Morphological, cellular, and molecular basis of brain infection in COVID-19 patients.

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

Dorsal hippocampus cholinergic and nitrergic neurotransmission modulates the cardiac baroreflex function in rats.

Hippocampus is a limbic structure involved in the baroreflex and chemoreflex control that receives extensive cholinergic input from basal forebrain. Hippocampal muscarinic receptors activation by acetylcholine might evoke nitric oxide synthesis, which is an important neuromodulator of cardiovascular responses. Thus, we hypothesize that cholinergic and nitrergic neurotransmission within the DH modulates the baroreflex and chemoreflex function. We have used vasoactive drugs (phenylephrine and sodium nitroprusside), and potassium cyanide infused peripherally to induce, respectively, baroreflex or chemoreflex responses in awake animals. Bilateral injection into the DH of the acetylcholinesterase inhibitor (neostigmine) reduced baroreflex responses. Meanwhile, the non-selective muscarinic receptor antagonist (atropine) or the M1-selective muscarinic receptor antagonist increased baroreflex responses (pirenzepine). Furthermore, the neuronal nitric oxide synthase inhibitor (N-propyl) or the intracellular NO scavenger (carboxy-PTIO) increased baroreflex responses, as well as the selective inhibitor of NO-sensitive guanylyl cyclase (ODQ), increased the baroreflex responses. Besides, bilateral administration of an ineffective dose of a neuronal nitric oxide synthase inhibitor abolished the reduction in the baroreflex responses evoked by an acetylcholinesterase inhibitor. On the other hand, we have demonstrated that hippocampal cholinergic neurotransmission did not influence the chemoreflex function. Taken together, our findings suggest that nNOS-derived nitric oxide in the DH participates in acetylcholine-evoked baroreflex responses.

Effect of chronic stress on cardiovascular and ventilatory responses activated by both chemoreflex and baroreflex in rats.

Chronic stress results in physiological and somatic changes. It has been recognized as a risk factor for several types of cardiovascular dysfunction and changes in autonomic mechanisms, such as baroreflex and chemoreflex activity. However, the effects of different types of chronic stress on these mechanisms are still poorly understood. Therefore, in the present study, we investigated, in adult male rats, the effect of repeated restraint stress (RRS) or chronic variable stress (CVS) on baroreflex, chemoreflex and heart rate variability in a protocol of 14 days of stress sessions. Exposure to RRS and CVS indicated no changes in the basal level of either arterial pressure or heart rate. However, RRS and CVS were able to attenuate sympathovagal modulation and spontaneous baroreflex gain. Additionally, only RRS was able to increase the power of the low-frequency band of the systolic blood pressure spectrum, as well as the slope of linear regression of baroreflex bradycardic and tachycardic responses induced by vasoactive compounds. Additionally, our study is one of the first to show that exposure to RRS and CVS decreases the magnitude of the pressor response and potentiates respiratory responses to chemoreflex activation, which can trigger cardiovascular and respiratory pathologies. Furthermore, the basal respiratory parameters, such as minute ventilation and tidal volume, were significantly decreased by both protocols of chronic stress. However, only CVS increased the basal respiratory frequency. In this way, the findings of the present study demonstrate the impact of chronic stress in terms of not only depressive-like behavior but also alterations of the autonomic baroreflex responses and cardiocirculatory variability (systolic blood pressure and pulse interval).Our results provide evidence that chronic stress promotes autonomic dysregulation, and impairment of baroreflex, chemoreflex and heart rate variability.