Neurobiology

Lisa V. Goodrich, Ph.D.

Assistant Professor of Neurobiology

Goodrich Lab Website:http://goodrich.med.harvard.edu/

We are interested in the development of neural circuits, from the determination and differentiation of neurons to the formation of axonal connections and ultimately the generation of behavior. The auditory and vestibular systems provide an exciting opportunity to link the assembly of neural circuits to their function, since these systems are closely related developmentally, but control the distinct perceptions of hearing and balance.  Moreover, defects in the patterning or wiring of the inner ear lead to hearing and balance disorders, ranging from complete deafness and vertigo to subtle defects in processing that may be associated with learning disabilities and autism.

We are using forward and reverse genetic approaches in the mouse to understand how genetic mutations lead to changes in the perceptions of hearing and balance.  One of the central goals is to understand the development of the circuits that connect the inner ear to the brain.  We have focused our efforts on the developmental paradigms affecting a single population of neurons, the spiral or cochlear ganglion.  These neurons faithfully transmit sound information from hair cells in the cochlea to auditory processing centers in the central nervous system.  For these studies, we have developed genetic tools that permit us to visualize and manipulate individual neurons along their entire trajectory (see right).  In combination with systematic gene expression profiling and analysis of tissue specific knock-outs, we are working to associate discrete steps in the development of spiral ganglion neurons with specific genetic programs and therefore achieve a systems level view of the assembly of complex neural networks.  Because hearing is easily assessed in mice, any changes in auditory circuitry can be correlated with changes in auditory function.

Conversely, it is relatively simple to identify mice with abnormal hearing or balance and then investigate the underlying cellular defect.  We screened a battery of mice generated by gene trap mutagenesis, a method that prevents gene function while simultaneously activating expression of a reporter gene under the control of the mutated gene’s promoter.  Furthermore, because the mutation is generated by insertion of a DNA vector, the gene of interest can be cloned easily, allowing rapid assessment of its molecular and cellular functions.  Using this method, we identified several mouse lines with restricted patterns of gene expression in the developing inner ear and then tested homozygous mutants for hearing and balance. One mouse line displays bidirectional circling behavior that is due to defects in semicircular canal morphogenesis.  The mutated gene encodes a novel cell surface protein that is also expressed in restricted populations of neurons, while a second gene trap line carries an insertion in another family member, which is highly expressed in the cochlear-vestibular ganglion. A major effort in the lab is underway to understand the biochemical functions of this family of molecules.  Other mutants in the laboratory include one with defects in auditory processing that appears to originate in the cochlear nuclei, and one with changes in the patterning of the sensory epithelia.  Analysis of this mutant may yield new insights into the differentiation of hair cells, which have extraordinarily complex morphologies and are packed into precisely organized mosaic arrays within the sensory epithelia (see below)

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Auditory (left) and vestibular (right) hair cells are organized into precise patterns within the sensory epithelia.  Hair cell stereocilia are stained for actin (green) and the kinocilia are stained for acetylated tubulin (red).