Many of the known coronaviruses are neurotropic, meaning they are able to infect neuron cells.  If these observed trends carry over to SARS-CoV-2, they could help to elucidate how the CNS is affected by COVID-19.  Some of the key observations include:

- human coronavirus OC43 was shown to transmit itself to different neurons via axons in mice
- neuronal ACE2 expression in mice was found to be in different pre-autonomic regions of the brain which could explain why infected COVID-19 patients with dangerously low blood oxygen levels don't gasp for air
- SARS-CoV was found to infect regions of the brain that deal with cardiopulmonary regulation in human ACE2 knock-in mice
- SARS-CoV patient autopsies showed that the virus affected neurons more than any other kind of cell

Trends in Other Coronaviruses Affecting the CNS
 Relevant to COVID-19

- Neuronal ACE2 Expression as a Risk Factor for COVID-19
- Neuronal ACE2 Internalization in COVID-19
- ACE2 Expression in BBB
- ACE2 Expression in neuroglial cells
- ACE2 Expression in the ENS and Choroid Plexas

ACE2 and its Implications in SARS-CoV2 infection of the CNS

- Autoimmune Response Contribution to Neurological Symptoms.
- Neuro-Immune Cellular Interactions from SARS-CoV-2 Infection.

Indirect/Downstream effects of SARS-CoV-2 on the CNS.

Even in the absence of typical respiratory symptoms such as fever, cough, and shortness of breath, various patients diagnosed with COVID-19 have presented neurological symptoms, such as:

- acute cerebrovascular diseases

- impaired consciousness

-  skeletal muscle injury

- encephalopathy (symptoms: ischemic stroke)

- loss of smell (anosmia) and taste (ageusia)

- stroke

- cranial nerve deficits

- delirium

- meningitis

- paralysis

- seizures

- neuroinflammatory syndromes

- high pressure CSF

- muscle stiffness

The list below includes less-common neurological symptoms of COVID-19:
- Guillain–Barré syndrome (GBS)
- Multisystem Inflammatory Syndrome in Children (MIS-C)

Neurological symptoms Presented in COVID-19 Patients

- Brain degeneration

- Cognitive decline

- Mental disorders


Expected Long-Term Outcomes of Acute SARS-Cov2 Infection on CNS

- Hypothesized Mechanisms for SARS-CoV-2 Direct Invasion of the CNS
- Controversy: Is SARS-CoV-2 "Neuroinvasive"?

Direct Effects of SARS-CoV-2 on the CNS.

COVID-19 patients have shown symptoms of direct and indirect neurological effects, from changes in taste and smell, to immunologic factors in cerebral spinal fluid (CSF).  It is unknown whether these phenomena are the result of neurological damage, of SARS-CoV-2 infection, and/or of indirect effects of the immune response. Furthermore, studies in mice have shown that neurons are susceptible to infection, suggesting that cells of the CNS may contribute to the deteriorating breathing and respiratory function of COVID-19 patients. The image below is an early hypothesized mechanism of viral entry through nasal and oral mucosa cells, though there is not yet any evidence to support this hypothesis.

Michigan State University

Smith College

Current studies show that many organs that are heavily affected by COVID-19 have a high expression level of ACE2.

- Cardiovascular system
- Central nervous system (CNS)
- Gastrointestinal tract (GI)
- Kidney
- Liver 
- Lungs (Respiratory System)
- Peripheral nervous system (PNS)
- Testis

Organs and Organ Systems Affected by COVID-19

The scientific field of study of nervous system function and development. The human nervous system is comprised of the central (brain and spinal cord) and peripheral  (nerves and ganglia branching from brain and spinal cord) nervous systems. These are referred to as the CNS and PNS, respectively.

Neuroscience (Neurobiology)

Tan, H. W., Xu, Y. M., & Lau, A. T. Angiotensin‐converting enzyme 2: The old door for new severe acute respiratory syndrome coronavirus 2 infection. Reviews in Medical Virology, e2122. https://onlinelibrary.wiley.com/doi/full/10.1002/rmv.2122

Angiotensin‐converting enzyme 2: The old door for new severe acute respiratory syndrome coronavirus 2 infection

Xu, J., & Lazartigues, E. (2020). Expression of ACE2 in Human Neurons Supports the Neuro-Invasive Potential of COVID-19 Virus. Cellular and Molecular Neurobiology, 1-5.
https://link.springer.com/article/10.1007/s10571-020-00915-1

Expression of ACE2 in Human Neurons Supports the Neuro-Invasive Potential of COVID-19 Virus

It has been observed that many COVID-19 patients develop renal conditions, including acute kidney injury.  Older patients or those who have kidney conditions are more likely to die from COVID-19 while hospitalized.  Kidneys are known to have a greater level of ACE 2 expression than the lungs.  Kidney disease caused by COVID-19 is directly related to ACE2 expression: a study confirmed by electron microscopy that viral particles have been found in the glomerulus of COVID-19 patients. 

Effects of COVID-19 on the Kidney

Liver injury has been observed in a percentage of COVID-19 patients.  Cholangiocytes, the epithelial lining cells of the bile ducts of the liver, are known to have a high level of ACE 2 expression.  Overall, the liver has a greater expression level of ACE 2 than the lungs.  However, no studies have shown that SARS-CoV-2 can infect hepatic cells.  

