Delaine D Larsen, PhD
Postdoctoral Researcher
University of California, Davis
Center for Neuroscience
1544 Newton Court
Davis, CA 95618
Ph.D. University of California San Diego, Neurosciences, 2005
M.S. Oregon State University, Zoology, 1998
B.S. Oregon State University, Biology, 1995 |
Main Research Interests:
I am interested in how interactions between intrinsic, genetically mediated programs and extrinsic factors, such as sensory driven activity, contribute to the development and evolution of the mammalian neocortex. To address this problem I am working on several projects in the Krubitzer laboratory.
Comparative in situ hybridization:
Cortical areas are a fundamental organizational feature of cortex and lay the framework through which information moves through the cortical circuit. Cortical areas are characterized using a variety of criteria including architectonic distinctions, topographic organization, neuronal response properties, and cortical and subcortical connections (Kaas, 1982; Kaas, 1983; Krubitzer, 1995). In order to gain a better understanding of how the cortex functions to produce complex behaviors, we need to understand the development and specification of cortical areas. In particular, how are molecular mechanisms employed in development to set up functionally distinct cortical areas? Although recent work has begun to establish the early steps in the genetic patterning of the cortex and has uncovered key players involved in cortical arealization (for review Monuki and Walsh, 2001; O'Leary and Nakagawa, 2002; Grove and Fukuchi-Shimogori, 2003; Sur and Rubenstein, 2005), important questions still remain on the precise relationship between genes and specific aspects of cortical area organization, such as relative size and position on the cortical sheet, and how species differences in these aspects of organization arise.
We are comparing three species that naturally have different sizes of primary sensory areas, the mouse (Mus musculus), the short-tailed opossum (Monodelphis domestica), and the prairie vole (Microtus ochrogaster; Figure 1). Mice depend largely on their somatosensory system to navigate through their environment, and primary somatosensory area (S1) and the representation of the whiskers on the face is relatively large compared to primary auditory area (A1) and primary visual area (V1) (Woolsey and Van der Loos, 1970; Woolsey et al., 1975). In contrast, opossums are very visually orientated in their behaviors and have a relatively large V1 compared to A1 and S1 (Kahn et al., 2000; Karlen and Krubitzer, 2006). Finally, prairie voles are highly social rodents with an extremely large primary auditory area (Campi et al., 2007). While the relative size of the primary cortical areas is different in each species, the overall size of the cortical sheet is similar. By comparing the expression of early patterning genes across the different species we can determine if there are shifts in gene expression profiles that would predict the observed size of the cortical areas found in each species. For example, it has been proposed that the differential expression of Fgf8 could account for the variability of cortical area sizes during evolution (Fukuchi-Shimogori and Grove, 2001). If this is the case, then we would expect to see a relative increase in Fgf8 expression in the mouse, which has a larger somatosensory cortex, when compared to the short-tailed opossum, which has a larger visual cortex. If we find no differences or shifts in the expression of the early patterning genes, then it is likely that extrinsic factors play a significant role in the final determination of cortical area size. We are also examining the regional-specific expression of genes, which have been used as markers for cortical areas, and could be involved in aspects of connectivity patterns of cortical areas.
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Figure 1. Size Comparison of Primary Sensory Cortical Areas Across Species
Schematics illustrate the organization of primary sensory cortical areas in 3 species. Cortical areas are drawn from electrophysiological studies combined with architectonic analysis. The amount of cortex devoted to each sensory system varies dramatically in the different species. Each sensory area is color coded across all three species with red representing primary somatosensory cortex (S1), blue representing primary visual cortex (V1), and yellow representing primary auditory cortex (A1). The data used to draw the three maps are from Hunt et al. (2006) for the mouse, Huffman et al. (1999) and Kahn et al. (2000) for the short-tailed opossum, and Campi et al. (2007) for the prairie vole. Scale bar = 1 mm and applies to all drawings.
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Cortical Organization and Connections in Transducin-a Knock-out Mice:
We are examining the consequences of early visual impairment on the functional organization and connectivity of primary visual cortex (V1) using Transducin-a (Gta) Knock-out mice. Gta is a subunit of the heterotrimeric G protein involved in phototransduction in rod photoreceptors. Gta -/- mice lack rod photoreceptor mediated vision and do not show large retinal degeneration, only mild retinal degeneration that occurs with age (Calvert et al., 2000). These mice still maintain cone mediated vision, but cones only account for approximately 3% of the photoreceptors in mice (Carter-Dawson and LaVail, 1979). Gta -/- mice show functional reorganization of V1 with neurons in V1 responding to visual, somatosensory and/or auditory stimulation (Fig 2). In addition, we also find alterations in the connectivity of V1 with aberrant connections with somatosensory and auditory cortical areas and thalamic nuclei (Fig 3). |
Figure 2. Functional organization in V1 in Gta-/- mice.
