Marla Feller
e-mail: mfeller@ucsd.edu |
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We are interested in how neural activity affects the assembly of neural circuits. There are several examples throughout the developing vertebrate nervous system, including the retina, spinal cord, hippocampus and neocortex, where immature neural circuits generate activity patterns that are distinct from the functioning adult circuitry. It has been proposed that these transitional circuits provide the "test patterns" necessary for normal development of the adult nervous system. In my laboratory, we study spontaneous activity in the immature retina, termed retinal waves, where it has been demonstrated that these correlated action potentials are involved in the organization of downstream visual centers.
We are currently pursuing two major research questions. First, we are using a combination of electrophysiology, imaging and transgenic mice to determine the cellular mechanisms that underlie the spontaneous generation of retinal waves. Retinal wave generation has three components: initiation (waves initiate spontaneously roughly once/minute), propagation (waves propagate at a speed of 120 microns/second) and refractoriness. We are testing the role of various circuit components, including the role of spontaneously depolarizing amacrine cells in the initiation of retinal waves. We are also studying the relative roles of chemical and electrical synapses in wave propagation. Although the developing retina is made up entirely of excitatory connections, individual waves propagate over the retina and with a non-uniform wavefront velocity and stop at well-defined, but shifting boundaries. Our work has shown that these boundaries are due in part to a refractory period - a finite time following activation of an area of the retina during which it cannot participate in a subsequent wave. A computational model of the retina demonstrates that these complex propagation properties of retinal waves can be explained by a single parameter, namely the fraction of nonrefractory cells in a retinal area. Recently, we have been able to test this hypothesis, and gain some insight into the source of cellular basis of the refractory period, through pharmacological manipulations. Our current hypothesis is that oscillations in the levels of the second messenger cAMP determine the refractory period, a hypothesis we are currently testing using live indictors of cAMP and PKA.
The second question addresses the role of retinal waves in the maturation retinal projection to its primary targets in the CNS. Specifically, we have studied the role of retinal waves in the segregation of retinal ganglion cell axons into eye-specific regions within the lateral geniculate nucleus. In binocular animals, retinal activity has been shown to drive the segregation of retinogeniculate synapses from an initially overlapping population of RGC axon terminals from the two eyes into regions that are eye-specific. We have found that mice lacking the b2 subunit of the neuronal nicotinic receptor lack retinal waves between the ages of P1 and P8 and that this disruption in the endogenous activity pattern prevents normal eye-specific layers from forming in the mouse. In contrast, mice lacking the gap junction protein Connexin 36 have abnormal firing patterns but normal eye-specific segregation. By comparing spiking pattern in b2-/- and Cx36-/- mice we determined what aspects of the spontaneous retinal activity are critical for the detailed anatomy of retinogeniculate projections. We continue to pursue these questions using additional transgenic mice with either altered retinal waves are downstream signaling
The third question addresses the role of retinal waves in the development of receptive fields of retinal ganglion cells. Retinal waves are detected during an extended period perinatally – from one week before birth to two weeks after birth in mice. There is a long period during which vision and retinal waves co-exist -- light responses have been recorded at P10 in mice, which is 3-4 days prior to eye-opening. The developmental impact of both spontaneous and evoked retinal activity prior to eye-opening is supported by several studies demonstrating that pharmacological manipulations of spontaneous activity and light-deprivation during this period both alter the refinement of circuits within the retina and retinal projections to visual thalamus. In collaboration with EJ Chichilnisky’s lab at the Salk Institute, we are using a multielectrode array to explore the interaction between these two sources of correlated activity – vision and retinal waves – to determine their relative role in the establishment of functional visual circuits.
Dunn, T *, C-T Wang*, M. A. Colicos, M. Zaccolo, L. M. Dipilato, J. Zhang, R. Y. Tsien, M B. Feller, (2006). “Imaging of cAMP levels and PKA activity reveals that retinal waves drive oscillations in second messenger cascades”, Journal of Neuroscience, in press (*co-first authors).
Hansen, K. A., C. L.
Torborg, J. Elstrott,, M. B. Feller, (2005). The
expression and function of Connexin 36 in the developing mouse
retina" J Comp Neurol.,12;493(2), 309-20.
Torborg C. L., K. A. Hansen, M. B. Feller, (2005). High frequency synchronized bursting drives eye-specific segregation of retinogeniculate projections" Nature Neuroscience, 8 (1), 72-8.
McLaughlin, T*. , C. L. Torborg*, M. B. Feller, D. D. O'Leary (2003). “Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development, Neuron 40, 1147–1160
Reviews
Torborg C. L. and M.
B. Feller (2005). Spontaneous patterned retinal activity and the
refinement of retinal projections, Progress in Neurobiology. 76(4):213-235.
Feller, M. B. and M. Scanziani (2005). A precritical period for
plasticity in visual cortex, Current Opinion in Neurobiology 15(1), 94-100.
Feller, M. B. (1999). Spontaneous correlated activity in developing neural circuits, Neuron 22, 653-656.
Dr. Feller received her A.B. and Ph.D. degrees in Physics from the University of California, Berkeley. She carried out postdoctoral work first in the laboratory of David Tank at Lucent Technology Bell Laboratories then in the laboratory of Dr. Carla Shatz at the University of California, Berkeley. She is a recipient of a Klingenstein Fellowship Award in Neurosciences, a Whitehall Foundation Award, a Scholar Award from the McKnight Endowment Fund for Neuroscience, and a Basil O'Connor Starter Scholar Research Award. Dr. Feller joined the faculty in 2000.