Effects of COVID-19 on the Liver

Because as many as 10% of COVID-19 patients have the symptom of diarrhea, it is hypothesized that SARS-CoV-2 can infect gastrointestinal cells.  Symptoms such as loss of appetite and nausea have been commonly found with patients as well. It is known that the GI tract overall has a high expression level of ACE 2, with the duodenum and small intestine having an especially high level of expression. Viral RNA has been found in both the sputum and feces of COVID-19 patients.  

Effects of COVID-19 on the Gastrointestinal (GI) Tract

A main feature of symptomatic COVID-19 disease is respiratory infection. Severe damage to the lungs during respiratory distress may cause pulmonary fibrosis, necessitating lung transplants. Lasting damages to the lungs may occur even in recovering patients with mild infections. SARS-CoV-2 targets the following cell types:

- Type I pneumocytes (AT1) 
- Type II pneumocytes (AT2) 
- alveolar macrophages

ACE2 expression is primarily seen in AT2 cells which have been shown to be involved in the reproduction and transmission of the virus.  Viral targeting of alveolar macrophages is evidenced by N antigen expression.

Effects of COVID-19 on the Lungs

Patients with COVID-19 are likely to experience symptoms that can be attributed to  the virus affecting the cardiovascular system. Common complications to the system include arrhythmia, cardiac injury, fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation. Severe cases of COVID-19 may lead to lasting cardiac damage and those with pre-existing cardiac issues are likely to have worse prognoses. 

Effects of COVID-19 on the Cardiovascular System 

Impaired male fertility is a known symptom of COVID-19.  It is thought that the testes' high expression level of ACE2 and immunoactivity could contribute to this manifestation of the disease.  

Effects of COVID-19 on the Testis   

Effects of COVID-19 on the Central Nervous System

Some COVID-19 patients have presented with peripheral neurological symptoms. Although it is not a common complication of COVID-19, it is worth investigating all possible causes of the neurological symptoms that arise.

Effects of COVID-19 on the Peripheral Nervous System

- SARS-CoV-2 can be blocked by physical barriers in the placenta, such as densely branched microvilli and cytoskeletal network
- placenta can attack the virus with the following 3 molecular pathways: type III IFN signaling, secreted miRNAs triggering autophagy, and NF-κB pathway
- immunomodulation can be employed after viral infection to alleviate cytokin storm

Effects of COVID-19 on the Placenta

- There have been two reports of COVID-19 positive patients with conjunctivitis or conjunctival congestion
- Ocular secretions were seen in those with the SARS-CoV-2 positive serology
- This presents the possibility that the SARS-CoV-2 virus can cause conjunctivitis
- However, this relationship is not very clear at this point due to a lack of studies comparing the two
- It has also been suggested that the ocular system is a potential route of transmission of the virus

Effects of COVID-19 on the Ocular System

The study of the physiological basis for cognition.

Cognitive Neuroscience

- Brain
- Neurons
- Peripheral nervous system (PNS)
- Neurological diseases
- Central nervous system (CNS)

Focuses of neuroscience (neurobiology) 

An intersection between psychology, neuroscience and economics that studies how brain activation corresponds with decisions of gains and losses.

Neuroeconomics

As the relapse prevention model discusses, many individuals recovering from addiction return to their behavior at some point during/after treatment. Researchers have begun to look at this idea of relapse and relapse prevention from a neuroscience perspective. This perspective could help further the understanding of why, on a brain level, individuals relapse and how we could possibly help. There is not a large consensus yet, but the research is looking at many factors including pathways, styles, and stages of recovery, as well as the possibility of reversing or diminishing the brain dysregulation that results from addiction.

Neuroscience approach to relapse and relapse prevention

The study of behavior, emotion, and cognition and how they relate to brain function

Neuropsychology

This looks at how behavior and the environment are affecting the neural development of humans through their lifetime.

Behavioral Neuroscience

Discipline that is concerned with hormonal development, its interaction with the nervous system, its secretion and associated physiological and behavioral effects.

Neuroendocrinology

A distinct line of inquiry with the goal of understanding which systems of the brain are activated during mindfulness practice to determine the effects that both short and long-term practice has on brain function and structure.

Neurobiology of Mindfulness

The study of Emotion Regulation within the lens of Neurobiology. More specifically, understanding what brain functions correspond to Emotion Regulation. 

The Neurobiology of Emotion Regulation

Biopsychology, also known as biological psychology, is a subfield of psychology that examines the influence of biological processes on behavior. It typically focuses on the immediate causes of behavior rooted in the physiology of an organism, with a primary emphasis on the nervous system's structure and function. This field is highly interdisciplinary, drawing on expertise from researchers with backgrounds in biology, medicine, physiology, and chemistry, and is considered a key component within the broader field of neuroscience.

Biopsychology (Biological Psychology)

A human's nervous system is in charge of managing our cognitions, movements, and responses. It is comprised of billions of neurons, glial cells, and the central and peripheral nervous systems. 

Nervous System

A person accidentally touches a hot surface and immediately withdraws their hand. Which of the following best analyzes the roles of the two major divisions of the nervous system in this reflex action?

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