Light affects the prefrontal cortex via intrinsically photosensitive retinal ganglion cells.

The ventromedial prefrontal cortex (vmPFC) is a part of the limbic system engaged in the regulation of social, emotional, and cognitive states, which are characteristically impaired in disorders of the brain such as schizophrenia and depression. Here, we show that intrinsically photosensitive retinal ganglion cells (ipRGCs) modulate, through light, the integrity, activity, and function of the vmPFC. This regulatory role, which is independent of circadian and mood alterations, is mediated by an ipRGC-thalamic-corticolimbic pathway. Lack of ipRGC signaling in mice causes dendritic degeneration, dysregulation of genes involved in synaptic plasticity, and depressed neuronal activity in the vmPFC. These alterations primarily undermine the ability of the vmPFC to regulate emotions. Our discovery provides a potential light-dependent mechanism for certain PFC-centric disorders in humans.

WITHDRAWN: Light affects the prefrontal cortex via intrinsically photosensitive retinal ganglion cells.

This manuscript has been withdrawn by bioRxiv following a formal request by the NIH Intramural Research Integrity Office owing to lack of author consent.

Neurexin 3 is required for the specific S-cone to S-cone bipolar cell synapse in the mammalian retina.

Specific wiring is essential for sensory systems to precisely relay information to higher brain regions. The retina, an approachable part of the brain, is an ideal model for studying neural circuits due to its well-organized structure. In the retina, S-cone photoreceptors sense and relay short-wavelength (e.g., blue) light signals for encoding color information and other environmental cues. S-cones usually account for less than 10% of cones and are precisely connected to S-cone bipolar cells (SCBCs). This connection is ancient and highly conserved across species, indicating essential functions. How this wiring specificity is formed and maintained, however, is not understood. To unveil the molecular mechanisms underlying this highly specific connection, we sequenced the transcriptomes of thirteen-lined ground squirrel (TLGS) photoreceptors. We chose TLGS for their cone-rich retina and the absence of cones that co-express multiple opsin proteins, as compared to mice. We used a targeted SMART-seq approach to obtain high-resolution transcriptomes from S- and M-cone photoreceptors and identified a cell-adhesion molecule, Nrxn3, as a potential candidate mediating the S-cone to SCBC connection. Given the limitations of genetic manipulation in TLGS, we utilized mouse models to study the function of Nrxn3 in S-cones. In 'true' S-cones (S-opsin+/M-opsin-) that lack Nrxn3 expression, the number of connections with SCBCs was drastically reduced, indicating a critical role of Nrxn3 for this synapse. While neurexins are well known for their diverse roles in regulating various synapses, this study is the first to document its crucial role in mediating or maintaining a specific synapse in the central nervous system. In addition, the differentially expressed genes identified here provide a valuable resource for further investigating cone subtype-specific functions.

Satellite glia modulate sympathetic neuron survival, activity, and autonomic function.

Satellite glia are the major glial cells in sympathetic ganglia, enveloping neuronal cell bodies. Despite this intimate association, the extent to which sympathetic functions are influenced by satellite glia in vivo remains unclear. Here, we show that satellite glia are critical for metabolism, survival, and activity of sympathetic neurons and modulate autonomic behaviors in mice. Adult ablation of satellite glia results in impaired mTOR signaling, soma atrophy, reduced noradrenergic enzymes, and loss of sympathetic neurons. However, persisting neurons have elevated activity, and satellite glia-ablated mice show increased pupil dilation and heart rate, indicative of enhanced sympathetic tone. Satellite glia-specific deletion of Kir4.1, an inward-rectifying potassium channel, largely recapitulates the cellular defects observed in glia-ablated mice, suggesting that satellite glia act in part via K+-dependent mechanisms. These findings highlight neuron-satellite glia as functional units in regulating sympathetic output, with implications for disorders linked to sympathetic hyper-activity such as cardiovascular disease and hypertension.

Daily changes in light influence mood via inhibitory networks within the thalamic perihabenular nucleus.

