Two-photon Ca  2  􏰀   imaging reveals that neurons in the inner nuclear layer (INL, top)   and ganglion cell layer (GCL;   bottom  ) participate in glutamatergic retinal waves.   See Firl et al, J. Neurophys, 2013

Two-photon Ca2􏰀 imaging reveals that neurons in the inner nuclear layer (INL, top) and ganglion cell layer (GCL; bottom) participate in glutamatergic retinal waves. See Firl et al, J. Neurophys, 2013

We are interested in the mechanisms underlying spontaneous activity in the developing nervous system and the role this activity plays in the construction of neuronal 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.

We study spontaneous activity in the immature mouse retina. Mice are born with their eyes closed. Light responses are first detected at postnatal day 10 (P10) and their eyes open at P14. During these first two postnatal weeks, immature retinal circuits spontaneously generate propagating bursts of action potentials termed retinal waves. During this same postnatal period, there is tremendous amount of development within the visual system, including formation of retinal circuits that mediate various light responses, as well as sculpting of retinal projections to their primary targets in the brain. Hence, the developing visual system is a premier model system for studying the role of spontaneous activity in the development of functional circuits.

We use a combination of imaging, electrophysiology, and anatomical techniques to address three major questions:

  • What are the cellular mechanisms underlying the generation and maintenance of retinal waves?

We work on several projects aimed at elucidating the synaptic mechanisms that underlie retinal waves. We use a combination of transgenic mice, 2-photon confocal calcium imaging and live imaging of glutamate, whole cell recording, and anatomy to study the role that developing cholinergic and glutamatergic circuits play in mediating retinal waves. We are also exploring the role of GABA, gap junctions, and non-synaptic mechanisms is regulating spontaneous firing patterns throughout retinal development.  In particular, we are interested in understanding how the circuits that mediate waves interact with emerging light responses in the retina.

  • What is the role of retinal waves in the development of visual circuits?
 Pseudo color representation of  eye-specific segregation of retinal projections to lateral geniculate nucleus of that thalamus 

Pseudo color representation of  eye-specific segregation of retinal projections to lateral geniculate nucleus of that thalamus 

We are interested in the role retinal waves play in setting up precise connectivity within the retina and between the retina and its primary targets in the brain. One approach is to assay retinal projections in genetically altered mice that have disrupted correlated activity patterns of waves. More recently we have focused on the role of retinal waves in setting up circuits within the retina itself.  

  • How do motion sensitive circuits arise during development?

How are neural circuits wired up during development to perform computations? A classic neural computation is that of detecting the direction of motion of an object within the visual scene. Direction-selective cells are found in the retina and function as the first component of the reflex that stabilizes the visual image on the retina when an animal is in motion. Direction-selective ganglion cells respond strongly to an image moving in the preferred direction and weakly to an image moving in the opposite direction. This computation relies upon an asymmetric set of connections between inhibitory neurons onto direction selective cells as well as non-linearities in the cells themselves. We use a combination of approaches including imaging, opto- and pharmacogenetics and electrophysiology to determine the mechanisms that underlie the development of these asymmetric circuits. In addition, we are studying the factors that dictate the maturation of different populations of direction-selective cells.

  • Interactions between retinal waves and intrinsically photosensitive retinal ganglion cells.

Intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin, are the first photoreceptors that mature in the retina, and they therefore provide the earliest light-driven signals to the brain. We have found that the chemical synaptic circuits that generate waves strongly and dynamically interact with the electrical synaptic circuits that link ipRGCs with other retinal cells. Specifically, we have revealed that acutely blocking retinal waves increases the number of light sensitive neurons. We continue to explore how these circuits interact and what role gap junctions play in the process.