David Hunter Hubel, the ‘Circe effect’, and SARS-CoV-2 infection of the human visual system

David Hunter Hubel (1926–2013) was an internationally recognized neurophysiologist and vision neuroscientist noted for his life-long studies on the columnar structure and highly integrated function of the brain’s primary and secondary visual cortex. He was co-recipient with the American neuropsychologist and neurobiologist Roger Wolcott Sperry (1913–1994) and the Swedish neurophysiologist Torsten Nils Wiesel (1924-present) of the 1981 Nobel Prize in Physiology or Medicine, for their significant discoveries concerning the functional specialization of the cerebral hemispheres, the layered structure of the human cerebral visual cortex and information processing in the visual system, how the human visual cortex is organized into columns, and how this remarkable cellular organization and connectivity for the human visual system can be modified by lifestyle, experience, aging and disease. This commentary integrates these significant findings with current observations on SARS-CoV-2, the causative agent of COVID-19, and its invasion of the human visual system via the angiotensin converting enzyme 2 (ACE2) receptor.


Introduction
Once during a lecture in the early 1980's, and just after receiving his Nobel prize in Physiology or Medicine Hubel described the columnar nature and the polarity of the visual circuitry of the human visual system and how signals travel from the exterior environment to the anterior surface of the eye, to the posterior of the eye, to the retina, through the optic nerves across the optic chiasm, optic tract and lateral geniculate nuclei (LGN), and on to the primary visual cortex in the occipital lobe at the posterior of the human cerebrum (Brodmann Area 17) [1,2].

Neurochemical gradients, visual signaling pathways and the 'Circe effect'
Hubel proposed that there might be some kind of a 'neurochemical gradient' driving visual signals along this neural pathway for vision, perhaps via a series of tandem receptors-initially at a low density to a higher density of the same receptor along a visual circuit culminating at the highest density of receptors in the occipital lobe in the deepest anatomical regions of the brain. Hubel went on to further describe the concept of the 'Circe effect, a phenomenon first proposed by the American biochemist William Platt Jencks (1927Jencks ( -2007, as has been since widely observed in chemical and biochemical signaling reactions (https://en.w ikipedia.org/wiki/Circe_effect; this process was named af-ter the enchantress Circe in Homer's Odyssey from Greek mythology who 'lured warriors to their fates') [3]. In modern biological chemistry the 'Circe effect' thereby involves a gradient of chemical, biochemical or biophysical components-such as receptors-from a lower to higher density that would initially attract and drive signals forward along a classical biochemical pathway involving an increasing gradient from a low to a higher molecular receptor density. Hubel provided an interesting analogy of a string of 10 lighted electrical lamp posts along a street with the faintest light at the top of the first lamp post and the brightest light along a gradient 10 lamp posts away. Hubel's electrical or molecular signals were represented by a box full of moths. As we all know moths are attracted to light and especially to bright lights-so when the moths were first released at the lamp post with the least bright light the moths initially clustered around the faintest light but as time passed all moths moved along the lighted pathway to the brightest light source 10 lamp posts away.
The analogy of the driving force for light signals travelling from the anterior to the posterior of the human visual pathway to moths moving up a gradient of dim light to bright lights was an insightful example of Hubel's creativity, innovation and genius. Fifty years after the Nobel laureate first proposed these innovative biological systems a very recent and exciting example is how the SARS-CoV-2 virus may move across the human visual system from the surface of the eye through to the optic nerve and ultimately to the primary visual cortex in deeper regions of the human brain.

Vision and visual processing disturbances associated with COVID-19 infection
Disturbances in vision and visual processing are commonly reported by COVID-19 patients. SARS-CoV-2 RNA has been found in tears of infected COVID-19 patients, and several reports suggest that the ocular surface could serve as a portal of entry and/or serve as a reservoir for viral transmission to the upper respiratory tract via the nasolacrimal duct [4]. Besides the respiratory and digestive tracts, the ocular exterior presents an additional mucosal surface that is constantly exposed to infectious droplets and direct/indirect contact, and there is abundant data that SARS-CoV-2 is most easily spread via an aerosolized transmission and captured by the moist surface of the eye [5][6][7].

