Postsynaptic neuronal activity promotes regeneration of retinal axons.

The wiring of visual circuits requires that retinal neurons functionally connect to specific brain targets, a process that involves activity-dependent signaling between retinal axons and their postsynaptic targets. Vision loss in various ophthalmological and neurological diseases is caused by damage to the connections from the eye to the brain. How postsynaptic brain targets influence retinal ganglion cell (RGC) axon regeneration and functional reconnection with the brain targets remains poorly understood. Here, we established a paradigm in which the enhancement of neural activity in the distal optic pathway, where the postsynaptic visual target neurons reside, promotes RGC axon regeneration and target reinnervation and leads to the rescue of optomotor function. Furthermore, selective activation of retinorecipient neuron subsets is sufficient to promote RGC axon regeneration. Our findings reveal a key role for postsynaptic neuronal activity in the repair of neural circuits and highlight the potential to restore damaged sensory inputs via proper brain stimulation.

Brief structured respiration practices enhance mood and reduce physiological arousal.

Controlled breathwork practices have emerged as potential tools for stress management and well-being. Here, we report a remote, randomized, controlled study (NCT05304000) of three different daily 5-min breathwork exercises compared with an equivalent period of mindfulness meditation over 1 month. The breathing conditions are (1) cyclic sighing, which emphasizes prolonged exhalations; (2) box breathing, which is equal duration of inhalations, breath retentions, and exhalations; and (3) cyclic hyperventilation with retention, with longer inhalations and shorter exhalations. The primary endpoints are improvement in mood and anxiety as well as reduced physiological arousal (respiratory rate, heart rate, and heart rate variability). Using a mixed-effects model, we show that breathwork, especially the exhale-focused cyclic sighing, produces greater improvement in mood (p < 0.05) and reduction in respiratory rate (p < 0.05) compared with mindfulness meditation. Daily 5-min cyclic sighing has promise as an effective stress management exercise.

Characterization of non-alpha retinal ganglion cell injury responses reveals a possible block to restoring ipRGC function.

Visual impairment caused by retinal ganglion cell (RGC) axon damage or degeneration affects millions of individuals throughout the world. While some progress has been made in promoting long-distance RGC axon regrowth following injury, it remains unclear whether RGC axons can properly reconnect with their central targets to restore visual function. Additionally, the regenerative capacity of many RGC subtypes remains unknown in part due to a lack of available genetic tools. Here, we use a new mouse line, Sema6ACreERT2, that labels On direction-selective RGCs (oDSGCs) and characterize the survival and regenerative potential of these cells following optic nerve crush (ONC). In parallel, we use a previously characterized mouse line, Opn4CreERT2, to answer these same questions for M1 intrinsically photosensitive RGCs (ipRGCs). We find that both M1 ipRGCs and oDSGCs are resilient to injury but do not display long-distance axon regrowth following Lin28a overexpression. Unexpectedly, we found that M1 ipRGC, but not oDSGC, intraretinal axons exhibit ectopic branching and are misaligned near the optic disc between one- and three-weeks following injury. Additionally, we observe that numerous ectopic presynaptic specializations associate with misguided ipRGC intraretinal axons. Taken together, these results reveal insights into the injury response of M1 ipRGCs and oDSGCs, providing a foundation for future efforts seeking to restore visual system function following injury.

Central nervous system regeneration.

Neurons of the mammalian central nervous system fail to regenerate. Substantial progress has been made toward identifying the cellular and molecular mechanisms that underlie regenerative failure and how altering those pathways can promote cell survival and/or axon regeneration. Here, we summarize those findings while comparing the regenerative process in the central versus the peripheral nervous system. We also highlight studies that advance our understanding of the mechanisms underlying neural degeneration in response to injury, as many of these mechanisms represent primary targets for restoring functional neural circuits.

Divergent outputs of the ventral lateral geniculate nucleus mediate visually evoked defensive behaviors.

