Tau P301S Transgenic Mice Develop Gait and Eye Movement Impairments That Mimic Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder with an estimated prevalence of 5-7 people in 100,000. Clinically characterized by impairments in gait, balance, and eye movements, as well as aggregated Tau pathology, PSP leads to death in approximately 5-8 years. No disease-modifying treatments are currently available.

A semi-automated method for quantifying optokinetic reflex tracking acuity.

Unlabelled: The study of murine behavioral responses to visual stimuli is a key component of understanding mammalian visual circuitry. One notable response is the optokinetic reflex (OKR), a highly conserved innate behavior necessary for image stabilization on the retina. The OKR provides a robust readout of image tracking ability and has been extensively studied to understand the logic of visual system circuitry and function in mice from different genetic backgrounds.

Asymmetric retinal direction tuning predicts optokinetic eye movements across stimulus conditions.

Across species, the optokinetic reflex (OKR) stabilizes vision during self-motion. OKR occurs when ON direction-selective retinal ganglion cells (oDSGCs) detect slow, global image motion on the retina. How oDSGC activity is integrated centrally to generate behavior remains unknown.

Inhibition, but not excitation, recovers from partial cone loss with greater spatiotemporal integration, synapse density, and frequency.

Neural circuits function in the face of changing inputs, either caused by normal variation in stimuli or by cell death. To maintain their ability to perform essential computations with partial inputs, neural circuits make modifications. Here, we study the retinal circuit's responses to changes in light stimuli or in photoreceptor inputs by inducing partial cone death in the mature mouse retina.

Impact of Photoreceptor Loss on Retinal Circuitry.

Our sense of sight relies on photoreceptors, which transduce photons into the nervous system's electrochemical interpretation of the visual world. These precious photoreceptors can be disrupted by disease, injury, and aging. Once photoreceptors start to die, but before blindness occurs, the remaining retinal circuitry can withstand, mask, or exacerbate the photoreceptor deficit and potentially be receptive to newfound therapies for vision restoration.

Disassembly and rewiring of a mature converging excitatory circuit following injury.

Specificity and timing of synapse disassembly in the CNS are essential to learning how individual circuits react to neurodegeneration of the postsynaptic neuron. In sensory systems such as the mammalian retina, synaptic connections of second-order neurons are known to remodel and reconnect in the face of sensory cell loss. Here we analyzed whether degenerating third-order neurons can remodel their local presynaptic connectivity.

Mature Retina Compensates Functionally for Partial Loss of Rod Photoreceptors.

Loss of primary neuronal inputs inevitably strikes every neural circuit. The deafferented circuit could propagate, amplify, or mitigate input loss, thus affecting the circuit's output. How the deafferented circuit contributes to the effect on the output is poorly understood because of lack of control over loss of and access to circuit elements.

Partial Cone Loss Triggers Synapse-Specific Remodeling and Spatial Receptive Field Rearrangements in a Mature Retinal Circuit.

Resilience of neural circuits has been observed in the persistence of function despite neuronal loss. In vision, acuity and sensitivity can be retained after 50% loss of cones. While neurons in the cortex can remodel after input loss, the contributions of cell-type-specific circuits to resilience are unknown.

Synaptic Convergence Patterns onto Retinal Ganglion Cells Are Preserved despite Topographic Variation in Pre- and Postsynaptic Territories.

Sensory processing can be tuned by a neuron's integration area, the types of inputs, and the proportion and number of connections with those inputs. Integration areas often vary topographically to sample space differentially across regions. Here, we highlight two visual circuits in which topographic changes in the postsynaptic retinal ganglion cell (RGC) dendritic territories and their presynaptic bipolar cell (BC) axonal territories are either matched or unmatched.

Synaptogenesis and synaptic protein localization in the postnatal development of rod bipolar cell dendrites in mouse retina.

Retinal responses to photons originate in rod photoreceptors and are transmitted to the ganglion cell output of the retina through the primary rod bipolar pathway. At the first synapse of this pathway, input from multiple rods is pooled into individual rod bipolar cells. This architecture is called convergence.

Photoreceptor ablation initiates the immediate loss of glutamate receptors in postsynaptic bipolar cells in retina.

Structural changes underlying neurodegenerative diseases include dismantling of synapses, degradation of circuitry, and even massive rewiring. Our limited understanding of synapse dismantling stems from the inability to control the timing and extent of cell death. In this study, selective ablation of cone photoreceptors in live mouse retina and tracking of postsynaptic partners at the cone-to-ON cone bipolar cell synapse reveals that early reaction to cone loss involves rapid and local changes in postsynaptic glutamate receptor distribution.

Wiring patterns in the mouse retina: collecting evidence across the connectome, physiology and light microscopy.

The visual system has often been thought of as a parallel processor because distinct regions of the brain process different features of visual information. However, increasing evidence for convergence and divergence of circuit connections, even at the level of the retina where visual information is first processed, chips away at a model of dedicated and distinct pathways for parallel information flow. Instead, our current understanding is that parallel channels may emerge, not from exclusive microcircuits for each channel, but from unique combinations of microcircuits.

Sensory experience shapes the development of the visual system's first synapse.

