COVID-19 and Neurological Impairment: Hypothalamic Circuits and Beyond

Abstract

In December 2019, a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, the capital of Hubei, China. The virus infection, coronavirus disease 2019 (COVID-19), represents a global concern, as almost all countries around the world are affected. Clinical reports have confirmed several neurological manifestations in COVID-19 patients such as headaches, vomiting, and nausea, indicating the involvement of the central nervous system (CNS) and peripheral nervous system (PNS). Neuroinvasion of coronaviruses is not a new phenomenon, as it has been demonstrated by previous autopsies of severe acute respiratory syndrome coronavirus (SARS-CoV) patients who experienced similar neurologic symptoms. The hypothalamus is a complex structure that is composed of many nuclei and diverse neuronal cell groups. It is characterized by intricate intrahypothalamic circuits that orchestrate a finely tuned communication within the CNS and with the PNS. Hypothalamic circuits are critical for maintaining homeostatic challenges including immune responses to viral infections. The present article reviews the possible routes and mechanisms of neuroinvasion of SARS-CoV-2, with a specific focus on the role of the hypothalamic circuits in mediating the neurological symptoms noted during COVID-19 infection.

Keywords: COVID-19; SARS-CoV-2; hypothalamic circuits; hypothalamic–pituitary–adrenocortical axis; neurological manifestations; olfactory bulb; respiratory centers; viral infection.

Figure 1

Schematic representation of the functional structure of hypothalamic circuits. (A) Location of hypothalamus within the ventral part of the diencephalon. (B) Location of hypothalamus in relation to the median eminence, infundibular stem, and pituitary glands. (C) Patterns of functional interaction between the hypothalamic nuclei (reproduced with permission from [48]). Abbreviations: AN: arcuate nucleus; AgRP: Agouti-related protein; AVP: arginine vasopressin; BBB: Blood brain barrier; CART: cocaine and amphetamine-regulated transcript; CRH: corticotrophin releasing hormone; GLP-1: Glucagon-like peptide-1; VMN: ventromedial nucleus; OT: oxytocin; DMN: dorsomedial nucleus; PVN: periventricular nucleus; DHA: dorsal hypothalamic area; IR: insulin receptor; PFA: perifornical area; LHA: lateral hypothalamic area; MCH: Melanin-concentrating hormone; MSH: melanocyte-stimulating hormones; CN: suprachiasmatic nucleus; SON: supraoptic nucleus; POA: preoptic area; POMC: Pro-opiomelanocortin; PPY: Polypeptide; ObRb: Leptin receptor; MB: mammillary bodies; ME: median eminence; NPY: Neuropeptide; III-V: third ventricle; TRH, thyrotropin-releasing hormone.

Figure 2

Proposed neuroinvasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and interrelationship between the hypothalamus and olfactory system. (A) Sagittal view of olfactory bulb, primary olfactory cortex, and the hypothalamus. (B) Complex connection between hypothalamic circuits and primary olfactory cortex (reproduced with permission from [70]). Abbreviations: ACN, amygdaloïd cortical nucleus; AON, anterior olfactory nucleus; ARC, arcuate nucleus; DMH, dorsomedial nucleus of the hypothalamus; EBOP, extra bulbar olfactory pathway; EC, entorhinal cortex; LH, lateral hypothalamus; OB, olfactory bulb; OE, olfactory epithelium; OT, olfactory tubercle; Pir, Piriform cortex; POA, preoptic area; PVN, paraventricular nucleus of the hypothalamus; TT, taenia tecta; VMH, ventromedial nucleus of the hypothalamus.

Figure 3

Mechanisms of hypothalamic–pituitary–adrenocortical (HPA) axis during viral infection. Viral infection activates innate proinflammatory cytokines (TNF-α, IL-1, and IL-6) and interferons, and late acquired T cell cytokines (IL-2 and IFN-γ), which activate the HPA axis and release of GCs. This, in turn, stimulates a negative feedback loop to control the immune response. Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing factor, TNF-α, Tumor Necrosis Factor-alpha; IL-1, Interleukin-1; IL-6, Interleukin-6; IL-2, Interleukin-2; IFN- γ, Interferon-gamma; GCs, glucocorticoids.