Helen Ramsden PhD

Helen Ramsden


Publications:
2015
  Laminar and Dorsoventral Molecular Organization of the Medial Entorhinal Cortex Revealed by Large-scale Anatomical Analysis of Gene Expression
Ramsden, HL, Surmeli, G, McDonagh, SG & Nolan, MF 2015, 'Laminar and Dorsoventral Molecular Organization of the Medial Entorhinal Cortex Revealed by Large-scale Anatomical Analysis of Gene Expression' PLoS Computational Biology, vol 11, no. 1, 1004032. DOI: 10.1371/journal.pcbi.1004032

Neural circuits in the medial entorhinal cortex (MEC) encode an animal's position and orientation in space. Within the MEC spatial representations, including grid and directional firing fields, have a laminar and dorsoventral organization that corresponds to a similar topography of neuronal connectivity and cellular properties. Yet, in part due to the challenges of integrating anatomical data at the resolution of cortical layers and borders, we know little about the molecular components underlying this organization. To address this we develop a new computational pipeline for high-throughput analysis and comparison of in situ hybridization (ISH) images at laminar resolution. We apply this pipeline to ISH data for over 16,000 genes in the Allen Brain Atlas and validate our analysis with RNA sequencing of MEC tissue from adult mice. We find that differential gene expression delineates the borders of the MEC with neighboring brain structures and reveals its laminar and dorsoventral organization. We propose a new molecular basis for distinguishing the deep layers of the MEC and show that their similarity to corresponding layers of neocortex is greater than that of superficial layers. Our analysis identifies ion channel-, cell adhesion-and synapse-related genes as candidates for functional differentiation of MEC layers and for encoding of spatial information at different scales along the dorsoventral axis of the MEC. We also reveal laminar organization of genes related to disease pathology and suggest that a high metabolic demand predisposes layer II to neurodegenerative pathology. In principle, our computational pipeline can be applied to high-throughput analysis of many forms of neuro-anatomical data. Our results support the hypothesis that differences in gene expression contribute to functional specialization of superficial layers of the MEC and dorsoventral organization of the scale of spatial representations.


