Motion Processing in the Retina

The retina is the brains window to the visual world. This circuit of neurons begins the process of vision by converting light into an electrical signal, much like the CCD in a video camera. But these signals are not transmitted back to the brain in raw form: they are immediately processed within the retina to allow extraction of the most important information. In other words, the retina is a neural circuit that computes. One of the most important computations that the retina carries out is to detect the motion of objects, allowing the animal to navigate the world and detect predators or prey. Many neurons also provide information about the direction in which the object moves. One of the key challenges in modern neuroscience is to understand how such a computation is implemented by the biological hardware of neurons connected into circuits through synaptic connections. it is particularly important to understand how signals are transmitted at synapses because this process is involved in key transformation of the visual signal as it travels through the retina.

To understand how the retina computes direction of motion we will observe the visual signal as it is transmitted between the different types of neuron while delivering stimuli moving in different directions. To achieve this, we will make genetically-modified zebrafish expressing fluorescent proteins that signal the activity of neurons and synapses as the retina processes visual stimuli. These signals consist of the emission of green or red light, which can be observed using a specialized (multiphoton) microscope that can be used to observe events within the retina of the live animal. One of the disadvantages of the retina compared to a video camera is that the light-sensitive neurons, the photoreceptors, take much longer to sense light than a CCD. This is a problem if the object is moving at any speed, because by the time the visual signal reaches the inner retina, the object generating that signal may have moved a considerable distance. For instance, a tennis ball served by Andy Murray will have moved nearly 5 m during the ~80 ms it takes our photoreceptors to respond. The retina therefore carries out a further computation, which is to extrapolate the position of the object on the retina ~80 ms into the future, based on the assumption that it is moving in a straight line. This process is called "motion prediction" and we will also investigate how it is implemented by the neural circuitry of the inner retina. The process of motion prediction is not perfect: if the object suddenly changes direction, the predictions will be wrong. The retina corrects this mistake quickly by re-calculating the new direction of motion. The need to recalculate the trajectory of the moving object is highlighted by an "alarm signal" consisting of a transient burst of electrical activity synchronized across a large number of neurons. Understanding how this alarm signal is generated is a key aspect of understanding how motion is processed by the retina.

We hope that the insights provided by this research will prove useful in a wide range of applications, from developing improved retinal prosthetics to provide vision for the blind to more efficient security cameras able to track moving objects. We also believe that the methods we are developing for observing synaptic transmission will be of general use in analyzing how circuits of neurons in other parts of the brain operate to carry out computations on incoming information.

The detection of moving stimuli is one of the most fundamental tasks of the visual system. Computations related to motion begin in the retina, but we still lack a comprehensive understanding of the underlying mechanisms. This project will use zebrafish to investigate the synaptic and cellular processes underlying three fundamental aspects of motion processing in the retina: i) directional selectivity in the excitatory signals that bipolar cells transmit to ganglion cells, ii) the prediction of object motion that corrects for the lag introduced by the slow speed of phototransduction in rod and cone photoreceptors, and iii) corrections in this prediction when the direction of motion suddenly changes. To unravel the underlying circuitry we will combine electrophysiology in ganglion cells with functional imaging of synaptic activity in both bipolar cells, providing excitation, and amacrine cells, providing inhibition. We will develop new approaches for analyzing the synaptic basis of neural circuit function by the simultaneous use of green- and red-fluorescent proteins targeted to genetically-defined populations of neurons. In particular, we will develop a red reporter of glutamate release from excitatory synapses. These approaches will allow analysis of motion processing in retinal flat-mounts and, for the first time, in vivo.

Investigating mechanisms of motion processing in the retina will help us understand the neural mechanisms underlying complex computations in other parts of the brain and may also help in the development of retinal prosthesics.

Potential beneficiaries of this research:

Academia: International research groups involved in Neuroscience research will benefit from the increased insight into the functions of the visual system. New and improved reporters of synaptic activity (especially a red glutamate sensor) will provide new tools for the study of neural circuits that will complement large-scale efforts to monitor neural activity in intact circuits that have been announced recently, including the "Brain Activity Map Project" (NIH) and "Mindscope" (Allen Institute). These initiatives aim to develop technologies that allow the operation of neural circuits to be observed in real-time, with an emphasis on the visual system. We will help advance these efforts by focusing squarely on one key component of all neural circuits - the presynaptic terminal.

Modern neuroscience is also investing in "connectomics": an ultrastructural approach aimed at delineating all the synaptic connections between neurons in defined circuits. To reap the fruits of these ventures the functional properties of synaptic connections must be related to the ultrastructure. The field of circuit neuroscience is therefore crying out for approaches that specifically assay the activity of complete synaptic populations with single-synapse resolution.

Medicine: Clinicians interested in restoring vision impaired by retinal dystrophies will benefit from our research into the circuit mechanisms of motion processing. At the moment, stem cell therapies for restoring vision are focused on the basic task of restoring light-sensitivity by replacing photoreceptors, but in the future these approaches may become sophisticated enough to take more specific approaches to restoring motion vision. For instance, it may be possible to identify key classes of bipolar cell and/or amacrine cell involved in motion processing and generate these from embryonic stem cells for injection into the retina.


Industry: Potential commercial interest in areas such as robotics, machine vision and the development of image-processing algorithms. All of these areas are strongly dependent on our understanding of the biological basis of visual processing in the retina. We also expect that the the "optophysiological" techniques that we are developing for analyzing nervous system function will contribute enormously to pharmaceutical research, especially enterprises focusing on drugs acting on the nervous system.

General public: Improved understanding of the sense of vision.