Skip to main content

The interpretation of retinal activity by the visual thalamus.

Periodic Reporting for period 3 - RETMUS (The interpretation of retinal activity by the visual thalamus.)

Reporting period: 2018-11-01 to 2020-04-30

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 is still largely 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 have 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.
Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. Here we found that the mutation of FRMD7, a gene that is defective in human congenital nystagmus, leads to the selective loss of the horizontal optokinetic reflex in mice, as it does in humans. This is accompanied by the selective loss of horizontal direction selectivity in retinal ganglion cells and the transition from asymmetric to symmetric inhibitory input to horizontal direction-selective ganglion cells. In wild-type retinas, we found FRMD7 specifically expressed in starburst amacrine cells, the interneuron type that provides asymmetric inhibition to direction-selective retinal ganglion cells. This work identifies FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and it suggests 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 performed targeted single-cell-initiated transsynaptic tracing to label the retinal ganglion cells that provide input to individual principal cells in the mouse lateral geniculate nucleus (LGN). We identified three modes of sensory integration by single LGN cells. In the first, 1-5 ganglion cells of mostly the same type converged from one eye, indicating a relay mode. In the second, 6-36 ganglion cells of different types converged from one eye, revealing a combination mode. In the third, up to 91 ganglion cells converged from both eyes, revealing a binocular combination mode in which functionally specialized ipsilateral inputs joined broadly distributed contralateral inputs. Thus, 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 examined this question in the context of visual-motion processing in the retina and primary visual cortex (V1) of mice. We disrupted retinal direction selectivity, either exclusively along the horizontal axis using FRMD7 mutants or along all directions by ablating starburst amacrine cells, and monitored neuronal activity in layer 2/3 of V1 during stimulation with visual motion. In control mice, we found an over-representation of cortical cells preferring posterior visual motion, the dominant motion direction an animal experiences when it moves forward. In mice with disrupted retinal direction selectivity, the over-representation of posterior-motion-preferring cortical cells disappeared, and their responses at higher stimulus speeds were reduced. This work reveals 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. Here we describe 'virus stamping', in which viruses are reversibly bound to a delivery vehicle-a functionalized glass pipette tip or magnetic nanoparticles in a pipette-that is brought into physical contact with the target cell on a surface or in tissue, using mechanical or magnetic forces. Different single cells in the same tissue can be infected with different viruses and an individual cell can be simultaneously infected with different viruses. We use rabies, lenti, herpes simplex, and adeno-associated viruses to drive expression of fluorescent markers or a calcium indicator in target cells in cell culture, mouse retina, human brain organoid, and the brains of live mice. Virus stamping 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. We detected 87 active brain regions during visual stimulation that evoked the optokinetic reflex, a visuomotor behavior that stabilizes the gaze both horizontally and vertically. Using a genetic mouse model of congenital nystagmus incapable of generating the horizontal reflex, we identified a subset of regions whose activity was reflex dependent. By blocking eye motion in control animals, we further separated regions whose activity depended on the reflex's motor output. Remarkably, all reflex-dependent but eye motion-independent regions were located in the thalamus. Our work identifies functional modules of brain regions involved in sensorimotor integration and provides an experimental approach to monitor whole-brain activity of mice in normal and disease states (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? We addressed this question in the mouse retina by chemogenetically perturbing horizontal cells, an interneuron type providing feedback at the first visual synapse, while monitoring the light-driven spiking activity in thousands of ganglion cells, the retinal output neurons. We uncovered six reversible perturbation-induced effects in the response dynamics and response range of ganglion cells. The effects were enhancing or suppressive, occurred in different response epochs, and depended on the ganglion cell type. A computational model of the retinal circuitry reproduced all perturbation-induced effects and led us to assign specific functions to horizontal cells with respect to different ganglion cell types. Our combined experimental and theoretical work reveals 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. We show that a number of these AAVs specifically target expression to neuronal and glial cell types in the mouse and non-human primate retina in vivo and in the human retina in vitro. We demonstrate applications for recording and stimulation, as well as the intersectional and combinatorial labeling of cell types. 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 tuned responses to different wavelengths, by using nanorods of different lengths, and to different radiant powers, by using engineered channels with different temperature thresholds. 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).
We have developed functional ultrasound imaging to record whole-brain activity in behaving mice at a resolution of ∼100 μm. Our work provides an experimental approach to monitor whole-brain activity of mice in normal and disease states (Mace et al, Neuron, 2018). We have developed 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). We identified the involvement of starburst amacrine cells neuron type in the pathophysiology of a frequent neurological disease, congenital nystagmus (Yonehara et al, Neuron, 2016). We have developed cell type targeting gene therapy vectors for neuronal and glial cell types (Juettner et al, Nature Neuroscience, 2019). We have developed a new vision restoration method that uses near-infrared light and can be tuned to different wavelengths (Nelidova et al, Science, 2020).
Ganglion cells traced and color-coded based on morphological type.