Cytokine Storm in COVID19: A Neural Hypothesis.

Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.

Happy Hypoxemia in COVID-19-A Neural Hypothesis.

Many COVID-19 patients are presenting with atypical clinical features. Happy hypoxemia with almost normal breathing, anosmia in the absence of rhinitis or nasal obstruction, and ageusia are some of the reported atypical clinical findings. Based on the clinical manifestations of the disease, we are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius may be the reason for happy hypoxemia in COVID-19 patients.

The supraspinal innervation of the left adrenal is more intense than that of the right one.

BACKGROUND AND PURPOSE: Previous studies using the viral transneuronal tracing technique demonstrated that central autonomic circuits are involved in the innervation of the adrenal gland. Since increasing number of data indicate laterality in the neuroendocrine system, we aimed to investigate whether the supraspinal innervation of the adrenal gland exhibits asymmetry or not. METHODS: The central circuitry involved in the innervation of the left and the right adrenal gland was studied in individual rats by dual transneuronal tracing using isogenic recombinant strains (BDG and BDL) of Bartha strain of pseudorabies virus. RESULTS: Viral infection of brain nuclei (dorsal vagal nucleus, nucleus of the solitary tract, caudal raphe nuclei, A5 cell group, hypothalamic paraventricular nucleus) from the left adrenal was more severe than that from the right organ. Dual-infected neurons from the two adrenals were also detected both in the brain stem and in the hypothalamus. CONCLUSION: The results indicate a predominance in the supraspinal innervation of the left adrenal gland. Data further suggest that each adrenal gland is innervated both by side-specific neurons and by neurons which project to both organs.

Localized gene transfer and its application for the study of central cardiovascular control.

The arterial baroreceptor reflex is the major feedback control system that acts to stabilize blood pressure. Abnormalities of this reflex are considered to be an underlying mechanism in the cardiovascular diseases such as hypertension and heart failure. There is accumulating evidence, however, that central nervous system mechanisms are involved in the enhanced sympathetic drive that occurs in these disease states. This article reviews studies performed in our laboratory in which a gene transfer technique, in combination with other methods, was used to determine the functional role of the central control of cardiovascular regulation. We developed a technique to transfer adenovirus vectors encoding specific genes into the nucleus tractus solitarii (NTS) or the rostral ventral medulla (RVLM) of rats in vivo. We applied this technique to hypertensive rats as well as in mice with heart failure to explore the pathophysiological significance of nitric oxide, reactive oxygen species, and Rho-kinase.

Modulation of synaptic transmission in the rat nucleus of the solitary tract by endomorphin-1.

Activation of opioid receptors in the periphery and centrally in the brain results in inhibition of gastric and other vagally mediated functions. The aim of this study was to examine the role of the endogenous opioid agonist endomorphin 1 (EM-1) in regulating synaptic transmission within the nucleus tractus solitarius (NTS), an integration site for autonomic functions. We performed whole cell patch-clamp recordings from coronal brain slices of the rat medulla. A subset of the neurons studied was prelabeled with a stomach injection of the transsynaptic retrograde virus expressing EGFP, PRV-152. Solitary tract stimulation resulted in constant latency excitatory postsynaptic currents (EPSCs) that were decreased in amplitude by EM-1 (0.01-10 microM). The paired-pulse ratio was increased with little change in input resistance, suggesting a presynaptic mechanism. Spontaneous EPSCs were decreased in both frequency and amplitude by EM-1, and miniature EPSCs were reduced in frequency but not amplitude, suggesting a presynaptic mechanism for the effect. Spontaneous inhibitory postsynaptic currents (IPSCs) were also reduced in frequency by EM-1, but the effect was blocked by TTX, suggesting activity at receptors on the somata of local inhibitory neurons. Synaptic input arising from local NTS neurons, which were activated by focal photolysis of caged glutamate, was inhibited by EM-1. The actions of EM-1 were similar to those of D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) and were blocked by naltrexone, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), or D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP). These results suggest that EM-1 acts at mu-opioid receptors to modulate viscerosensory input and specific components of local synaptic circuitry in the NTS.