Exposure to irregular lighting schedules leads to deficits in affective behaviors. The retino-recipient perihabenular nucleus (PHb) of the dorsal thalamus has been shown to mediate these effects in mice. However, the mechanisms of how light information is processed within the PHb remains unknown. Here, we show that the PHb contains a distinct cluster of GABAergic neurons that receive direct retinal input. These neurons are part of a larger inhibitory network composed of the thalamic reticular nucleus and zona incerta, known to modulate thalamocortical communication. In addition, PHbGABA neurons locally modulate excitatory-relay neurons, which project to limbic centers. Chronic exposure to irregular light-dark cycles alters photo-responsiveness and synaptic output of PHbGABA neurons, disrupting daily oscillations of genes associated with inhibitory and excitatory PHb signaling. Consequently, selective and chronic PHbGABA manipulation results in mood alterations that mimic those caused by irregular light exposure. Together, light-mediated disruption of PHb inhibitory networks underlies mood deficits.

Diversity of satellite glia in sympathetic and sensory ganglia.

Satellite glia are the major glial type found in sympathetic and sensory ganglia in the peripheral nervous system, and specifically, contact neuronal cell bodies. Sympathetic and sensory neurons differ in morphological, molecular, and electrophysiological properties. However, the molecular diversity of the associated satellite glial cells remains unclear. Here, using single-cell RNA sequencing analysis, we identify five different populations of satellite glia from sympathetic and sensory ganglia. We define three shared populations of satellite glia enriched in immune-response genes, immediate-early genes, and ion channels/ECM-interactors, respectively. Sensory- and sympathetic-specific satellite glia are differentially enriched for modulators of lipid synthesis and metabolism. Sensory glia are also specifically enriched for genes involved in glutamate turnover. Furthermore, satellite glia and Schwann cells can be distinguished by unique transcriptional signatures. This study reveals the remarkable heterogeneity of satellite glia in the peripheral nervous system.

Light Affects Mood and Learning through Distinct Retina-Brain Pathways.

Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN's pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning.

A subset of ipRGCs regulates both maturation of the circadian clock and segregation of retinogeniculate projections in mice.

The visual system consists of two major subsystems, image-forming circuits that drive conscious vision and non-image-forming circuits for behaviors such as circadian photoentrainment. While historically considered non-overlapping, recent evidence has uncovered crosstalk between these subsystems. Here, we investigated shared developmental mechanisms. We revealed an unprecedented role for light in the maturation of the circadian clock and discovered that intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for this refinement process. In addition, ipRGCs regulate retinal waves independent of light, and developmental ablation of a subset of ipRGCs disrupts eye-specific segregation of retinogeniculate projections. Specifically, a subset of ipRGCs, comprising ~200 cells and which project intraretinally and to circadian centers in the brain, are sufficient to mediate both of these developmental processes. Thus, this subset of ipRGCs constitute a shared node in the neural networks that mediate light-dependent maturation of the circadian clock and light-independent refinement of retinogeniculate projections.

Electron Transport Chain Remodeling by GSK3 during Oogenesis Connects Nutrient State to Reproduction.

Reproduction is heavily influenced by nutrition and metabolic state. Many common reproductive disorders in humans are associated with diabetes and metabolic syndrome. We characterized the metabolic mechanisms that support oogenesis and found that mitochondria in mature Drosophila oocytes enter a low-activity state of respiratory quiescence by remodeling the electron transport chain (ETC). This shift in mitochondrial function leads to extensive glycogen accumulation late in oogenesis and is required for the developmental competence of the oocyte. Decreased insulin signaling initiates ETC remodeling and mitochondrial respiratory quiescence through glycogen synthase kinase 3 (GSK3). Intriguingly, we observed similar ETC remodeling and glycogen uptake in maturing Xenopus oocytes, suggesting that these processes are evolutionarily conserved aspects of oocyte development. Our studies reveal an important link between metabolism and oocyte maturation.