in order to change a mesenchymal cell-cell contact into an epithelial interaction and vice versa.

Amount: £3,500
Funder: The Wellcome Trust
Recipient: University College London

VEGF signalling in the nervous system. 27 Jan 2012

This project aims to examine if VEGF-C patterns the nervous system during axon guidance or synapse formation, and to define the molecular pathway by which VEGF-A signals in neurons independently of its role in blood vessels. Define the role of VEGF-C and its receptor VEGFR3 in axon pathfinding Determine if VEGF-A and VEGF-C function co-operatively to control axon pathfinding Identify NRP1 co-receptor(s) essential for VEGF-A signalling in neurons Examine if VEGF-A and/or VEGF-C control synapse development and function

Amount: £29,300
Funder: The Wellcome Trust
Recipient: University College London

What is the difference between epithelial and mesenchymal cell junctions: understanding the molecular basis of contact inhibition of locomotion and epithelial-mesenchymal transition. 27 Jan 2012

When two epithelial cells make contact they form a stable cell adhesion complex that finally results in the formation of an epithelium. However when two mesenchymal cells make contact the outcome is completely different: they do not form a permanent adhesion complex and very frequently they move away from each other in a behavior called contact inhibition of locomotion [1]. Intriguingly, cell adhesion molecules such as cadherins are known to be involved in both kinds of cell interaction. The formation and dynamics of the adhesion complex in epithelial cells has been extensively studied [2], but the study of cell-cell interactions and cell adhesion in mesenchymal cells has been rather neglected. The aim of this project is to compare cell adhesion complex formation between epithelial cells and between mesenchymal cells, in order to understand the different outcomes of these two cell interactions. This knowledge would help us to better understand important processes such as epithelial-to-mesenchymal transition and contact inhibition of locomotion; two cell behaviors that are central to both cancer metastasis and cell migration during embryo development. We will use two embryonic cell populations whose behavior has been very well characterized in our lab: neural crest (as a mesenchymal cell type) and placode cells (as an epithelial cell type). Most of the experiments will be performed using Xenopus cells cultured in vitro, but we will also analyze cell behavior in vivo, using zebrafish and Xenopus embryos. The cell adhesion complex has been well characterized in epithelial cells, and several key molecules have been described, such as cadherins, catenins, and elements of the cytoskeleton like actin and myosin. In addition, the regulation of small GTPases, such as RhoA and Rac, has been shown to be essential for the formation and maintenance of epithelial junctions. In this project, we will study in placode (epithelial) and neural crest (mesenchymal) cells: i) the dynamic localization of molecules of the cell adhesion complex during cell contact ii) the dynamics of small GTPases during cell contact and their regulation by elements of the adhesion complex. iii) From the above experiments we expect to find the key elements that regulate the different outcome of epithelial and mesenchymal cell-cell contacts. Based on these results, we will perform functional studies with these molecules in order to change a mesenchymal cell-cell contact into an epithelial interaction and vice versa.

Amount: £40,170
Funder: The Wellcome Trust
Recipient: University College London

Interplay between cAMP and Ca2+ signalling cascades: focus on store-operated Ca2+ entry. 27 Jan 2012

The relationship between cyclic adenosine monophosphate (cAMP) and Ca2+ signalling cascades will be investigated in primary pancreatic acinar cells and in established pancreatic cancer cell lines. Particular attention will be given to relationships between cAMP signalling and store-operated Ca2+ entry (SOCE). 1) To determine the effect of Ca2+ signaling on cAMP level, and on Protein Kinase A (PKA) and Exchange protein activated by cAMP (EPAC) activity. 2) To characterise the effect of cAMP increases on Ca2+ signalling mechanisms and specifically on SOCE. 3) To determine the effect of cAMP on junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) and on proteins involved in SOCE. 4) To determine the relative positioning of Ca2+ sensitive adenylate cyclases and ER-PM junctions.

Amount: £1,690
Funder: The Wellcome Trust
Recipient: University of Liverpool

Isoform-specific Ras function during development. 27 Jan 2012

Ras proto-oncogenes are key signalling intermediates controlling cell proliferation, differentiation and survival. Whilst most attention has focussed on the role of aberrant Ras signalling in cancer, normal Ras function is critical for embryonic development. Intriguingly, this process appears to be differentially dependent on individual Ras isoforms for reasons that remain unclear. Our study will characterise: 1. Tissue-specific gene expression and protein abundance patterns of Ras isoforms during early mouse development. 2. The contribution of Ras isoform-specific signalling networks to early embryonic development. 3. What signalling networks are engaged by Ras mutations associated with developmental disorders compared to those engaged by classical oncogenic mutations. This will allow us to ask whether and how different Ras isoforms contribute to the development of different tissue lineages and lead us to mechanistic insights into the specific pathways regulated by Ras isoforms to promote differentiation versus stemness. In later work we will develop isogenic cell models containing HRAS or KRAS mutations associated with developmental disorders. These mutations are believed to be less potent than oncogenic mutations; we will investigate whether this is the case and how this translates into differential coupling to Ras effector pathways.

