Periodic Reporting for period 4 - RETMUS (The interpretation of retinal activity by the visual thalamus.)
Reporting period: 2020-05-01 to 2020-10-31
Sensory systems of the brain inform cortical centers about the outside world via the thalamus. Despite its central location between the sensory periphery and the primary sensory cortex, the functional role of the thalamus in sensory processing has still largely been unknown.
Understanding the role of thalamic circuits and their modulation by other brain areas is important for several reasons. First, in order to dissect the functional role of higher brain regions, such as sensory cortical areas, it is critical that we understand what kind of input they receive from the thalamus. The thalamus takes information from several different sensory channels, carrying different sensory features. Whether these features are simply relayed to higher centers, or perhaps recombined into new features in the thalamus, is not known. Second, as a central station in sensory processing, the thalamus is thought to gate behaviorally relevant sensory information. In addition to the input from the sensory periphery, the thalamus receives input from several other brain regions. How these inputs modulate or gate sensory information in vivo is not well understood. Finally, in the case of the visual system, an important unmet medical need is optic nerve degeneration caused by end-stage glaucoma, which leads to blindness. Here the input to thalamus is lost, yet the thalamic and cortical circuits are not severely affected. New methods to reactivate the thalamic neurons by channeling visual information directly to these neurons may help to restore some visual capability after the loss of optic nerve fibers.
We had four objectives. First, to understand the logic of connectivity between retinal ganglion cell types and LGN cells, at the resolution of single LGN and retinal cells. Second, to reveal the rules of neuronal activity transformations in the LGN. Third, to understand the role of different brain regions in modulating the incoming or outgoing parallel visual streams in the LGN. Fourth, to restore some visual function in blind animals by targeting optogenetic sensors to LGN cells and stimulating their axon terminals with light patterns.
During the five years of the project, we addressed each of the aims and described the results in a set of publications (Cowan et al, Cell, 2020; Nelidova et al, Science, 2020; Jüttner et al, Nature Neuroscience, 2019; Mace et al, Neuron, 2018; Drinnenberg et al, Neuron, 2018; Schubert et al, Nature Biotechnology, 2018; Hillier et al, Nature Neuroscience, 2017; Rompani et al, Neuron, 2017; Yonehara et al, Neuron, 2016).
Understanding the role of thalamic circuits and their modulation by other brain areas is important for several reasons. First, in order to dissect the functional role of higher brain regions, such as sensory cortical areas, it is critical that we understand what kind of input they receive from the thalamus. The thalamus takes information from several different sensory channels, carrying different sensory features. Whether these features are simply relayed to higher centers, or perhaps recombined into new features in the thalamus, is not known. Second, as a central station in sensory processing, the thalamus is thought to gate behaviorally relevant sensory information. In addition to the input from the sensory periphery, the thalamus receives input from several other brain regions. How these inputs modulate or gate sensory information in vivo is not well understood. Finally, in the case of the visual system, an important unmet medical need is optic nerve degeneration caused by end-stage glaucoma, which leads to blindness. Here the input to thalamus is lost, yet the thalamic and cortical circuits are not severely affected. New methods to reactivate the thalamic neurons by channeling visual information directly to these neurons may help to restore some visual capability after the loss of optic nerve fibers.
We had four objectives. First, to understand the logic of connectivity between retinal ganglion cell types and LGN cells, at the resolution of single LGN and retinal cells. Second, to reveal the rules of neuronal activity transformations in the LGN. Third, to understand the role of different brain regions in modulating the incoming or outgoing parallel visual streams in the LGN. Fourth, to restore some visual function in blind animals by targeting optogenetic sensors to LGN cells and stimulating their axon terminals with light patterns.
During the five years of the project, we addressed each of the aims and described the results in a set of publications (Cowan et al, Cell, 2020; Nelidova et al, Science, 2020; Jüttner et al, Nature Neuroscience, 2019; Mace et al, Neuron, 2018; Drinnenberg et al, Neuron, 2018; Schubert et al, Nature Biotechnology, 2018; Hillier et al, Nature Neuroscience, 2017; Rompani et al, Neuron, 2017; Yonehara et al, Neuron, 2016).
Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. We identified FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and suggested the involvement of a specific inhibitory neuron type in the pathophysiology of a neurological disease (Yonehara et al, Neuron, 2016).
The thalamus receives sensory input from different circuits in the periphery. How these sensory channels are integrated at the level of single thalamic cells is not well understood. We showed that the LGN employs at least three modes of visual input integration, each exhibiting different degrees of specialization (Rompani et al, Neuron, 2017).
How neuronal computations in the sensory periphery contribute to computations in the cortex is not well understood. We revealed the existence of two functionally distinct, sensory-periphery-dependent and -independent computations of visual motion in the cortex (Hillier et al, Nature Neuroscience, 2017).
Genetic engineering by viral infection of single cells is useful to study complex systems such as the brain. However, available methods for infecting single cells have drawbacks that limit their applications. We described 'virus stamping', which provides a versatile solution for targeted single-cell infection of diverse cell types, both in vitro and in vivo (Schubert et al, Nature Biotechnology, 2018).
