Nervous System-Systemic Crosstalk in SARS-CoV-2/COVID-19: A Unique Dyshomeostasis Syndrome.

SARS-CoV-2 infection is associated with a spectrum of acute neurological syndromes. A subset of these syndromes promotes higher in-hospital mortality than is predicted by traditional parameters defining critical care illness. This suggests that deregulation of components of the central and peripheral nervous systems compromises the interplay with systemic cellular, tissue and organ interfaces to mediate numerous atypical manifestations of COVID-19 through impairments in organismal homeostasis. This unique dyshomeostasis syndrome involves components of the ACE-2/1 lifecycles, renin-angiotensin system regulatory axes, integrated nervous system functional interactions and brain regions differentially sculpted by accelerated evolutionary processes and more primordial homeostatic functions. These biological contingencies suggest a mechanistic blueprint to define long-term neurological sequelae and systemic manifestations such as premature aging phenotypes, including organ fibrosis, tissue degeneration and cancer. Therapeutic initiatives must therefore encompass innovative combinatorial agents, including repurposing FDA-approved drugs targeting components of the autonomic nervous system and recently identified products of SARS-CoV-2-host interactions.

Redundancy and multifunctionality among spinal locomotor networks.

c-Fos is used to identify system-wide neural activation with cellular resolution in vivo. However, c-Fos can only capture neural activation of one event. Targeted recombination in active populations (TRAP) allows the capture of two different c-Fos activation patterns in the same animal. So far, TRAP has only been used to examine brain circuits. This study uses TRAP to investigate spinal circuit activation during resting and stepping, giving novel insights of network activation during these events. The level of colabeled (c-Fos+ and TRAP+) neurons observed after performing two bouts of stepping suggests that there is a probabilistic-like phenomenon that can recruit many combinations of neural populations (synapses) when repetitively generating many step cycles. Between two 30-min bouts of stepping, each consisting of thousands of steps, only ∼20% of the neurons activated from the first bout of stepping were also activated by the second bout. We also show colabeling of interneurons that have been active during stepping and resting. The use of the FosTRAP methodology in the spinal cord provides a new tool to compare the engagement of different populations of spinal interneurons in vivo under different motor tasks or under different conditions.NEW & NOTEWORTHY The results are consistent with there being an extensive amount of redundancy among spinal locomotor circuits. Using the newly developed FosTRAP mouse model, only ∼20% of neurons that were active (labeled by Fos-linked tdTomato expression) during a first bout of 30-min stepping were also labeled for c-Fos during a second bout of stepping. This finding suggests variability of neural networks that enables selection of many combinations of neurons (synapses) when generating each step cycle.