Emergence of Modularity and Discrete Multimodal Maps in the Inferior Colliculus

Gabriele, Mark

Abstract

Neural maps preserve spatial information and segregate distinct processing streams throughout the nervous system. Auditory maps are typically categorized as ?continuous,? with layered arrangements that emphasize tonotopic order. In lieu of frequency-specific laminae, ?discrete? maps predominate in non-lemniscal auditory areas and remain poorly understood. The auditory midbrain, or inferior colliculus (IC), is an intriguing structure as adjacent subdivisions exhibit contrasting map features. The central nucleus of the IC (CNIC) and deep aspects of its neighboring lateral cortex (LCIC) receive continuously mapped inputs from primarily auditory sources. Far less characterized is the discretely- mapped multimodal LCIC, with its discontinuous patch/matrix-like organization. The present proposal seeks 1) to determine the registry of developing auditory and somatosensory inputs with defined LCIC modular fields, 2) to identify signaling mechanisms that influence the alignment of multimodal maps with emerging LCIC compartments, and 3) to test the functionality of established multisensory circuits using clinically-relevant behavioral measures. To realize these objectives a combination of neuroanatomical and behavioral approaches will be utilized in a developmental series of control (C57BL/6J, CBA/CaJ), GAD67-GFP knock-in, and Eph-ephrin mutant mice. We hypothesize that LCIC multimodal maps arise early in development, require cell-to-cell signaling (Eph-ephrins), and influence multisensory behavioral processing. Recent findings from our lab show ephrin-B2 and EphA4 LCIC expression is modular and complementary to that of extramodular ephrin-B3. The first objective tests the correlation of Eph-ephrin patterns with the known neurochemically-defined LCIC modular framework (GAD67, parvalbumin, CO, NADPH-d, AChE). Further, combined tract-tracing and immunocytochemical approaches in control and GAD67-GFP mice examine the alignment of two auditory (cortico- and colliculo-collicular) and somatosensory (spinal trigeminal, Sp5, and dorsal column) LCIC inputs with respect to each other and defined LCIC compartments. Analogous experiments in ephrin-B2, -B3 and EphA4 mutants pursue the second objective, assessing Eph-ephrin guidance mechanisms in multimodal map formation. To achieve the final behavioral goal, we propose measuring the reflexive decrement of the acoustic startle response (pre-pulse inhibition) in control and mutant lines following auditory and/or somatosensory pre-pulse cues. The planned experiments advance our understanding of the development, organization, and functionality of a multimodal structure important for orientation and reflexive behaviors. Such a foundation is essential for interpreting how map reorganization and cross-modal dysfunction impair human communication and health, and how they may be exploited to prevent and better treat debilitating conditions like tinnitus.

Public Health Relevance

In addition to encoding sound, certain aspects of the auditory system also process somatosensory information, making them multisensory in nature. Despite the functional significance of cross-modal interactions and their implications for innovative approaches (e.g. noninvasive tinnitus treatment), rudimentary questions concerning the development, organization, and behavioral relevance of multimodal circuits remain unaddressed. The goals of the present project are to: 1) characterize the emergence of multimodal maps in the auditory midbrain, 2) determine guidance mechanisms (Eph- ephrin protein signaling) that shape patterned inputs to these areas, 3) assess the behavioral significance of appropriately established multimodal circuits, and 4) share findings with clinically- relevant fields of neuromodulation and plasticity.