hippocampus – American ME and CFS Society

Replicating human characteristics: A promising animal model of central fatigue

Highlights:

A new method: Modified Multiple Platform Method combined with alternate-day fasting.
Modeling method has successfully constructed animal model of central fatigue.
Our rat model mimics human emotional, cognitive, and physical fatigue.
Hippocampus and muscle tissues show damage and mitochondrial changes.
Mitochondrial dysfunction and oxidative stress in hippocampus and muscle tissues.

Abstract:

Central fatigue is a common pathological state characterized by psychological loss of drive, lack of appetite, drowsiness, and decreased psychic alertness. The mechanism underlying central fatigue is still unclear, and there is no widely accepted successful animal model that fully represents human characteristics. We aimed to construct a more clinically relevant and comprehensive animal model of central fatigue.

In this study, we utilized the Modified Multiple Platform Method (MMPM) combined with alternate-day fasting (ADF) to create the animal model. The model group rats are placed on a stationary water environment platform for sleep deprivation at a fixed time each day, and they were subjected to ADF treatment. On non-fasting days, the rats were allowed unrestricted access to food. This process was sustained over a period of 21 days.

We evaluated the model using behavioral assessments such as open field test, elevated plus maze test, tail suspension test, Morris water maze test, grip strength test, and forced swimming test, as well as serum biochemical laboratory indices. Additionally, we conducted pathological observations of the hippocampus and quadriceps muscle tissues, transmission electron microscope observation of mitochondrial ultrastructure, and assessment of mitochondrial energy metabolism and oxidative stress-related markers.

The results revealed that the model rats displayed emotional anomalies resembling symptoms of depression and anxiety, decreased exploratory behavior, decline in learning and memory function, and signs of skeletal muscle fatigue, successfully replicating human features of negative emotions, cognitive decline, and physical fatigue. Pathological damage and mitochondrial ultrastructural alterations were observed in the hippocampus and quadriceps muscle tissues, accompanied by abnormal mitochondrial energy metabolism and oxidative stress in the form of decreased ATP and increased ROS levels.

In conclusion, our ADF+MMPM model comprehensively replicated the features of human central fatigue and is a promising platform for preclinical research. Furthermore, the pivotal role of mitochondrial energy metabolism and oxidative stress damage in the occurrence of central fatigue in the hippocampus and skeletal muscle tissues was corroborated.

Source: Zhang Y, Zhang Z, Yu Q, Lan B, Shi Q, Li R, Jiao Z, Zhang W, Li F. Replicating human characteristics: A promising animal model of central fatigue. Brain Res Bull. 2024 Jun 15;212:110951. doi: 10.1016/j.brainresbull.2024.110951. Epub 2024 Apr 19. PMID: 38642899. https://www.sciencedirect.com/science/article/pii/S0361923024000844 (Full text)

Role of Microglia, Decreased Neurogenesis and Oligodendrocyte Depletion in Long COVID-Mediated Brain Impairments

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a recent worldwide coronavirus disease-2019 (COVID-19) pandemic. SARS-CoV-2 primarily causes an acute respiratory infection but can progress into significant neurological complications in some. Moreover, patients with severe acute COVID-19 could develop debilitating long-term sequela.

Long-COVID is characterized by chronic symptoms that persist months after the initial infection. Common complaints are fatigue, myalgias, depression, anxiety, and “brain fog,” or cognitive and memory impairments. A recent study demonstrated that a mild COVID-19 respiratory infection could generate elevated proinflammatory cytokines and chemokines in the cerebral spinal fluid.

This commentary discusses findings from this study, demonstrating that even a mild respiratory SARS-CoV-2 infection can cause considerable neuroinflammation with microglial and macrophage reactivity. Such changes could also be gleaned by measuring chemokines and cytokines in the circulating blood. Moreover, neuroinflammation caused by mild SARS-CoV-2 infection can also impair hippocampal neurogenesis, deplete oligodendrocytes, and decrease myelinated axons.

All these changes likely contribute to cognitive deficits in long-COVID syndrome. Therefore, strategies capable of restraining neuroinflammation, maintaining better hippocampal neurogenesis, and preserving oligodendrocyte lineage differentiation and maturation may prevent or reduce the incidence of long-COVID after SARS-CoV-2 respiratory infection.