Large numbers of brain regions are active during behaviors. A high-resolution, brain-wide activity map could identify brain regions involved in specific behaviors. We have developed functional ultrasound imaging to record whole-brain activity in behaving mice at a resolution of ∼100 μm (Mace et al, Neuron, 2018).
Many brain regions contain local interneurons of distinct types. How does an interneuron type contribute to the input-output transformations of a given brain region? Our combined experimental and theoretical work revealed how a single interneuron type can differentially shape the dynamical properties of distinct output channels of a brain region (Drinnenberg et al, Neuron, 2018).
Targeting genes to specific neuronal or glial cell types is valuable for both understanding and repairing brain circuits. Adeno-associated viruses (AAVs) are frequently used for gene delivery, but targeting expression to specific cell types is an unsolved problem. We created a library of 230 AAVs, each with a different synthetic promoter designed using four independent strategies. These resources and approaches allow economic, fast and efficient cell-type targeting in a variety of species, both for fundamental science and for gene therapy. (Juettner et al, Nature Neuroscience, 2019).
Enabling near-infrared light sensitivity in a blind human retina may supplement or restore visual function in patients with regional retinal degeneration. We induced near-infrared light sensitivity using gold nanorods bound to temperature-sensitive engineered transient receptor potential (TRP) channels. We expressed mammalian or snake TRP channels in light-insensitive retinal cones in a mouse model of retinal degeneration. Near-infrared stimulation increased activity in cones, ganglion cell layer neurons, and cortical neurons, and enabled mice to perform a learned light-driven behavior. We targeted TRP channels to human retinas, which allowed the postmortem activation of different cell types by near-infrared light. (Nelidova et al, Science, 2020).
Human organoids recapitulating the cell-type diversity and function of their target organ are valuable for basic and translational research. We developed light-sensitive human retinal organoids with multiple nuclear and synaptic layers, and functional synapses (Cowan et al, Cell, 2020).
The thalamus receives sensory input from different circuits in the periphery. How these sensory channels are integrated at the level of single thalamic cells is not well understood. We showed that the LGN employs at least three modes of visual input integration, each exhibiting different degrees of specialization (Rompani et al, Neuron, 2017).
How neuronal computations in the sensory periphery contribute to computations in the cortex is not well understood. We revealed the existence of two functionally distinct, sensory-periphery-dependent and -independent computations of visual motion in the cortex (Hillier et al, Nature Neuroscience, 2017).
Genetic engineering by viral infection of single cells is useful to study complex systems such as the brain. However, available methods for infecting single cells have drawbacks that limit their applications. We described 'virus stamping', which provides a versatile solution for targeted single-cell infection of diverse cell types, both in vitro and in vivo (Schubert et al, Nature Biotechnology, 2018).
Large numbers of brain regions are active during behaviors. A high-resolution, brain-wide activity map could identify brain regions involved in specific behaviors. We have developed functional ultrasound imaging to record whole-brain activity in behaving mice at a resolution of ∼100 μm (Mace et al, Neuron, 2018).
Many brain regions contain local interneurons of distinct types. How does an interneuron type contribute to the input-output transformations of a given brain region? Our combined experimental and theoretical work revealed how a single interneuron type can differentially shape the dynamical properties of distinct output channels of a brain region (Drinnenberg et al, Neuron, 2018).
Targeting genes to specific neuronal or glial cell types is valuable for both understanding and repairing brain circuits. Adeno-associated viruses (AAVs) are frequently used for gene delivery, but targeting expression to specific cell types is an unsolved problem. We created a library of 230 AAVs, each with a different synthetic promoter designed using four independent strategies. These resources and approaches allow economic, fast and efficient cell-type targeting in a variety of species, both for fundamental science and for gene therapy. (Juettner et al, Nature Neuroscience, 2019).
Enabling near-infrared light sensitivity in a blind human retina may supplement or restore visual function in patients with regional retinal degeneration. We induced near-infrared light sensitivity using gold nanorods bound to temperature-sensitive engineered transient receptor potential (TRP) channels. We expressed mammalian or snake TRP channels in light-insensitive retinal cones in a mouse model of retinal degeneration. Near-infrared stimulation increased activity in cones, ganglion cell layer neurons, and cortical neurons, and enabled mice to perform a learned light-driven behavior. We targeted TRP channels to human retinas, which allowed the postmortem activation of different cell types by near-infrared light. (Nelidova et al, Science, 2020).
Human organoids recapitulating the cell-type diversity and function of their target organ are valuable for basic and translational research. We developed light-sensitive human retinal organoids with multiple nuclear and synaptic layers, and functional synapses (Cowan et al, Cell, 2020).
We have developed several new technologies and tools: functional ultrasound imaging to record whole-brain activity in behaving mice at a resolution of ∼100 μm (Mace et al, Neuron, 2018), virus stamping to provide a versatile solution for targeted single-cell infection of diverse cell types, both in vitro and in vivo (Schubert et al, Nature Biotechnology, 2018), cell type targeting gene therapy vectors for neuronal and glial cell types (Juettner et al, Nature Neuroscience, 2019), a new vision restoration method that uses near-infrared light and can be tuned to different wavelengths (Nelidova et al, Science, 2020), and light-sensitive human retinal organoids with multiple nuclear and synaptic layers, and functional synapses (Cowan et al, Cell, 2020).