Leslie M. Kay, PhD - US grants

DESCRIPTION (provided by applicant): The mammalian olfactory system is unique among sensory systems in its dense interconnectivity with the limbic system, which has been shown to be involved in processes such as memory, emotion and spatial and other types of cognitive processes. It is therefore important to understand the olfactory system's role in attentional processes as they relate to the changing demands of an individual's environment. These processes are significantly impacted in Alzheimer's and Parkinson's diseases and in schizophrenia and depression (among others), all of which are accompanied by mild to severe olfactory deficits. Recent studies in our laboratories and in others have implicated oscillatory synchrony in attention and sensory processing. We therefore propose multi-disciplinary research aimed at describing the functional role of oscillatory neural synchrony in perception, attention and learning of sensory information in mammalian cortex. The olfactory system is used to study the sensory cortical circuit, the olfactory bulb (OB) and piriform cortex (PC). We emphasize the bidirectional connectivity of these two structures, which few studies have done. Oscillations occur at the level of neural populations, and activity will be studied at this and the single neuron levels in rats performing olfactory discrimination and attention tasks. We use waking animals because many types of oscillatory activity are seen only in alert and attentive states, and these unique oscillations provide a tool by which to investigate the biophysical basis, behavioral dependence and interactions of these oscillations. An advantage of using the olfactory system lies in the breadth of physiological, anatomical and modeling efforts that have addressed this system at many levels of analysis, from single neuron biophysics to neural populations. These studies aim to 1) describe the sources of several types of oscillatory activity associated with sensory processing and attention in waking rats; 2) describe how these types of oscillations change with learning and context; and 3) manipulate inhibitory action in the underlying circuits pharmacologically, relating these manipulations to changes in olfactory discrimination. Each portion of the physiological studies are closely coupled with computational modeling, acting in both a descriptive and predictive fashion. Detailed analysis of this system in waking animals will provide a foundation from which to understand the complex system effects in cognitive disorders. We anticipate that understanding how olfactory deficits arise from changes in the limbic system associated with many of these disorders, will help us to understand the mechanisms that produce cognitive malfunctioning.

DESCRIPTION (provided by applicant): The emergence of coherent local field potentials (LFPs) in the beta (15-30 Hz) and gamma (35-100 Hz) frequency bands has been associated with attention, sensorimotor integration, and other active information processing states within and among brain regions. Beta/gamma coherence is broadly associated with action potential synchronization, which in turn has been hypothesized to define and delimit neural assemblies, and further to enable multiple assemblies of neurons within a population to synchronize within each assembly (but not among different assemblies) so that these multiple assemblies can compete to determine the systems output. The olfactory system has a strong and complex complement of LFP oscillations. Several different frequency bands are routinely observed, and are associated with particular behavioral tasks or states, such as acute sensory activity, resting alertness, and respiratory phases. Some oscillations coexist in the same structure; others appear to give way to one another. Some are local; others mediate interareal coupling either via LFP coherence or via subtler spike-field coherence in which periodic activity in the OB shapes the timing of action potentials in a limited assembly of neurons in a follower structure. Moreover, the olfactory system juxtaposes bottom-up network dynamics resulting from afferent stimulation with top-down dynamics arising from behavioral state factors, both affecting sensory information exported from olfactory bulb. Overall, the olfactory system is a particularly rich fied in which to study the biophysics and ethological utility of these neuronal dynamical systems in concert and within experimentally accessible tissues. This project will establish a robust, mechanistic, biophysically-based model of oscillations and synchronization in the mammalian olfactory system. The PIs will combine multichannel unit and LFP recordings from awake/behaving rats and from acute slices of the mouse OB using planar multielectrode array, and use the results to shape the expansion of an existing, biophysically detailed model of the early olfactory system. They will determine the extent to which the OB forms competing assemblies of gamma-coupled neurons and study beta oscillations as an interregional coupling mechanism with piriform cortex (PC) that supersedes these local gamma-coupled assemblies. Additional, less well-established OB interactions with olfactory tubercle and orbitofrontal cortex during odor sampling and response decisions also will be studied. Integrating these datasets into a common Hodgkin/Huxley-based network model will explicate the construction and utility of these systemwide dynamics based on their underlying cellular and network mechanisms. The proposed work takes a fairly well-characterized network and, via computational modeling, combines studies across different levels of analysis to build a mechanistic model of a complex dynamical system. The results will enable a deeper understanding of the dynamical flexibility of cortical circuits at many levels of analysis. Behavior provides tight control over oscillatory staes and cognitive processes associated with them, enabling explication of intact functional circuits. Slice electrophysiology and computational modeling will provide greater detail on the mechanistic, synaptic, neuromodulatory, and dynamical principles involved in generating and switching among these multiple states. The collaboration will benefit students at both institutions by integrating them into an interdisciplinary framework encompassing computational and experimental approaches, exposing students from diverse backgrounds to new research techniques and interdisciplinary and computational approaches to neuroscience. Close collaboration of the two investigators will transfer knowledge and methods across laboratories. Both laboratories actively train undergraduates in research and include them on many publications, and both laboratories actively recruit and train female and minority scientists in STEM fields. PI Kay has initiated participation in Project Exploration, an outreach program that provides access to science and scientists to underrepresented minority children and girls, and PI Cleland participates in the Leadership Alliance and Cornell Biology Scholars program for underrepresented minority and first-in-family students, and has published papers with undergraduate coauthors enrolled in these programs.