General Information
Organisations: Edinburgh Neuroscience.
Authors: Ramsden, Helen L., Surmeli, Gulsen, McDonagh, Steven G. & Nolan, Matthew F..
Keywords: (PREFERENTIAL NEURONAL LOSS, GENOME-WIDE ASSOCIATION, TEMPORAL-LOBE EPILEPSY, LAYER V NEURONS, ALZHEIMERS-DISEASE, MOUSE-BRAIN, GRID CELLS, ELECTROPHYSIOLOGICAL CHARACTERISTICS, SYSTEMATIC METAANALYSES, PARAHIPPOCAMPAL REGION. )
Number of pages: 38
Publication Date: 23 Jan 2015
Publication Information
Category: Article
Journal: PLoS Computational Biology
Volume: 11
Issue number: 1
ISSN: 1553-734X
Original Language: English
DOIs: 10.1371/journal.pcbi.1004032
2012
  Exploration induces hippocampus-independent up-regulation of Arc in layer V of mouse medial entorhinal cortex
Ramsden, HL & Nolan, M 2012, 'Exploration induces hippocampus-independent up-regulation of Arc in layer V of mouse medial entorhinal cortex' Champalimaud Neuroscience Symposium 2012, Lisbon, Portugal, 30/09/12 - 3/10/12, .
Neurons in medial entorhinal cortex (MEC) encode an animal’s position in space and are the main path for routing information between the neocortex and hippocampus. Superficial layers of the MEC project to the hippocampus, whereas deep layers are believed to be primarily driven by hippocampal output. The activityregulated cytoskeleton-associated protein, Arc, is a marker of neuronal activity and is necessary for forms of plasticity and spatial learning. Its expression pattern may therefore provide insight into the MEC networks involved in typical spatial behaviours. Using mice that express an enhanced GFP construct under the control of the endogenous Arc promoter (Wang et al., 2006), we investigated changes in the spatial patterns of both active Arc transcription and protein expression following exposure to a novel environment. We show that Arc expression in MEC is very low in naïve animals. Exposing animals to a novel environment significantly up-regulates GFP and Arc protein expression in MEC layer V, but not in in MEC layer II. Up-regulation of GFP and Arc protein expression is also evident across visual cortex. Using ibotenic acid-induced lesions of the CA1 region of hippocampus, we found that up-regulation of Arc in MEC layer V does not depend on input from dorsal CA1. This result contrasts with the long-held view that the major input to MEC is from the hippocampus, via deep layers of the MEC. It will be important to identify the neurons that provide the inputs responsible for increased Arc expression and the cell populations in which it occurs.
General Information
Organisations: Centre for Integrative Physiology.
Authors: Ramsden, Helen L. & Nolan, Matthew.
Publication Date: 2012
Publication Information
Category: Poster
Original Language: English
  Gene Expression Patterns Reflect Anatomical And Physiological Variation In Adult Mouse Medial Entorhinal Cortex
Ramsden, HL, Simpson, TI & Nolan, M 2012, 'Gene Expression Patterns Reflect Anatomical And Physiological Variation In Adult Mouse Medial Entorhinal Cortex' 8th Fens Forum of Neuroscience, Barcelona, Spain, 14/07/12 - 18/07/12, .
Using mRNA in situ hybridization data and tools from the Allen Brain Atlas, we explored whether patterns of gene expression in medial entorhinal cortex (MEC) map on to physiological variation in cellular properties. The MEC is a critical component of memory circuitry and possesses cells with diverse functions, including cells that exhibit grid-like spatial firing patterns during exploration (Hafting et al., 2005). Grid cell properties vary along a dorsal-ventral gradient (Hafting et al., 2005), an organization that is mirrored by a gradient in integration of synaptic responses (Garden et al., 2008). We sought to identify spatially patterned and layer-specific genes using a combination of unbiased, automated analyses of expression levels and enrichment, NeuroBlast searches for genes with correlated expression patterns, and manual validation. We examined functional enrichment, disease links, and homology across species within and across gene lists. We also tested whether genes with similar expression patterns are under common transcriptional control by performing a transcription factor binding site screen of constrained elements in the mouse genome and mapping them to MEC genes. Thousands of genes exhibit patterned or layer-specific expression across MEC, hundreds of which show a strong dorsal-ventral gradient in layer II where grid cells are most frequently found. Using gene ontology analysis we find functional enrichment of ion transport, synaptic transmission and behavioural functions in MEC layer-enriched genes but not in uniformly expressed genes. Furthermore, dendritic, synaptic and projection-located genes are highly overrepresented. We also identify transcription factor families that show clustered patterns of enrichment within patterned-gene lists. It will be important to consider how patterns of enrichment in MEC compare with those of neocortex and hippocampus.
General Information
Organisations: Centre for Integrative Physiology.
Authors: Ramsden, Helen L., Simpson, T. Ian. & Nolan, Matthew.
Publication Date: 2012
Publication Information
Category: Poster
Original Language: English
  Intrinsic electrophysiological properties of entorhinal cortex stellate cells and their contribution to grid cell firing fields
Pastoll, H, Ramsden, HL & Nolan, MF 2012, 'Intrinsic electrophysiological properties of entorhinal cortex stellate cells and their contribution to grid cell firing fields' Frontiers in neural circuits, vol 6, 1, pp. -. DOI: 10.3389/fncir.2012.00017

The medial entorhinal contex (MEC) is an increasingly important focus for investigation of mechanisms for spatial representation. Grid cells found in layer II of the MEC are likely to be stellate cells, which form a major projection to the dentate gyrus. Entorhinal stellate cells are distinguished by distinct intrinsic electrophysiological properties, but how these properties contribute to representation of space is not yet clear. Here, we review the ionic conductances, synaptic, and excitable properties of stellate cells, and examine thier implication for models of grid firing fields. We discuss why existing data are inconsistent with models of grid fields that require stellate cells to generate periodic oscillation. An alternate possibility is that the intrinsic electrophysiological properties of stellate cells are tuned specifically to control integration of synaptic input. We highlight recent evidence that the dorsal-ventra; organization of synaptic integraiton by stellate cells, through differences in currents mediated by HCN and leak potassium channels, influences the corresponding organization of grid fields. Because accurate cellular data will be important for distinguishing mechanisms for generation of grid fields, we introduce new date comparing properties measured with whole-cell and perforated patch-clamp recordings. We find that clustered patterns of action potential firing and the action potential after-hyperpolarization (AHP) are particularly sensitive to recording condition. Neverthless, with both methods, these properties, resting membrane properties and resonance follow a dorsal-ventral organization. Further investigation of the molecular basis for synaptic integration by stellate cells will be important for understanding mechanisms for generation of grid fields.


General Information
Organisations: Centre for Integrative Physiology.
Authors: Pastoll, Hugh, Ramsden, Helen L. & Nolan, Matthew F..
Keywords: (#dtc-s0782616, #dtc-s0898676, , , . )
Number of pages: 21
Pages: -
Publication Date: 24 Apr 2012
Publication Information
Category: Article
Journal: Frontiers in neural circuits
Volume: 6
ISSN: 1662-5110
Original Language: English
DOIs: 10.3389/fncir.2012.00017

Projects:
Mapping genetic expression to layer-specific characteristics in entorhinal cortex (PhD)