Persistent olfactory learning deficits during and post-COVID-19 infection

Bhowmik, Rajdeep; Pardasani, Meenakshi; Mahajan, Sarang; Magar, Rahul; Joshi, Samir; Nair, Ganesh Ashish; Bhattacharjee, Anindya S.; Abraham, Nixon M.

doi:10.1016/j.crneur.2023.100081

Cited by 6 publications

(10 citation statements)

References 69 publications

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“…Having observed sensory as well as cognitive deficits in ACE2 KO mice, we further studied if these phenotypes were triggered by any anxiety-related or depressive behaviors that might be caused by the knockout of ACE2 receptors. This study was also prompted by the observations of long-term sensory and cognitive deficits ( Bhattacharjee et al, 2020 ; Bhowmik et al, 2023 ) and mood disorders ( Lamontagne et al, 2021 ) reported during and post-COVID conditions. We employed an array of commonly used behavioral paradigms to quantify these behaviors ( Belovicova et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

“…Neurological complications of long-COVID may challenge the global health for many more years ( Kay, 2022 ). Various olfactory problems including hyposmia, anosmia, and parosmia have been reported during infection and under long-COVID conditions ( Bhattacharjee et al, 2020 ; Pardasani and Abraham, 2022 ; Bhowmik et al, 2023 ). While infection at the olfactory periphery and the neuronal loss may explain the transient hyposmic and anosmic conditions, parosmia may result from the mis-targeting of regenerating OSNs during the recovery period ( Costanzo, 2000 ; John and Key, 2003 ; Cooper et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…The COVID-19 infection also causes learning and cognitive impairments that even persisted in the post-COVID conditions ( Hampshire et al, 2021 ; Hugon et al, 2022 ; Bhowmik et al, 2023 ). Our observations of ACE2 KO animals having deficits in detection, discrimination, and novel odor recognition were similar to clinical observations made in patients.…”

Section: Discussionmentioning

confidence: 99%

“…Brain imaging data further confirmed the structural abnormalities caused by the viral infection ( Douaud et al, 2022 ). Moreover, long-lasting brain dysfunctions have become a serious challenge in post-COVID-19 conditions ( Pardasani and Abraham, 2022 ; Bhowmik et al, 2023 ). Therefore, probing the mechanisms underlying these deficits using animal models is a pressing need of global health.…”

Section: Introductionmentioning

confidence: 99%

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Knockout of angiotensin converting enzyme-2 receptor leads to morphological aberrations in rodent olfactory centers and dysfunctions associated with sense of smell

Mahajan,

Sen,

Sunil

et al. 2023

Front. Neurosci.

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Neuronal morphological characterization and behavioral phenotyping in mouse models help dissecting neural mechanisms of brain disorders. Olfactory dysfunctions and other cognitive problems were widely reported in asymptomatic carriers and symptomatic patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This led us to generate the knockout mouse model for Angiotensin Converting Enzyme-2 (ACE2) receptor, one of the molecular factors mediating SARS-CoV-2 entry to the central nervous system, using CRISPR-Cas9 based genome editing tools. ACE2 receptors and Transmembrane Serine Protease-2 (TMPRSS2) are widely expressed in the supporting (sustentacular) cells of human and rodent olfactory epithelium, however, not in the olfactory sensory neurons (OSNs). Hence, acute inflammation induced changes due to viral infection in the olfactory epithelium may explain transient changes in olfactory detectabilities. As ACE2 receptors are expressed in different olfactory centers and higher brain areas, we studied the morphological changes in the olfactory epithelium (OE) and olfactory bulb (OB) of ACE2 KO mice in comparison with wild type animals. Our results showed reduced thickness of OSN layer in the OE, and a decrease in cross-sectional area of glomeruli in the OB. Aberrations in the olfactory circuits were revealed by lowered immunoreactivity toward microtubule associated protein 2 (MAP2) in the glomerular layer of ACE2 KO mice. Further, to understand if these morphological alterations lead to compromised sensory and cognitive abilities, we performed an array of behavioral assays probing their olfactory subsystems’ performances. ACE2 KO mice exhibited slower learning of odor discriminations at the threshold levels and novel odor identification impairments. Further, ACE2 KO mice failed to memorize the pheromonal locations while trained on a multimodal task implying the aberrations of neural circuits involved in higher cognitive functions. Our results thus provide the morphological basis for the sensory and cognitive disabilities caused by the deletion of ACE2 receptors and offer a potential experimental approach to study the neural circuit mechanisms of cognitive impairments observed in long COVID.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Knockout of angiotensin converting enzyme-2 receptor leads to morphological aberrations in rodent olfactory centers and dysfunctions associated with sense of smell

Mahajan,

Sen,

Sunil

et al. 2023

Front. Neurosci.