Rapid alternations between exploration and defensive reactions require ongoing risk assessment. How visual cues and internal states flexibly modulate the selection of behaviors remains incompletely understood. Here, we show that the ventral lateral geniculate nucleus (vLGN)-a major retinorecipient structure-is a critical node in the network controlling defensive behaviors to visual threats. We find that vLGNGABA neuron activity scales with the intensity of environmental illumination and is modulated by behavioral state. Chemogenetic activation of vLGNGABA neurons reduces freezing, whereas inactivation dramatically extends the duration of freezing to visual threats. Perturbations of vLGN activity disrupt exploration in brightly illuminated environments. We describe both a vLGN→nucleus reuniens (Re) circuit and a vLGN→superior colliculus (SC) circuit, which exert opposite influences on defensive responses. These findings reveal roles for genetic- and projection-defined vLGN subpopulations in modulating the expression of behavioral threat responses according to internal state.

Human Responses to Visually Evoked Threat.

Vision is the primary sense humans use to evaluate and respond to threats. Understanding the biological underpinnings of the human threat response has been hindered by lack of realistic in-lab threat paradigms. We established an immersive virtual reality (VR) platform to simultaneously measure behavior, physiological state, and neural activity from the human brain using chronically implanted electrodes. Subjects with high anxiety showed increased visual scanning in response to threats as compared to healthy controls. In both healthy and anxious subjects, the amount of scanning behavior correlated with the magnitude of physiological arousal, suggesting that visual scanning behavior is directly linked to internal state. Intracranial electroencephalography (iEEG) recordings from three subjects suggested that high-frequency gamma activity in the insula positively correlates with physiological arousal induced by visual threats and that low-frequency theta activity in the orbitofrontal cortex (OFC) negatively correlates with physiological arousal induced by visual threats. These findings reveal a key role of eye movements and suggest that distinct insula and OFC activation dynamics may be important for detecting and adjusting human stress in response to visually perceived threats.

Neurotoxic Reactive Astrocytes Drive Neuronal Death after Retinal Injury.

Glaucoma is a neurodegenerative disease that features the death of retinal ganglion cells (RGCs) in the retina, often as a result of prolonged increases in intraocular pressure. We show that preventing the formation of neuroinflammatory reactive astrocytes prevents the death of RGCs normally seen in a mouse model of glaucoma. Furthermore, we show that these spared RGCs are electrophysiologically functional and thus still have potential value for the function and regeneration of the retina. Finally, we demonstrate that the death of RGCs depends on a combination of both an injury to the neurons and the presence of reactive astrocytes, suggesting a model that may explain why reactive astrocytes are toxic only in some circumstances. Altogether, these findings highlight reactive astrocytes as drivers of RGC death in a chronic neurodegenerative disease of the eye.

Neuroscience: A Chromatic Retinal Circuit Encodes Sunrise and Sunset for the Brain.

A new study reveals the retinal circuit for encoding the types of light prominent at sunrise and sunset. The output of that circuit is conveyed to the brain's master circadian clock. Subconscious processing of sky color changes may therefore be the key stimulus for conveying morning and evening information to the circadian timing system in the brain.

Fear: It's All in Your Line of Sight.

The brain circuits that create our sense of fear rely on ancient 'hard-wired' components of the limbic system, but also use sensory processing to determine what we become afraid of. A new study shows that, when viewing of simple oriented line stimuli is coupled with aversive experiences, neurons in primary visual cortex rapidly alter their responses in a manner that indicates the line stimuli become a source of fear.

Molecular Fingerprinting of On-Off Direction-Selective Retinal Ganglion Cells Across Species and Relevance to Primate Visual Circuits.