Source: Wei ZD, Liang K, Shetty AK. Role of Microglia, Decreased Neurogenesis and Oligodendrocyte Depletion in Long COVID-Mediated Brain Impairments. Aging Dis. 2023 Sep 24. doi: 10.14336/AD.2023.10918. Epub ahead of print. PMID: 37815903. https://www.aginganddisease.org/EN/10.14336/AD.2023.10918 (Full text)

Cognitive impairment after Long COVID-19: Current Evidence and Perspectives

Abstract:

COVID-19 is a respiratory infectious disease caused by the SARS-CoV-2 virus. Most patients recover after treatment, but COVID-19 treatment may lead to cognitive impairment. Recent studies have found that some recoverers experience cognitive impairments such as decreased memory and attention, and sleep disorder, indicating that COVID-19 may have longerterm effects on cognitive function.

Studies have found that COVID-19 may cause cognitive decline by damaging key brain regions such as the hippocampus and anterior cingulate cortex. Studies have also found that COVID-19 patients have active neuroinflammation, mitochondrial dysfunction, and microglial activation, suggesting that neuroinflammation, mitochondrial stress, and neurodegenerative changes may be potential mechanisms leading to cognitive impairment.

In summary, the possibility of cognitive impairment after COVID-19 treatment deserves close attention. Large-scale follow-up studies will help further explore the impact of COVID-19 on cognitive function and provide evidence to support clinical treatment and rehabilitation practices. Neuropathological and biological studies can explore precise mechanisms in-depth and provide a theoretical basis for prevention, treatment, and intervention research.

Given the risks of long-term COVID-19 and reinfection, it is necessary to integrate basic and clinical research data to maximize the maintenance of patient’s cognitive function and life quality. This also provides important experience in responding to similar public health events. This article integrates clinical and basic evidence of cognitive impairment after COVID-19 and discusses potential mechanisms and future research directions.

Source: Zhi-Tao Li, ZHANG ZHEN, Zhuoya Zhang, Zhi-Yong Wang, Hao Li. Cognitive impairment after Long COVID-19: Current Evidence and Perspectives. Front. Neurol. Sec. Neuroinfectious Diseases. Volume 14 – 2023 | doi: 10.3389/fneur.2023.1239182 https://www.frontiersin.org/articles/10.3389/fneur.2023.1239182/abstract

Effect of transcutaneous electrical acupoint stimulation on learning and memory ability of chronic fatigue syndrome rats and its mechanisms

Abstract:

in English, Chinese

Objective: To observe the effect of transcutaneous electrical acupoint stimulation (TEAS) on the histomorphological manifestations of hippocampal CA1 region and the expression of extracellular regulatory protein kinase (ERK), cyclic adenosine response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in chronic fatigue syndrome (CFS) rats, so as to explore the mechanisms of TEAS in improving the learning and memory abilities of CFS rats.

Methods: Forty male Wistar rats were randomly divided into normal group (10 rats) and modeling group (30 rats); then after modeling, they were selected and randomly divided into model group (10 rats) and TEAS group (10 rats). CFS rats model was prepared by sleep deprivation combined with weight-bearing swimming. Rats in the TEAS group were stimulated with Han’s acupoint nerve stimulator at bilateral “Zusanli” (ST36) and “Shenshu” (BL23) (2 Hz/15 Hz, 1-2 mA), 20 min each time, once a day for 4 weeks with 1 d rest every 6 d. The score of general conditions of rats was evaluated. The learning and memory ability was tested with Morris water maze. The morphology and ultrastructure of hippocampal CA1 region were observed by HE staining and transmission electron microscopy. The expression levels of ERK, CREB and BDNF mRNAs and proteins in hippocampus were detected by real time quantitative PCR and Western blot, respectively.

