Exploring the Neurological Impact of SARS-CoV-2: Insights into Dopaminergic Neurons and Long COVID

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Two years into the SARS-CoV-2 pandemic, significant strides have been made in scientific and medical research, particularly in the development and deployment of vaccines aimed at containing the severe and fatal outcomes of COVID-19.

While these efforts have been crucial in mitigating the immediate health crisis, a growing concern has emerged surrounding a subset of patients who, even after an initial recovery from COVID-19, continue to experience persistent and uncertain symptoms.

This condition, which manifests during or following SARS-CoV-2 infection and lasts for more than 12 weeks, is now widely recognized as Long COVID or Post-COVID condition. This article delves into the complexities of Long COVID, its symptoms, and its potential neurological underpinnings.

The Long COVID Enigma

Recent studies have shed light on the prevalence and diversity of Long COVID symptoms. It has been reported that more than 80% of recovered hospitalized COVID-19 patients continue to experience at least one persistent symptom two months after the onset of symptoms, often involving fatigue and dyspnea.

As time progresses, the scope of symptoms widens, with over 30% of patients still grappling with issues such as post-exertional malaise, brain fog, neurological sensations, headaches, memory problems, insomnia, muscle aches, dizziness, balance issues, speech difficulties, joint pain, sleep disturbances, anxiety, and depression.

This protracted and multi-faceted syndrome poses a significant challenge to both patients and healthcare providers.

Neurological Complications of SARS-CoV-2

From the early days of the pandemic, it became evident that SARS-CoV-2 was not limited to causing respiratory illness but could also infiltrate the nervous system, leading to a range of neurological complications. These complications include common symptoms like anosmia (loss of smell) and ageusia (loss of taste) experienced by 26% of infected individuals, as well as more severe issues such as headaches and, in rare cases, encephalitis.

A recent breakthrough in understanding the neurological impact of SARS-CoV-2 came from studies that demonstrated direct effects on the brain. These studies revealed significant reductions in grey matter thickness, increased markers of tissue damage in regions connected to the olfactory cortex, and an overall reduction in brain size following SARS-CoV-2 infection.

Moreover, individuals with pre-existing neurological disorders appear to be at a heightened risk of developing COVID-19-related neurological symptoms, highlighting the virus’s affinity for the nervous system.

The Intriguing Link to Dopaminergic Neurons

A significant piece of the puzzle in understanding Long COVID and the neurological effects of SARS-CoV-2 lies in the relationship between the virus and dopaminergic neurons (DA neurons). Dopamine is a critical neurotransmitter associated with mood regulation, reward processing, and motor control.

Emerging evidence suggests that SARS-CoV-2 may impact dopamine production and the functioning of these neurons, which could contribute to the neuropsychiatric symptoms observed in Long COVID patients.

Scientific inquiries into this matter have pointed to the ability of SARS-CoV-2 to infect various types of neurons to varying degrees. There have been suggestions that the virus may exploit dopamine receptors as entry points into these neurons, but concrete evidence remains elusive. Additionally, it has been hypothesized that SARS-CoV-2 might affect dopamine production, which could potentially explain some of the mood and cognitive symptoms seen in Long COVID.

A Glimpse into Research Findings

In an effort to unravel this complex interplay between SARS-CoV-2 and dopaminergic neurons, recent in-vitro research has focused on human-induced pluripotent stem cells (iPSC) differentiated into dopaminergic neurons. These experiments involved exposing these neurons to three different SARS-CoV-2 variants: EU, Delta, and Omicron.

The findings of this study were intriguing. Infected dopaminergic neurons exhibited a marked increase in neuronal stress markers, indicative of cellular distress. Moreover, alterations in the expression of both mRNA and proteins involved in dopamine metabolism were observed. Most significantly, SARS-CoV-2 infection resulted in a decrease in dopamine production, with the extent of this reduction varying depending on the specific viral variant involved.

Discussion

The Neurotropic Nature of Viruses

The discussion begins with an exploration of the broader virological context of neurotropic viruses. The infection of immune-privileged sites such as the brain has long been recognized as a critical aspect of virology. This is due, in part, to the post-mitotic nature of neurons, making them vulnerable to long-term consequences.

While many viruses have been documented to infect neurons, the focus here is on the family Coronaviridae, which has garnered less attention in this regard. Historical records from the 1918 H1N1 influenza pandemic provide intriguing insights, suggesting a link between viral infection and conditions like lethargic encephalitis and Parkinsonism.