Specific connectivity patterns among neurons create the basic architecture underlying parallel processing in our nervous system. Here we focus on the visual system's first synapse to examine the structural and functional consequences of sensory deprivation on the establishment of parallel circuits. Dark rearing reduces synaptic strength between cones and cone bipolar cells, a previously unappreciated effect of sensory deprivation.

The spatial structure of a nonlinear receptive field.

Understanding a sensory system implies the ability to predict responses to a variety of inputs from a common model. In the retina, this includes predicting how the integration of signals across visual space shapes the outputs of retinal ganglion cells. Existing models of this process generalize poorly to predict responses to new stimuli.

Diverse strategies engaged in establishing stereotypic wiring patterns among neurons sharing a common input at the visual system's first synapse.

Sensory circuits use common strategies, such as convergence and divergence, typically at different synapses, to pool or distribute inputs. Inputs from different presynaptic cell types converge onto a common postsynaptic cell, acting together to shape neuronal output (Klausberger and Somogyi, 2008). Also, individual presynaptic cells contact several postsynaptic cell types, generating divergence of signals.

Spontaneous olfactory receptor neuron activity determines follower cell response properties.

Noisy or spontaneous activity is common in neural systems and poses a challenge to detecting and discriminating signals. Here we use the locust to answer fundamental questions about noise in the olfactory system: Where does spontaneous activity originate? How is this activity propagated or reduced throughout multiple stages of neural processing? What mechanisms favor the detection of signals despite the presence of spontaneous activity? We found that spontaneous activity long observed in the secondary projection neurons (PNs) originates almost entirely from the primary olfactory receptor neurons (ORNs) rather than from spontaneous circuit interactions in the antennal lobe, and that spontaneous activity in ORNs tonically depolarizes the resting membrane potentials of their target PNs and local neurons (LNs) and indirectly tonically depolarizes tertiary Kenyon cells (KCs). However, because these neurons have different response thresholds, in the absence of odor stimulation, ORNs and PNs display a high spontaneous firing rate but KCs are nearly silent.

Single-photon absorptions evoke synaptic depression in the retina to extend the operational range of rod vision.

Adaptation or gain control allows sensory neurons to encode diverse stimuli using a limited range of output signals. Rod vision exemplifies a general challenge facing adaptational mechanisms-balancing the benefits of averaging to create a reliable signal for adaptation with the need to adapt rapidly and locally. The synapse between rod bipolar and AII amacrine cells dominates adaptation at low light levels.

Light adaptation in cone vision involves switching between receptor and post-receptor sites.

We see over an enormous range of mean light levels, greater than the range of output signals retinal neurons can produce. Even highlights and shadows within a single visual scene can differ approximately 10,000-fold in intensity-exceeding the range of distinct neural signals by a factor of approximately 100. The effectiveness of daylight vision under these conditions relies on at least two retinal mechanisms that adjust sensitivity in the approximately 200 ms intervals between saccades.

Synaptic influences on rat ganglion-cell photoreceptors.

The intrinsically photosensitive retinal ganglion cells (ipRGCs) provide a conduit through which rods and cones can access brain circuits mediating circadian entrainment, pupillary constriction and other non-image-forming visual functions. We characterized synaptic inputs to ipRGCs in rats using whole-cell and multielectrode array recording techniques. In constant darkness all ipRGCs received spontaneous excitatory and inhibitory synaptic inputs.

The impact of photoreceptor noise on retinal gain controls.

Multiple retinal mechanisms preserve visual sensitivity as the properties of the light inputs change. Rapid gain controls match the effective signaling range of retinal neurons to the local image statistics. Such gain controls trade an increased sensitivity for some aspects of the inputs for a decreased sensitivity to others.

Controlling the gain of rod-mediated signals in the Mammalian retina.

Effective sensory processing requires matching the gain of neural responses to the range of signals encountered. For rod vision, gain controls operate at light levels at which photons arrive rarely at individual rods, light levels too low to cause adaptation in rod phototransduction. Under these conditions, adaptation within a conserved pathway in mammalian retina maintains sensitivity as light levels change.

Photoreceptor adaptation in intrinsically photosensitive retinal ganglion cells.

A rare type of mammalian retinal ganglion cell (RGC) expresses the photopigment melanopsin and is a photoreceptor. These intrinsically photosensitive RGCs (ipRGCs) drive circadian-clock resetting, pupillary constriction, and other non-image-forming photic responses. Both the light responses of ipRGCs and the behaviors they drive are remarkably sustained, raising the possibility that, unlike rods and cones, ipRGCs do not adjust their sensitivity according to lighting conditions ("adaptation").

Visual pigment phosphorylation but not transducin translocation can contribute to light adaptation in zebrafish cones.

The ability of cone photoreceptors to adapt to light is extraordinary. In this study we evaluated two biochemical processes, visual pigment phosphorylation and transducin translocation, for their ability to contribute to light adaptation in zebrafish cones. Since cytoplasmic Ca2+ regulates light adaptation, the sensitivities of these processes to both light and Ca2+ were examined.

Phototransduction by retinal ganglion cells that set the circadian clock.

Light synchronizes mammalian circadian rhythms with environmental time by modulating retinal input to the circadian pacemaker-the suprachiasmatic nucleus (SCN) of the hypothalamus. Such photic entrainment requires neither rods nor cones, the only known retinal photoreceptors. Here, we show that retinal ganglion cells innervating the SCN are intrinsically photosensitive.