Final Report Summary - CELLTYPESANDCIRCUITS (Neural circuit function in the retina of mice and humans)
The mammalian brain is assembled from thousands of neuronal cell types, which are organized into distinct circuits to perform behaviorally relevant computations. These local circuits are found in different brain regions such as the spinal cord, amygdala, and retina that act in concert in behaving animals. To gain a mechanistic insight about brain function it is crucial to understand what these local circuits are computing and how these computations are achieved. Furthermore, to treat specific diseases of the nervous system, one has to understand the function of the particular circuits involved.
The retina serves as a unique model system to local circuit computations for the following reasons. Firstly, and most importantly, the retina is a self-contained system in the sense that if a particular neural computation can be recorded in the retina, this computation can be understood by studying the circuit elements within the retina in isolation. Secondly, in the last few decades a large number of investigations have pointed to the existence of specialized cell types, and found that these cell types and consequently the local circuits are organized in neural layers in the retina. This greatly simplifies the study of connectivity between neurons. Furthermore, retinal cell types are arranged in mosaics, covering and tiling the retina. This mosaic arrangement and the layered structure of retinal cell types have allowed us and others to describe a number of mouse lines in which specific retinal cell types, or combinations of a few cell types, are genetically labeled with fluorescent markers. With the help of two-photon microscopy we can target these cell types for physiological recordings. Furthermore, we can initiate transsynaptic tracers from identified output cells, the ganglion cells of the retina, to yield a connectivity map for an identified circuit. Finally, it is easy to isolate and maintain the retina in vitro and its natural input, the dynamically changing light pattern, can be quantified and presented to the isolated retina. It is feasible to record neural activity from any retinal cell types.
In this project we have described how retinal and cortical circuits detect motion (Yonehara et al., 2013, Nature, Wertz et al, 2015, Science). Next, we showed that adult neuronal cell types of the retina have a unique transcriptional code and we mapped disease-associated genes to retinal cell types that express them (Siegert et al., 2012, Nature Neuroscience, Busskamp et al, 2014, Neuron, Yonehara et al, 2015, Neuron). Finally, we showed how identified retinal circuits change their computation depending on the sensory input (Farrow et al, 2013, Neuron, Szikra et al, 2014, Nature Neuroscience). Our scientific results and patents, together with results from other groups, led to the formation of a startup company, Gensight Biologics, which specializes on the development of innovative gene therapies for eye diseases.
The retina serves as a unique model system to local circuit computations for the following reasons. Firstly, and most importantly, the retina is a self-contained system in the sense that if a particular neural computation can be recorded in the retina, this computation can be understood by studying the circuit elements within the retina in isolation. Secondly, in the last few decades a large number of investigations have pointed to the existence of specialized cell types, and found that these cell types and consequently the local circuits are organized in neural layers in the retina. This greatly simplifies the study of connectivity between neurons. Furthermore, retinal cell types are arranged in mosaics, covering and tiling the retina. This mosaic arrangement and the layered structure of retinal cell types have allowed us and others to describe a number of mouse lines in which specific retinal cell types, or combinations of a few cell types, are genetically labeled with fluorescent markers. With the help of two-photon microscopy we can target these cell types for physiological recordings. Furthermore, we can initiate transsynaptic tracers from identified output cells, the ganglion cells of the retina, to yield a connectivity map for an identified circuit. Finally, it is easy to isolate and maintain the retina in vitro and its natural input, the dynamically changing light pattern, can be quantified and presented to the isolated retina. It is feasible to record neural activity from any retinal cell types.
In this project we have described how retinal and cortical circuits detect motion (Yonehara et al., 2013, Nature, Wertz et al, 2015, Science). Next, we showed that adult neuronal cell types of the retina have a unique transcriptional code and we mapped disease-associated genes to retinal cell types that express them (Siegert et al., 2012, Nature Neuroscience, Busskamp et al, 2014, Neuron, Yonehara et al, 2015, Neuron). Finally, we showed how identified retinal circuits change their computation depending on the sensory input (Farrow et al, 2013, Neuron, Szikra et al, 2014, Nature Neuroscience). Our scientific results and patents, together with results from other groups, led to the formation of a startup company, Gensight Biologics, which specializes on the development of innovative gene therapies for eye diseases.