Clinical review of retinotopy

Two observations made 29 years apart are the cornerstones of this review on the contributions of Dr Gordon T. Plant to understanding pathology affecting the optic nerve. The first observation laid the anatomical basis in 1990 for the interpretation of optical coherence tomography (OCT) findings in 2009. Retinal OCT offers clinicians detailed in vivo structural imaging of individual retinal layers. This has led to novel observations which were impossible to make using ophthalmoscopy. The technique also helps to re-introduce the anatomically grounded concept of retinotopy to clinical practise. This review employs illustrations of the anatomical basis for retinotopy through detailed translational histological studies and multimodal brain-eye imaging studies. The paths of the prelaminar and postlaminar axons forming the optic nerve and their postsynaptic path from the dorsal lateral geniculate nucleus to the primary visual cortex in humans are described. With the mapped neuroanatomy in mind we use OCT-MRI pairings to discuss the patterns of neurodegeneration in eye and brain that are a consequence of the hard wired retinotopy: anterograde and retrograde axonal degeneration which can, within the visual system, propagate trans-synaptically. The technical advances of OCT and MRI for the first time enable us to trace axonal degeneration through the entire visual system at spectacular resolution. In conclusion, the neuroanatomical insights provided by the combination of OCT and MRI allows us to separate incidental findings from sinister pathology and provides new opportunities to tailor and monitor novel neuroprotective strategies.

Mechanisms of Plasticity in Subcortical Visual Areas

Visual plasticity is classically considered to occur essentially in the primary and secondary cortical areas. Subcortical visual areas such as the dorsal lateral geniculate nucleus (dLGN) or the superior colliculus (SC) have long been held as basic structures responsible for a stable and defined function. In this model, the dLGN was considered as a relay of visual information travelling from the retina to cortical areas and the SC as a sensory integrator orienting body movements towards visual targets. However, recent findings suggest that both dLGN and SC neurons express functional plasticity, adding unexplored layers of complexity to their previously attributed functions. The existence of neuronal plasticity at the level of visual subcortical areas redefines our approach of the visual system. The aim of this paper is therefore to review the cellular and molecular mechanisms for activity-dependent plasticity of both synaptic transmission and cellular properties in subcortical visual areas.

Mechanisms of functional plasticity in subcortical visual areas

Visual plasticity is classically considered to occur essentially in the primary and secondarycortical areas. Subcortical visual areas such as the dorsal lateral geniculate nucleus (dLGN)or the superior colliculus (SC) have long been held as basic structures responsible for a stableand defined function. In this model, the dLGN was considered as a relay of visual informationtravelling from the retina to cortical areas and the SC as a sensory integrator orienting bodymovements towards visual targets. However, recent findings suggest that both dLGN and SCneurons express functional plasticity, adding unexplored layers of complexity to theirpreviously attributed functions. The existence of neuronal plasticity at the level of visualsubcortical areas redefines our approach of the visual system. The aim of this paper istherefore to review the cellular and molecular mechanisms for activity-dependent plasticity ofsynaptic transmission and of cellular properties in subcortical visual areas.

The synaptic basis of activity-dependent eye-specific competition

Binocular vision requires proper developmental wiring of eye-specific inputs to the brain. Axons from the two eyes initially overlap in the dorsal lateral geniculate nucleus and undergo activity-dependent competition to segregate into target domains. The synaptic basis of such refinement is unknown. Here we used volumetric super-resolution imaging to measure the nanoscale molecular reorganization of developing retinogeniculate eye-specific synapses in the mouse brain. The outcome of binocular synaptic competition was determined by the relative eye-specific maturation of presynaptic vesicle content. Genetic disruption of spontaneous retinal activity prevented subsynaptic vesicle pool maturation, recruitment of vesicles to the active zone, synaptic development and eye-specific competition. These results reveal an activity-dependent presynaptic basis for axonal refinement in the mammalian visual system.

Single-cell and single-nucleus RNA-seq uncovers shared and distinct axes of variation in dorsal LGN neurons in mice, non-human primates, and humans

Abundant evidence supports the presence of at least three distinct types of thalamocortical (TC) neurons in the primate dorsal lateral geniculate nucleus (dLGN) of the thalamus, the brain region that conveys visual information from the retina to the primary visual cortex (V1). Different types of TC neurons in mice, humans, and macaques have distinct morphologies, distinct connectivity patterns, and convey different aspects of visual information to the cortex. To investigate the molecular underpinnings of these cell types, and how these relate to differences in dLGN between human, macaque, and mice, we profiled gene expression in single nuclei and cells using RNA-sequencing. These efforts identified four distinct types of TC neurons in the primate dLGN: magnocellular (M) neurons, parvocellular (P) neurons, and two types of koniocellular (K) neurons. Despite extensively documented morphological and physiological differences between M and P neurons, we identified few genes with significant differential expression between transcriptomic cell types corresponding to these two neuronal populations. Likewise, the dominant feature of TC neurons of the adult mouse dLGN is high transcriptomic similarity, with an axis of heterogeneity that aligns with core vs. shell portions of mouse dLGN. Together, these data show that transcriptomic differences between principal cell types in the mature mammalian dLGN are subtle relative to the observed differences in morphology and cortical projection targets. Finally, alignment of transcriptome profiles across species highlights expanded diversity of GABAergic neurons in primate versus mouse dLGN and homologous types of TC neurons in primates that are distinct from TC neurons in mouse.

