Mammalian perception is a dynamic process. Animals and humans can exist in a variety of environments, and can optimize performance for distinct sensory tasks. This perceptual adaptability is believed to depend on the flexibility of neocortical circuits, and specifically on the sensory tuning of excitatory neurons. Several theories have proposed that diversity in the sensory tuning of inhibitory interneurons (IN) is key to neocortical dynamics. In support of this idea, in vitro studies have distinguished 2 IN classes by their responses to excitatory input. One IN type is sensitive, responding robustly to weak initial stimuli and subsequently adapting if a high-frequency stimulus is maintained. This IN type typically demonstrates fast- spiking action potentials and parvalbumin expressing. A second type of IN is initially insensitive, but subsequently facilitates if stimuli persist. This type is typically regular-spiking and somatostatin expressing. Despite the theoretical importance of this prediction, and in vitro support for it, these IN types have not been distinguished in vivo. We will test the hypothesis that different IN types show distinct sensitivity to the strength of sensory stimuli, and distinct dynamic adjustments to sustained high-frequency input. We will test this hypothesis by measuring IN receptive fields in layers II/III of the vibrissa barrel cortex with 3 complementary techniques: Extracellular recording, intracellular recording, and 2-photon imaging. Tetrode recording will provide a high neural yield, and allow distinction between regular- and fast-spiking neurons. Intracellular recording will provide conclusive cell type identification and unique access to subthreshold responses. 2-photon imaging will provide direct visualization of IN sub-types in mice with fluorescently labeled neurons, and the ability to track their activation using calcium imaging. We will test this hypothesis by parametric variation of the velocity and frequency of vibrissa motion, and with increasingly naturalistic stimuli, including whisking in air and across a surface. Accessibility of active sensing (whisking) in a preparation amenable to stable recording is a key advantage of this system. The barrel cortex has distinct benefits for testing our hypothesis. Barrel cortex is a high-resolution sensory area in a rodent, where unique techniques (e.g., imaging fluorescently labeled IN) are possible. Further, our laboratory has substantial expertise in this system. Testing IN receptive fields follows directly from our prior studies, and from our working theory of sensory-driven neocortical dynamics. These IN are hypothesized to contribute not only to normal function, but also to disease. For example, maladaptive changes in parvalbumin staining IN are predicted to be causal in schizophrenia. While systematic probes of IN function are more complicated in higher areas, sensory input to primary areas is an ideal initial preparation to test this hypothesis, and should provide insight into IN function across cortical areas.

Public Health Relevance

These studies have direct relevance to understanding basic mechanisms underlying human mental illness. The key hypothesis tested is that distinct types of neocortical interneurons have distinct functions in the in vivo cortex. Maladaptive changes in the exact types we will examine are thought to be causal in Epilepsy and Schizophrenia: Understanding their potentially crucial role in information processing should have direct implications for interpretation of deficits in these maladies, and may potentially suggest avenues for remediation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Sensorimotor Integration Study Section (SMI)
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Gnadt, James W
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Brown University
Schools of Medicine
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