Reconstructions of multiunit electrophysiological recordings from 2 Gta -/- mice are shown in which boundaries of primary sensory areas, as determined by myeloarchitecture, are denoted by black lines and recording sites are denoted by black dots (A, C). Enlargements of the results around V1 are shown in which recording sites are denoted by color coded dots indicating the sensory modality mapped to that location (B, D). Unlike normal animals, in which neurons in V1 respond solely to visual stimulation, in Gta -/-mice neurons at only a few recording sites responded only to visual stimulation. At most other sites in which neurons were responsive, they responded to auditory stimulation, somatosensory stimulation or some combination of modalities of stimulation. Scale bars = 1mm |
Figure 3. Cortical recontructions of neuroanatomical tracer injections in V1.
Reconstructions of cortical connections in C57Bl6 and Gta -/- mice showing the location of retrogradely labeled cell bodies from neuroanatomical tracer injections in V1 relative to the archtecitectonically defined cortical fields. The dots mark the locations of labeled cell bodies. The locations of the injection sites are marked by black ovals and cortical field boundaries are represented by the thin black lines. Scale bar = 1 mm
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Figure 4. Thalamic reconstructions of of neuroanatomical tracer injections in V1.
Reconstructions of a series of thalamic sections sectioned in the coronal plane representing label from 1 injection site in C57Bl6 and 2 injection sites in Gta -/- mice. The location of the injection site is denoted in the cortical representation to the left of the thalamic series. The dots mark the locations of labeled cell bodies and are color coded by the neuroantomical tracer used: blue = BDA, red = FluoroRuby. The shaded regions are areas of anterograde axonal arborization fields. Thin lines represent cytoarchitectonic borders drawn from adjacent Nissl and cytochrome oxidase stained sections. Scale bar = 1 mm. |
Future directions
In the future we are also working on developing a model to look at the recovery of vision at different developmental ages in the Gta -/- mice to determine the effect of early vision loss has on the recovery of visually mediated behaviors in these mice.
Development of Corticocortical Connections in Transducin-a -/- and C57Bl6 Mice:
In the transducin-a and bilaterally enucleated opossum model systems used in the Krubitzer laboratory we have found changes in the functional organization and the underlying cortical connectivity after the loss of a sensory driven activity. We are interested in determining the developmental mechanisms that are responsible for the observed changes in connectivity. We are currently doing experiments to determine when during development the abnormal cortical connectivity emerges in the Gta -/- mice. |
Publications:
Journal Articles:
DeLaine D. Larsen, Ian R. Wickersham, and Edward M. Callaway. (2008) Retrograde Tracing with Recombinant Rabies Virus Reveals Correlations between Projection Targets and Dendritic Architecture in Layer 5 of Mouse Barrel Cortex. Frontiers in Neural Circuits. 1:5
DeLaine D. Larsen and Leah Krubitzer. (2008) Genetic and Epigenetic Contributions to the Cortical Phenotype in Mammals. Brain Research Bulletin. 75: 391-397
DeLaine D. Larsen and Edward M. Callaway. (2006) Development of Layer-specific Axonal Arborizations in Mouse Primary Somatosensory Cortex. Journal of Comparative Neurology 494:398-414
David A. Gold, Sung Hee Baek, Nicholas J. Schork, David W. Rose, DeLaine D. Larsen, Benjamin D. Sachs, Michael G. Rosenfeld, and Bruce A. Hamilton. (2003) RORα Coordinates Reciprocal Signaling in Cerebellar Development through Sonic hedgehog and Calcium-Dependent Pathways. Neuron 40:1119-1131
Abstracts:
Larsen, D.D., Luu, J.D., Burns, M.E., and Krubitzer, L.A. (2007). Cortical organization and connections in mice with congenital visual impairment. Society for Neuroscience Abstracts, submitted.
DeLaine D. Larsen, Ian R. Wickersham, Stefan Finke, Karl-Klaus Conzelman, and Edward M. Callaway. (2005) Correlation between projection targets and pyramidal neuronal cell types in layer 5 of mouse primary somatosensory cortex. Society for Neuroscience 35th Annual Meeting, Washington, D.C.
DeLaine D. Larsen and Edward M. Callaway. (2004) Development of laminar-specific axonal arborizations in barrel cortex of mice. Cold Spring Harbor Laboratory Axon Guidance & Neural Plasticity Meeting, Cold Spring Harbor, NY
DeLaine D. Larsen and Edward M. Callaway. (2004) Development of laminar-specific axonal arborizations in barrel cortex of mice. St. Jude’s National Graduate Student Symposium, Memphis, TN
DeLaine D. Larsen and Edward M. Callaway. (2003) Development of laminar-specific axonal arborizations in barrel cortex of mice. Society for Neuroscience 33rd Annual Meeting, New Orleans, LA
David A. Gold, Sung Hee Baek, Nicholas J. Schork, DeLaine D. Larsen, Michael G. Rosenfeld, and Bruce A. Hamilton. (2003) RORa coordinates Sonic Hedgehog and calcium signaling pathways in Purkinje cell differentiation. Society for Neuroscience 33rd Annual Meeting, New Orleans, LA
DeLaine D. Larsen and Barbara J. Taylor. (1998) Genetic control of sex-specific motorneurons in the abdominal ganglion. 39th Annual Drosophila Research Conference, Washington, DC
DeLaine D. Larsen and Barbara J. Taylor. (1997) Sex-specific programmed cell death during metamorphosis in D. melanogaster. 38th Annual Drosophila Research Conference, Chicago, IL
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