Optogenetic suppression of corticogeniculate feedback in anesthetized ferrets is overridden by visual stimulation

The feedforward projection from the retina shapes the spatial receptive field properties of neurons in the dorsal lateral geniculate nucleus of the thalamus (LGN). Corticogeniculate feedback from the visual cortex appears to exert a more subtle, modulatory influence on LGN responses. Studies involving manipulations of corticogeniculate feedback have yielded inconsistent findings, but the reasons for these inconsistencies are not known. To examine the functional contributions of corticogeniculate feedback, and to resolve past inconsistencies, we examined the effects of selective optogenetic suppression of corticogeniculate neurons in anesthetized ferrets. In particular, we examined the responses of LGN and V1 neurons during optogenetic suppression of corticogeniculate feedback in the presence and absence of visual stimulation and across conditions in which the frequency of LED illumination varied. Optogenetic suppression of corticogeniculate feedback decreased activity among LGN neurons in the absence of visual stimulation, dispelling the notion that anesthesia causes a floor effect. In contrast, suppressing corticogeniculate feedback did not affect the visual responses of LGN neurons, suggesting that feedforward visual stimulus drive overrides weak corticogeniculate influence. Optogenetic effects on LGN and V1 neuronal responses depended on the frequency of LED illumination, with higher frequency illumination inducing slow oscillations in V1, dis-inhibiting V1 neurons locally, and producing more suppression among LGN neurons. These results demonstrate that corticogeniculate influence depends on stimulation parameters including visual stimulus conditions and frequency of inactivation. Furthermore, weak corticogeniculate influence is overridden by strong feedforward visual stimulus drive; this attribute is the most likely source of inconsistencies in past studies.

Participation of L-Lactate and Its Receptor HCAR1/GPR81 in Neurovisual Development

During the development of the retina and the nervous system, high levels of energy are required by the axons of retinal ganglion cells (RGCs) to grow towards their brain targets. This energy demand leads to an increase of glycolysis and L-lactate concentrations in the retina. L-lactate is known to be the endogenous ligand of the GPR81 receptor. However, the role of L-lactate and its receptor in the development of the nervous system has not been studied in depth. In the present study, we used immunohistochemistry to show that GPR81 is localized in different retinal layers during development, but is predominantly expressed in the RGC of the adult rodent. Treatment of retinal explants with L-lactate or the exogenous GPR81 agonist 3,5-DHBA altered RGC growth cone (GC) morphology (increasing in size and number of filopodia) and promoted RGC axon growth. These GPR81-mediated modifications of GC morphology and axon growth were mediated by protein kinases A and C, but were absent in explants from gpr81−/− transgenic mice. Living gpr81−/− mice showed a decrease in ipsilateral projections of RGCs to the dorsal lateral geniculate nucleus (dLGN). In conclusion, present results suggest that L-lactate and its receptor GPR81 play an important role in the development of the visual nervous system.

Presence of the Endocannabinoid System in the Inferior Pulvinar of the Vervet Monkey

The expression of the endocannabinoid (eCB) system, including cannabinoid receptor type 1 (CB1R) and the cannabinoid synthesizing (NAPE-PLD) and degrading (FAAH) enzymes, has been well-characterized in the retina of rodents and monkeys. More recently, the presence of CB1R was localized throughout the dorsal lateral geniculate nucleus of the thalamus of vervet monkeys. Given that the retina projects also to the pulvinar either via a direct projection or via the superior colliculus, it was reasonable to assume that this system would be present therein. The visual pulvinar, namely the inferior pulvinar (PI) region, was delineated with calbindin immunohistochemical staining. Using Western blots and immunofluorescence, we demonstrated that CB1R, NAPE-PLD and FAAH are expressed in the PI of the vervet monkey. Throughout the PI, CB1R was mainly colocalized with VGLUT2-positive axon terminals in the vicinity of calbindin and parvalbumin-positive neurons. NAPE-PLD and FAAH rather colocalized with calbindin over the somatodendritic compartment of PI neurons. Our results suggest that visual information coming from the retina and entering the PI is modulated by the eCB system on its way to the dorsal visual stream. These results provide insights for understanding the role of eCBs in the modulation of visual thalamic inputs and, hence, visual perception.

Gamma rhythms and visual information in mouse V1 specifically modulated by somatostatin+ neurons in reticular thalamus

Visual perception in natural environments depends on the ability to focus on salient stimuli while ignoring distractions. This kind of selective visual attention is associated with gamma activity in the visual cortex. While the nucleus reticularis thalami (nRT) has been implicated in selective attention, its role in modulating gamma activity in the visual cortex remains unknown. Here we show that somatostatin- (SST) but not parvalbumin-expressing (PV) neurons in the visual sector of the nRT preferentially project to the dorsal lateral geniculate nucleus (dLGN), and modulate visual information transmission and gamma activity in primary visual cortex (V1). These findings pinpoint the SST neurons in nRT as powerful modulators of the visual information encoding accuracy in V1, and represent a novel circuit through which the nRT can influence representation of visual information.