Results: Compared with the normal group, the score of general condition was increased (P<0.01); the escape latency was prolonged (P<0.05, P<0.01) and the times of crossing the original platform was decreased (P<0.05); the expression levels of ERK, CREB and BDNF mRNAs and proteins in hippocampus were decreased (P<0.05, P<0.01) in the model group. Compared with the model group, the scores of general condition on the 42^nd and 49^th day were decreased (P<0.05, P<0.01); the escape latency was shortened (P<0.01, P<0.05)and the times of crossing the original platform were increased (P<0.05); the expression levels of ERK, CREB and BDNF mRNAs and proteins in hippocampus were increased (P<0.01, P<0.05) in the TEAS group. The morphology of neurons in hippocampal CA1 region was normal in the normal group. In the model group, the number of neurons in hippocampal CA1 region decreased, the arrangement of nerve cells was scattered, the number of apoptotic cells increased, some nuclear structures disappeared, nuclear heterochromatin increased, the cell membrane wrinkled, the chromatin appeared empty bright area, and the crista was incomplete. Compared with the model group, the nerve cells morphology in hippocampal CA1 region was more regular, the number of apoptotic cells decreased, the chromatin and the cytoplasm were uniformly distributed, and the crista was relatively intact in the TEAS group.

Conclusion: TEAS can improve the learning and memory ability of CFS rats, the mechanisms may be related to improving the neural structure of hippocampal CA1 region and up-regulating the expression levels of ERK/CREB/BDNF.

Source: Zhong XL, Tong BY, Yang YH, Zeng HL, Lin C, Jing Y, He LL, You SJ. [Effect of transcutaneous electrical acupoint stimulation on learning and memory ability of chronic fatigue syndrome rats and its mechanisms]. Zhen Ci Yan Jiu. 2023 Apr 25;48(4):317-24. Chinese. doi: 10.13702/j.1000-0607.20221032. PMID: 37186194. https://pubmed.ncbi.nlm.nih.gov/37186194/

Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process-Multi-Cohort Multi-Modal Evidence

Abstract:

Differential axonal myelination synchronises signalling over different axon lengths. The consequences of myelination processes described at the cellular level for the regulation of myelination at the macroscopic level are unknown. We analysed multiple cohorts of myelin-sensitive brain MRI. Our aim was to (i) confirm a previous report of anti-correlation between myelination in subcortical and sensorimotor areas in healthy subjects, (ii) and thereby test our hypothesis for a regulatory interaction between them.

We analysed nine image-sets across three different human cohorts using six MRI modalities. Each image-set contained healthy controls (HC) and ME/CFS subjects. Subcortical and Sensorimotor regions of interest (ROI) were optimised for the detection of anti-correlations and the same ROIs were used to test the HC in all image-sets. For each cohort, median MRI values were computed in both regions for each subject and their correlation across the cohort was computed.

We confirmed negative correlations in healthy controls between subcortical and sensorimotor regions in six image-sets: three T1wSE (p = 5 × 10^-8, 5 × 10^-7, 0.002), T2wSE (p =2 × 10^-6), MTC (p = 0.01), and WM volume (p = 0.02). T1/T2 was the exception with a positive correlation (p = 0.01). This myelin regulation study is novel in several aspects: human subjects, cross-sectional design, ROI optimization, spin-echo MRI and reproducible across multiple independent image-sets.

In multiple independent image-sets we confirmed an anti-correlation between subcortical and sensorimotor myelination which supports a previously unreported regulatory interaction. The subcortical region contained the brain’s primary regulatory nuclei. We suggest a mechanism has evolved whereby relatively low subcortical myelination in an individual is compensated by upregulated sensorimotor myelination to maintain adequate sensorimotor performance.

Source: Barnden L, Crouch B, Kwiatek R, Shan Z, Thapaliya K, Staines D, Bhuta S, Del Fante P, Burnet R. Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process-Multi-Cohort Multi-Modal Evidence. Brain Sci. 2022 Dec 9;12(12):1693. doi: 10.3390/brainsci12121693. PMID: 36552153; PMCID: PMC9776387. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776387/ (Full text)

Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms

Abstract:

Coronavirus disease 2019 (COVID-19), represents an enormous new threat to our healthcare system and particularly to the health of older adults. Although the respiratory symptoms of COVID-19 are well recognized, the neurological manifestations, and their underlying cellular and molecular mechanisms, have not been extensively studied yet. Our study is the first one to test the direct effect of serum from hospitalised COVID-19 patients on human hippocampal neurogenesis using a unique in vitro experimental assay with human hippocampal progenitor cells (HPC0A07/03 C). We identify the different molecular pathways activated by serum from COVID-19 patients with and without neurological symptoms (i.e., delirium), and their effects on neuronal proliferation, neurogenesis, and apoptosis.

