The study of local circuits in cerebral cortex has relied on physiological measures of the responses of single neurons to stimulation. The obvious missing ingredient in current approaches to cortical function is the ability to study the normal function of large groups of neurons working together. We have developed an experimental procedure which makes it possible, for the first time, to study the metabolic activity of every immunohistochemically labeled neuron in a neural system of interest. The procedure combines a high-resolution 2-deoxyglucose (2DG) technique, immunostaining for glutamate decarboxylase (GAD) and other antigens, and extensively automated data collection and analysis. These materials allow a direct assessment of the extent of excitation and inhibition in individual neurons. We propose to make extensive use of this double-labeling technology to study local circuitry in the whisker- related barrel field of rodent somatosensory cortex. We will quantitatively map and analyze the cellular patterns of cortical 2DG labeling seen in behaving hamsters and mice. We will compare cortices from normal, acutely whisker-trimmed, artificially stimulated, and chronically whisker-trimmed rodents with respect to the underlying distribution of GAD and other immunostains. We will generate complete high resolution functional maps of the stimulated and surrounding portions of the barrel field, enabling accurate comparison of the metabolic activities in antigenically defined compartments across the cortex. From the database represented by these maps, we will test a number of specific hypotheses about cortical function and information flow in the trigeminal system of the behaving animal. A detailed comparison of our previous 2DG data and predictions derived from single-unit physiology shows good agreement despite vast differences in the two methods. We will pursue this line of evidence by looking for parallels in 2DG/immunostained materials to functional groups of neurons that have been physiologically characterized by other workers. We will then examine by anatomical means the projection fields of excitatory and inhibitory populations of neurons, and correlate the results of these measures with the extent of excitation and inhibition in individual neurons with different combinations of stimulated whiskers. We will assess the specific contribution of cortical and subcortical circuitry by comparing the activation patterns in various stations of the trigeminal pathway with the patterns of whiskers remaining on the face. Finally, we will characterize the plasticity in barrel cortex by comparing the normal patterns of cortical labeling with those observed following prolonged deprivation (whisker trimming) or artificial whisker stimulation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Sensory Disorders and Language Study Section (CMS)
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Washington University
Schools of Medicine
Saint Louis
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Kelly, Emily A; Tremblay, Marie-Eve; McCasland, James S et al. (2010) Postsynaptic deregulation in GAP-43 heterozygous mouse barrel cortex. Cereb Cortex 20:1696-707
Donovan, Stacy L; McCasland, James S (2008) GAP-43 is critical for normal targeting of thalamocortical and corticothalamic, but not trigeminothalamic axons in the whisker barrel system. Somatosens Mot Res 25:33-47
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Donovan, Stacy L; Mamounas, Laura A; Andrews, Anne M et al. (2002) GAP-43 is critical for normal development of the serotonergic innervation in forebrain. J Neurosci 22:3543-52
Shen, Yiping; Mani, Shyamala; Donovan, Stacy L et al. (2002) Growth-associated protein-43 is required for commissural axon guidance in the developing vertebrate nervous system. J Neurosci 22:239-47
Maier, D L; Mani, S; Donovan, S L et al. (1999) Disrupted cortical map and absence of cortical barrels in growth-associated protein (GAP)-43 knockout mice. Proc Natl Acad Sci U S A 96:9397-402

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