Understanding how brain pathways form, how the pattern of activity conveyed by them shapes processing networks, and how inputs, pathways and networks together mediate behavior, are central themes in understanding mammalian brain development and plasticity. We propose to examine mechanisms responsible for the specific targeting of projections from the retina to the thalamus, and utilize an induced miss targeting of projections to ask how patterned activity shapes the function of subsequent structures. Retinal projections to visual thalamic targets such as the lateral genicutate nucleus (LGN) require specific molecular cues, and these are altered when retinal projections are routed to the medial geniculate nuclus (MGN) of the auditory thalamus. Such rewiring then provides a means to examine how a very different pattern of activity, that driven by vision rather than by audition, influences the development, organization and function of pathways which normally mediate auditory functions and behaviors. Specific questions are: 1. What are the molecular determinants and mechanisms responsible for generating target specificity in retinothalamic projections? We hypothesize that: retinal projections to specific targets, are mediated by molecules such as the ephrins that also generate topographic order. We shall use wild type mice and mice lacking ephrin A2/A5 or Eph B2/B3 to examine whether retinal projections to the LGN and rewired MGN are similarly disrupted. Additional factors also operate during normal development to generate specificity of axon projections. We will use laser micro-dissection and DNA micro-array analyses to discover genes and signaling molecules that normally regulate containment of retinal ganglion cell axons to the LGN and that promote miss targeting of these axons to the MGN after rewiring. 2. How does the pattern of input activity influence visual feature processing networks in cortex? We hypothesize that a key role for patterned activity is to shape the cortical networks that generate and map multiple stimulus features according to rules of coverage and continuity. We will use optical imaging and single unit recording in ferret primary visual cortex (V1) and rewired primary auditory cortex (A1) to examine the relationships between maps of retinotopy, orientation, ocular dominance, spatial frequency, and direction. 3. How does visual input influence the hierarchical processing of cortical information? We hypothesize that visual activity shapes the serial processing of visual motion in cortex. We will examine the analysis of motion, including direction selectivity, in a hierarchy of areas in the visual cortex and rewired auditory cortex. 4. Can a behavior be specified by its inputs, measured as the influence of vision on fear conditioning? We hypothesize that visual inputs directed to the auditory thalamus instruct the function of subsequent projections and structures. We will use a fear conditioning paradigm, exploiting the slow rate of acquisition of visual compared to auditory cued fear, to examine whether visual inputs routed to the auditory pathway accelerate visual cued fear conditioning in rewired mice.
| Horng, Sam; Kreiman, Gabriel; Ellsworth, Charlene et al. (2009) Differential gene expression in the developing lateral geniculate nucleus and medial geniculate nucleus reveals novel roles for Zic4 and Foxp2 in visual and auditory pathway development. J Neurosci 29:13672-83 |
| Wilson, Nathan R; Ty, Michael T; Ingber, Donald E et al. (2007) Synaptic reorganization in scaled networks of controlled size. J Neurosci 27:13581-9 |
| Newton, Jessica R; Ellsworth, Charlene; Miyakawa, Tsuyoshi et al. (2004) Acceleration of visually cued conditioned fear through the auditory pathway. Nat Neurosci 7:968-73 |