The ability to detect moving objects is an ethologically salient function. Direction-selective neurons have been identified in the retina, thalamus, and cortex of many species, but their homology has remained unclear. For instance, it is unknown whether direction-selective retinal ganglion cells (DSGCs) exist in primates and, if so, whether they are the equivalent to mouse and rabbit DSGCs. Here, we used a molecular/circuit approach in both sexes to address these issues. In mice, we identify the transcription factor Satb2 (special AT-rich sequence-binding protein 2) as a selective marker for three RGC types: On-Off DSGCs encoding motion in either the anterior or posterior direction, a newly identified type of Off-DSGC, and an Off-sustained RGC type. In rabbits, we find that expression of Satb2 is conserved in On-Off DSGCs; however, it has evolved to include On-Off DSGCs encoding upward and downward motion in addition to anterior and posterior motion. Next, we show that macaque RGCs express Satb2 most likely in a single type. We used rabies virus-based circuit-mapping tools to reveal the identity of macaque Satb2-RGCs and discovered that their dendritic arbors are relatively large and monostratified. Together, these data indicate Satb2-expressing On-Off DSGCs are likely not present in the primate retina. Moreover, if DSGCs are present in the primate retina, it is unlikely that they express Satb2.SIGNIFICANCE STATEMENT The ability to detect object motion is a fundamental feature of almost all visual systems. Here, we identify a novel marker for retinal ganglion cells encoding directional motion that is evolutionarily conserved in mice and rabbits, but not in primates. We show in macaque monkeys that retinal ganglion cells (RGCs) that express this marker comprise a single type and are morphologically distinct from mouse and rabbit direction-selective RGCs. Our findings indicate that On-Off direction-selective retinal neurons may have evolutionarily diverged in primates and more generally provide novel insight into the identity and organization of primate parallel visual pathways.

Sub-topographic maps for regionally enhanced analysis of visual space in the mouse retina.

In many species, neurons are unevenly distributed across the retina, leading to nonuniform analysis of specific visual features at certain locations in visual space. In recent years, the mouse has emerged as a premiere model for probing visual system function, development, and disease. Thus, achieving a detailed understanding of mouse visual circuit architecture is of paramount importance. The general belief is that mice possess a relatively even topographic distribution of retinal ganglion cells (RGCs)-the output neurons of the eye. However, mouse RGCs include ∼30 subtypes; each responds best to a specific feature in the visual scene and conveys that information to central targets. Given the crucial role of RGCs and the prominence of the mouse as a model, we asked how different RGC subtypes are distributed across the retina. We targeted and filled individual fluorescently tagged RGC subtypes from across the retinal surface and evaluated the dendritic arbor extent and soma size of each cell according to its specific retinotopic position. Three prominent RGC subtypes: On-Off direction selective RGCs, object-motion-sensitive RGCs, and a specialized subclass of nonimage-forming RGCs each had marked topographic variations in their dendritic arbor sizes. Moreover, the pattern of variation was distinct for each RGC subtype. Thus, there is increasing evidence that the mouse retina encodes visual space in a region-specific manner. As a consequence, some visual features are sampled far more densely at certain retinal locations than others. These findings have implications for central visual processing, perception, and behavior in this prominent model species.

An Unbiased View of Neural Networks: More than Meets the Eye.

In this issue of Neuron, Macé et al. (2018) use whole-brain functional ultrasound imaging in mice to unveil the circuits involved reflexive eye movements. They separated the sensory and motor networks and discovered that certain eye movements robustly suppress the amygdala.

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. Despite this difference, in both circuits, the proportion of inputs from each BC type, i.e., synaptic convergence between specific BCs and RGCs, remained constant across varying dendritic territory sizes. Furthermore, synapse density between BCs and RGCs was invariant across topography. Our results demonstrate a wiring design, likely engaging homotypic axonal tiling of BCs, that ensures consistency in synaptic convergence between specific BC types onto their target RGCs while enabling independent regulation of pre- and postsynaptic territory sizes and synapse number between cell pairs.

Assembly and repair of eye-to-brain connections.

Vision is the sense humans rely on most to navigate the world and survive. A tremendous amount of research has focused on understanding the neural circuits for vision and the developmental mechanisms that establish them. The eye-to-brain, or 'retinofugal' pathway remains a particularly important model in these contexts because it is essential for sight, its overt anatomical features relate to distinct functional attributes and those features develop in a tractable sequence. Much progress has been made in understanding the growth of retinal axons out of the eye, their selection of targets in the brain, the development of laminar and cell type-specific connectivity within those targets, and also dendritic connectivity within the retina itself. Moreover, because the retinofugal pathway is prone to degeneration in many common blinding diseases, understanding the cellular and molecular mechanisms that establish connectivity early in life stands to provide valuable insights into approaches that re-wire this pathway after damage or loss. Here we review recent progress in understanding the development of retinofugal pathways and how this information is important for improving visual circuit regeneration.