Arboviruses, well-known for affecting neurons, are also noted for their impact on catecholamine biosynthesis, and Herpes simplex virus is known to target specific neuronal populations. These examples underscore the potential of viruses to affect the nervous system and impact various neurological functions.

SARS-CoV-2 and Its Neurological Implications

The discussion then shifts to the current pandemic and the emerging evidence of SARS-CoV-2’s impact on the central nervous system (CNS) and peripheral nervous system (PNS). A significant fraction of COVID-19 patients experiences a wide array of neurological symptoms, including post-exertional malaise, brain fog, headaches, and more. Additionally, the virus has been associated with a range of dopaminergic system-related signs.

However, the extent of SARS-CoV-2’s presence in the human brain remains somewhat uncertain. Clinical evidence supports the notion that the virus may impact neuronal homeostasis. Recent research, such as the work by Pedrosa et al., has suggested that SARS-CoV-2, particularly the EU variant, may have a limited capability to infect neurons directly.

Instead, it tends to infect astrocytes, which subsequently induce an inflammatory response that indirectly leads to neuronal damage. This tropism for astrocytes has been confirmed by other researchers, and mouse models have indicated increased susceptibility to oxidative stress in dopaminergic neurons following infection.

The Role of Dopaminergic Neurons in SARS-CoV-2 Infection

The focus then narrows down to the role of dopaminergic neurons (DA neurons) in the context of SARS-CoV-2 infection. These neurons play a pivotal role in dopamine production within the brain, influencing mood, reward, and motor control. Existing studies have hinted at the potential for SARS-CoV-2 to impact dopamine metabolism, offering a possible explanation for mood and cognitive symptoms seen in Long COVID patients.

To address this issue, the authors conducted in-vitro experiments using human DA neurons derived from induced pluripotent stem cells (iPSCs). These neurons exhibited a limited infection with the EU, Delta, and Omicron variants of SARS-CoV-2, even at high multiplicities of infection (MOI).

Importantly, infection with EU and Delta variants triggered an innate immune response in the neurons, as evidenced by increased mRNA expression of MxA and IFITM3, both crucial components of the interferon response against viruses. The specificity of this antiviral response was further highlighted by the lack of upregulation of IFITM1.

Furthermore, the study found that EU variant infection resulted in the upregulation of the neuronal stress marker S100B. These findings indicate that SARS-CoV-2 infection disrupts the homeostasis of DA neurons, which are central to dopamine production.

Implications for Long COVID and Parkinson’s Disease

The discussion then delves into the potential clinical implications of these findings. It is hypothesized that the observed reduction in dopamine production in DA neurons following SARS-CoV-2 infection may contribute to the neuropsychiatric symptoms seen in Long COVID patients. The severity of these symptoms may vary depending on the SARS-CoV-2 variant involved, potentially explaining the differences in symptomatology observed in patients infected with EU or Delta variants compared to Omicron.

The authors suggest that this insight may also shed light on the experiences of Parkinson’s disease patients who contract COVID-19. It is proposed that these patients may temporarily experience worsened symptoms during COVID-19 infection and its aftermath, only to return to their pre-infection condition once fully recovered.

Conclusion and Future Directions

In conclusion, this chapter has highlighted the complex relationship between SARS-CoV-2 and the nervous system, focusing on dopaminergic neurons and dopamine metabolism. The study’s findings suggest that SARS-CoV-2 infection disrupts dopamine production in DA neurons, potentially contributing to the neuropsychiatric symptoms seen in Long COVID. These insights offer a path forward for targeted therapies for both Long COVID patients and individuals with Parkinson’s disease who contract COVID-19.

Future research will be essential to confirm and expand upon these findings, deepening our understanding of the neurological impact of SARS-CoV-2 and its implications for patient care.

Conclusion

As the SARS-CoV-2 pandemic enters its third year, the focus is no longer solely on preventing severe illness and mortality but also on understanding and addressing the lingering effects of the virus, particularly in Long COVID patients. Emerging research underscores the intricate relationship between SARS-CoV-2 and the nervous system, with a particular emphasis on dopaminergic neurons and their role in mood and cognition.

While the precise mechanisms through which SARS-CoV-2 impacts dopaminergic neurons are still being elucidated, these findings provide a crucial step towards unraveling the mysteries of Long COVID. As scientists continue to piece together the puzzle, further understanding of the neurological aspects of SARS-CoV-2 infection may pave the way for more effective treatments and interventions for Long COVID patients, offering hope for those who continue to grapple with the enduring effects of this global pandemic.

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