Discussion
Keeping this in mind, Table 1 (Ref. [20,22,23]) shows the density of the angiotensin converting enzyme 2 (ACE2) receptor along a gradient from the anterior surface of the eye through to the primary visual cortex. ACE2 is known to be the primary and critical cell surface receptor for the SARS-CoV-2 virus essential for viral entry into host cells, necessary for successful infection, and is the causative agent for COVID-19. It appears that just like in Hubel's proposed model in line with the concept of the 'Circe effect' signaling, an increasing gradient of the ACE2 receptor might enable the single-stranded RNA (ssRNA) SARS-CoV-2 virus to travel from the exterior surface of the eye into deeper visual processing regions of the brain. There visual disturbances and dysfunction in vision and visual neuropathology may develop as a consequence of a successful SARS-CoV-2-mediated viral invasion of susceptible human host cells along these visual pathways. Visual signals and visual signal processing in humans typically proceeds from the outer eye and retina into deeper areas of the brain, and different cell types, tissues or anatomical structures are encountered along this major sensory pathway. The visual pathway extends from the corneal epithelial cells of the outermost layer of the cornea of the external eye through to the primary visual cortex located deep in the occipital lobe of the brain. Interestingly, SARS-CoV-2 infection is also associated with olfactory disturbances, however a similar gradient for the ACE2 receptor along single bipolar olfactory neurons from the cribiform plate of the nasal cavity into deeper brain regions of the olfactory lobe has yet to be demonstrated. The numbers in Table 1 are representative of the densities of the primary SARS-CoV-2 viral receptor, the angiotensin converting enzyme 2 (ACE2) cell surface acceptor protein, from the anterior (outer) surface of the eye to the primary visual processing center in the occipital lobe (Brodmann area 17) of the brain; ACE2 receptor abundance was determined employing an ELISA assay using a quantitative colorimetric (450 nm) sandwich ELISA specific for human ACE2 and a Fluoroskan Ascent FL Microplate Fluorometer and Luminometer (Cat no. 5200220, ThermoFisher Scientific, Waltham MA; sensitivity 1052 pg/mL; detection range 1.5 ng/mL-255 ng/mL; human ACE2 ELISA Kit ab235649; Abcam Cambridge MA, USA) as previously described in detail [20,22,23]. The numbers in Table 1 represent the statistical mean of 3-5 analyses for each visual pathway cell, tissue or anatomical structure.

Conclusions
From these observations we can speculate that other neuroanatomical, neurochemical and/or neurobiological pathways may utilize 'Circe effect' signaling in the transmission of biological entities or molecular-encoded information by means of specific receptor gradients in the brain and CNS both in health and during microbial infection and associated neurological disease.

Ethics approval and consent to participate
The acquisition, handling, experimental, and analytical procedures involving postmortem human brain and retinal tissues were carried out in an ethical manner in strict accordance with the ethics review board policies at brain and eye tissue donor institutions (listed above) and at the Louisiana State University (LSU) Health Sciences Center. The ethical use of postmortem human brain and eye tissues and their analyses were also carried out in strict accordance with the Institutional Biosafety Committee and the Institutional Review Board Committee (IBC/IRBC) ethical guidelines IBC#18059 and IRBC#6774 at the LSU Health Sciences Center, New Orleans LA 70112 USA. Project identification codes: NIA AG18031 and NIA AG038834 (WJL).

Acknowledgment
The experimental, analytical and statistical work in this communication was presented, in part, at the Society for Neuroscience (SFN) online Annual Meeting 19-23 October 2019 in Chicago IL, USA. Sincere thanks are extended to the late JM Hill (LSU Neuroscience Center; Louisiana State University, New Orleans LA 70112) for helpful discussions on this research area and to C. Eicken, C. Hebel, and K. Navel for postmortem human tissue extraction and/or preliminary analysis and to D. Guillot and A.I. Pogue for expert technical assistance. High quality human brain and eye tissues were obtained from: the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda MD USA; the Oregon Health Sciences University, Portland OR, USA; the University of California (UCI) MIND Institute, Irvine CA, USA; and the Louisiana State University (LSU) Neuroscience Center, New Orleans LA USA. Thanks are also extended to the many neuropathologists, physicians and researchers of the US, Canada, Europe and the Russian Federation who have provided high quality, short postmortem interval (PMI) human CNS or extracted brain and/or eye tissue fractions for scientific study. Lastly, we would like to thank the two anonymous reviewers and the Journal of Frontiers in Bioscience-Landmark Editor for their comments and constructive criticism of this communication prior to publication.

Funding
Research on metal neurotoxicity, human and murine microRNAs, small noncoding RNA (sncRNA), SARS-CoV-2 and other neurotropic viruses and proinflammatory and pathogenic signaling in the Lukiw laboratory involving the innate-immune response, amyloidogenesis and inflammatory neurodegeneration in Alzheimer's disease (AD), prion disease (PrD) and in other human neurological disorders was supported through an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB); The Brown Foundation, Joe and Dorothy Dorsett Innovation in Science Healthy Aging Award; the Louisiana Biotechnology Research Network (LBRN), the Alzheimer Association and NIH grants NEI EY006311, NIA AG18031 and NIA AG038834 (WJL).