Trigemino-autonomic connections in the muskrat: the neural substrate for the diving response.

Stimulation of the anterior ethmoidal nerve of the muskrat produces a cardiorespiratory depression similar to the diving response. This includes an apnea, a parasympathetic bradycardia, and a selective increase in sympathetic vascular tone. However, the brainstem circuitry that links the afferent stimulus to the efferent autonomic responses is unknown. We used the anterograde transneuronal transport of the herpes simplex virus (HSV-1), strain 129, after its injection into the anterior ethmoidal nerve to determine the primary, secondary, and tertiary brainstem relays responsible for this cardiorespiratory response. In an effort to check the validity of this relatively untested tracer, we also injected the medullary dorsal horn with biotinylated dextran amine to determine the secondary trigemino-autonomic projections. Approximately 1 microl (6x10(6) PFU) of the HSV-1 virus was injected directly into the anterior ethmoidal nerve of muskrats. After 2-6 days, their trigeminal ganglions, spinal cords and brainstems were cut and immunohistologically processed for HSV-1. Initially (2 days), HSV-1 was observed only in the trigeminal ganglion. After approximately 3 days, HSV-1 was observed first in many brainstem areas optimally labeled between 4 and 4.5 days. In these cases, the ventrolateral superficial medullary dorsal horn, the ventral paratrigeminal nucleus and the interface between the interpolar and caudal subnuclei were labeled ipsilaterally. The nucleus tractus solitarius (NTS), especially its ventrolateral, dorsolateral, and commissural subnuclei were labeled as well as the caudal, intermediate and rostral ventrolateral medulla. Within the pons, the superior salivatory nucleus, the A5 area, the ventrolateral part of the parabrachial nucleus and the Kölliker-Fuse nucleus were labeled. Only after a survival of 4 days or more, the locus coeruleus, the nucleus raphe magnus, the nucleus paragigantocellularis, pars alpha, and the pontine raphe nucleus were labeled. Injections of biotinylated dextran amine were made into the medullary dorsal horn (MDH) in a location similar to that labeled after the viral injections. Fine fibers and terminals were labeled in the same brainstem areas labeled after injections of HSV-1 into the anterior ethmoidal nerve. This study outlines the potential brainstem circuit for the diving response, the most powerful autonomic reflex known. It also confirms the efficacy for using HSV-1, strain 129, as an anterograde transneuronal transport method.

Dendritic morphology of cardiac related medullary neurons defined by circuit-specific infection by a recombinant pseudorabies virus expressing beta-galactosidase.

The transneuronal herpesvirus tracer, pseudorabies virus (PRV) was used to determine the dendritic architecture of cardiac-related neurons. We constructed a derivative of the Bartha strain of PRV called PRV-BaBlu, that carries the lacZ gene of E. coli. Expression of beta-galactosidase by this recombinant virus enabled us to define the dendritic morphology of motoneurons and interneurons that innervate the heart. beta-galactosidase antigen filled dendritic processes that were clearly revealed by antibodies to beta-galactosidase. In contrast, the standard enzymatic reaction for detection of beta-galactosidase activity stained the cell soma well, but was inferior for labeling dendrites. Following PRV-BaBlu cardiac injection, infected neurons were clearly defined and labeled dendrites could be traced for long distances, sometimes greater than 800 microns from the cell body. Labeled dendrites of cardiomotor neurons primarily located in the nucleus ambiguus (NA) were extensive and sometimes intertwined with dendrites from other labeled motoneurons. Dendrites of labeled neurons in the dorsal motor nucleus of the vagus (DMV) typically extended in the mediolateral direction in the transverse plane. Transynaptically labeled interneurons interposed between the cardiorespiratory region of the nucleus tractus solitarius (NTS) and the NA were primarily located in the NA region and the reticular arc, the area between the DMV and NA. These interneurons had long dendrites extending along the reticular arc in the transverse plane. The dendritic arborizations of infected cardiac-related neurons in the NTS were variable in extent. We conclude that antibody detection of beta-galactosidase expressed by PRV-BaBlu after infection of neural cardiac circuits provides a superior method to define the dendrites and dendritic fields of cardiac-related motoneurons and interneurons.