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“…Indeed, these states can be induced by ELA too. Therefore, quantifying olfactory fitness of the ELA-affected population using precise methods may help in identifying and characterising sensory and cognitive deficits at early stages and help in designing better treatment strategies [ 58 – 62 ].…”

Section: Discussionmentioning

confidence: 99%

Perceptual learning deficits mediated by somatostatin releasing inhibitory interneurons of olfactory bulb in an early life stress mouse model

Pardasani,

Ramakrishnan,

Mahajan

et al. 2023

Mol Psychiatry

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Early life adversity (ELA) causes aberrant functioning of neural circuits affecting the health of an individual. While ELA-induced behavioural disorders resulting from sensory and cognitive disabilities can be assessed clinically, the neural mechanisms need to be probed using animal models by employing multi-pronged experimental approaches. As ELA can alter sensory perception, we investigated the effect of early weaning on murine olfaction. By implementing go/no-go odour discrimination paradigm, we observed olfactory learning and memory impairments in early life stressed (ELS) male mice. As olfactory bulb (OB) circuitry plays a critical role in odour learning, we studied the plausible changes in the OB of ELS mice. Lowered c-Fos activity in the external plexiform layer and a reduction in the number of dendritic processes of somatostatin-releasing, GABAergic interneurons (SOM-INs) in the ELS mice led us to hypothesise the underlying circuit. We recorded reduced synaptic inhibitory feedback on mitral/tufted (M/T) cells, in the OB slices from ELS mice, explaining the learning deficiency caused by compromised refinement of OB output. The reduction in synaptic inhibition was nullified by the photo-activation of ChR2-expressing SOM-INs in ELS mice. The role of SOM-INs was revealed by learning-dependent refinement of Ca2+dynamics quantified by GCaMP6f signals, which was absent in ELS mice. Further, the causal role of SOM-INs involving circuitry was investigated by optogenetic modulation during the odour discrimination learning. Photo-activating these neurons rescued the ELA-induced learning deficits. Conversely, photo-inhibition caused learning deficiency in control animals, while it completely abolished the learning in ELS mice, confirming the adverse effects mediated by SOM-INs. Our results thus establish the role of specific inhibitory circuit in pre-cortical sensory area in orchestrating ELA-dependent changes.

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Long COVID: From olfactory dysfunctions to viral Parkinsonism

Pandey,

Bapat,

Abraham

et al. 2024

World j. otorhinolaryngol.-head neck surg.

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Neurological and psychiatric complications continue to be a public health concern in long coronavirus disease 2019 (COVID‐19). This varies from olfactory dysfunctions such as parosmia to cognitive and emotional challenges. Historically, the surge of neurological disorders followed the viral pandemics, for example, the emergence of Encephalitis Lethargica after the outbreak of Spanish Influenza. During and after COVID‐19 infection, the problems associated with the sense of smell and the reports of affected olfactory and limbic brain areas are leading to a growing concern about the similarity with the symptoms and the pattern of degeneration observed at the onset of Parkinson's disease and Alzheimer's disease. These reports reveal the essentiality of long‐term studies of olfactory and cognitive functions in the post‐COVID era and the experiments using animal models to dissect the neural basis of these complications. In this manuscript, we summarize the research reporting the potential correlation between neurological disorders and viral pandemic outbreaks with a historical perspective. Further, we discuss the studies providing evidence of neurodegeneration due to severe acute respiratory syndrome coronavirus 2 infection by focusing on viral Parkinsonism.

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Persistent olfactory learning deficits during and post-COVID-19 infection

Cited by 6 publications

References 69 publications

Knockout of angiotensin converting enzyme-2 receptor leads to morphological aberrations in rodent olfactory centers and dysfunctions associated with sense of smell

Knockout of angiotensin converting enzyme-2 receptor leads to morphological aberrations in rodent olfactory centers and dysfunctions associated with sense of smell

Perceptual learning deficits mediated by somatostatin releasing inhibitory interneurons of olfactory bulb in an early life stress mouse model

Long COVID: From olfactory dysfunctions to viral Parkinsonism

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