Amount: £1,011
Funder: The Wellcome Trust
Recipient: University of Liverpool

Store operated Ca2+ entry in apoptotic cells. 27 Jan 2012

1. To characterise apoptosis-induced changes in store-operated Ca2+ entry (SOCE) pathway including: 1.1) Changes of Ca2+ influx. 1.2) Modifications of proteins involved in SOCE. 1.3) Changes in cellular structures serving as platforms for SOCE. 2. To characterise the role of apoptosis-induced regulation of SOCE in determining the mode of cell death of pancreatic acinar cells triggered by inducers of acute pancreatitis.

Amount: £2,572
Funder: The Wellcome Trust
Recipient: University of Liverpool

Functional properties of ontogenetically related neurons 27 Jan 2012

The overall aim of this project is to investigate whether the ontogenetic relatedness of neurons informs the functional circuits into which they integrate. I will examine this question in the context of two structures ? the optic tectum of the Xenopus laevis tadpole and the neocortex of the mouse. There are four specific experimental goals: I. To examine the visual response characteristics of clonally-related and unrelated neurons in the optic tectum, and to determine whether related neurons show clustered receptive field properties. II. To test whether changes in the functional properties of tectal neurons induced by manipulations of neural activity, such as dark- or strobe-rearing and receptive field conditioning, correlate within clonal lineages. III. To investigate whether clonally-related neurons in mouse cortex exhibit correlated activity during periods of spontaneously generated network activity. IV. To use the activation of cortical inputs to test whether clonally-related and unrelated cortical neurons differ in their response to evoked network activity.

Amount: £16,800
Funder: The Wellcome Trust
Recipient: University of Oxford

Comparative transcription analysis across LRRK2 models of Parkinson's Diesase to identify early pathways in disease pathogenesis 27 Jan 2012

The goal of this project is to identify the earliest cellular pathways involved in Parkinson's Disease pathogenesis by examining the effect of the causative G2019S and R1441C LRRK2 mutations on the transcriptome of SNpc dopaminergic neurons. Towards this goal, this project consists of three distinct and complementary aims: 1) To identify and compare the perturbations in cellular pathways caused by G2019S and R1441C mutant LRRK2 in advance of PD pathology in vitro through high-resolution transcriptome analysis of the most physiologically relevant cell culture model of human SNpc dopaminergic neurons currently available. 2) To examine the emergence and evolution of these perturbations in the cell biology of SNpc dopaminergic neurons over the time course of disease progression within a whole organism using a LRRK2 bacterial artificial chromosome transgenic rat model of PD. 3) To assess the physiological and pathophysiological relevance of human induced pluripotent stem cell models to healthy and diseased human SNpc and to examine differential effects of G2019S and R1441C mutations in states of advanced disease through comparison with human post-mortem tissue from LRRK2 mutant carriers and healthy controls.

Amount: £45,643
Funder: The Wellcome Trust
Recipient: University of Oxford

Exosome-based gene therapy for Huntington's disease 27 Jan 2012

1. To investigate the optimal strategies for exosome targeting to the brain in HD 2. To identify the optimal exosome RNAi cargo for suppression of htt expression 3. To evaluate brain-targeted exosomes for their ability to reduce htt expression in vivo and to prevent and/or reverse disease phenotype in a HD disease model.

Amount: £35,540
Funder: The Wellcome Trust
Recipient: University of Oxford

Support for a Wellcome Trust/Academy of Medical Science Internship 19 Mar 2012

During my Ph.D. I shall further explore in role of CaMKil and CASK in synaptic function and learning using Drosophila. I will also test to see if hCASK mutations alter CASK protein interactions at the synapse, such as its ability to dynamically regulate CaMKII autophosphorylation, and the effects of these mutations results in impaired on synaptic function and learning. This work could allow important insights into the pathology of mental retardation due to CASK mutations, and how the molecular machinery that is involved in synaptic plasticity is organised and regulated during learning. These aims are summarized below; Science l. 2. Investigate if the synaptic and behavioural function of CASK is conserved between humans and Drosophila. Use Drosophila to model how CASK disease-causing mutations affect synaptic function and behaviour.

Amount: £5,330
Funder: The Wellcome Trust
Recipient: University of Bristol