We collected serum sample twice, at time of hospital admission and approximately 5 days after hospitalization. We found that treatment with serum samples from COVID-19 patients with delirium (n = 18) decreased cell proliferation and neurogenesis, and increases apoptosis, when compared with serum samples of sex- and age-matched COVID-19 patients without delirium (n = 18). This effect was due to a higher concentration of interleukin 6 (IL6) in serum samples of patients with delirium (mean ± SD: 229.9 ± 79.1 pg/ml, vs. 32.5 ± 9.5 pg/ml in patients without delirium).

Indeed, treatment of cells with an antibody against IL6 prevented the decreased cell proliferation and neurogenesis and the increased apoptosis. Moreover, increased concentration of IL6 in serum samples from delirium patients stimulated the hippocampal cells to produce IL12 and IL13, and treatment with an antibody against IL12 or IL13 also prevented the decreased cell proliferation and neurogenesis, and the increased apoptosis. Interestingly, treatment with the compounds commonly administered to acute COVID-19 patients (the Janus kinase inhibitors, baricitinib, ruxolitinib and tofacitinib) were able to restore normal cell viability, proliferation and neurogenesis by targeting the effects of IL12 and IL13.

Overall, our results show that serum from COVID-19 patients with delirium can negatively affect hippocampal-dependent neurogenic processes, and that this effect is mediated by IL6-induced production of the downstream inflammatory cytokines IL12 and IL13, which are ultimately responsible for the detrimental cellular outcomes.

Source: Borsini, A., Merrick, B., Edgeworth, J. et al. Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01741-1 (Full text)

COVID-19 induces CNS cytokine expression and loss of hippocampal neurogenesis

Abstract:

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with acute and postacute cognitive and neuropsychiatric symptoms including impaired memory, concentration, attention, sleep and affect. Mechanisms underlying these brain symptoms remain understudied.

Here we report that SARS-CoV-2-infected hamsters exhibit a lack of viral neuroinvasion despite aberrant blood-brain barrier permeability. Hamsters and patients deceased from coronavirus disease 2019 (COVID-19) also exhibit microglial activation and expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the medulla oblongata, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uraemia or trauma. In the hippocampal dentate gyrus of both COVID-19 hamsters and humans, we observed fewer neuroblasts and immature neurons.

Protracted inflammation, blood-brain barrier disruption and microglia activation may result in altered neurotransmission, neurogenesis and neuronal damage, explaining neuropsychiatric presentations of COVID-19. The involvement of the hippocampus may explain learning, memory and executive dysfunctions in COVID-19 patients.

Source: Soung AL, Vanderheiden A, Nordvig AS, Sissoko CA, Canoll P, Mariani MB, Jiang X, Bricker T, Rosoklija GB, Arango V, Underwood M, Mann JJ, Dwork AJ, Goldman JE, Boon ACM, Boldrini M, Klein RS. COVID-19 induces CNS cytokine expression and loss of hippocampal neurogenesis. Brain. 2022 Aug 25:awac270. doi: 10.1093/brain/awac270. Epub ahead of print. PMID: 36004663. https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac270/6672950?login=false (Full text)

Volumetric differences in hippocampal subfields and associations with clinical measures in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients suffer from a cognitive and memory dysfunction. Because the hippocampus plays a key role in both cognition and memory, we tested for volumetric differences in the subfields of the hippocampus in ME/CFS.

We estimated hippocampal subfield volumes for 25 ME/CFS patients who met Fukuda criteria only (ME/CFS_Fukuda ), 18 ME/CFS patients who met the stricter ICC criteria (ME/CFS_ICC ), and 25 healthy controls (HC). Group comparisons with HC detected extensive differences in subfield volumes in ME/CFS_ICC but not in ME/CFS_Fukuda . ME/CFS_ICC patients had significantly larger volume in the left subiculum head (p < 0.001), left presubiculum head (p = 0.0020), and left fimbria (p = 0.004).

Correlations of hippocampus subfield volumes with clinical measures were stronger in ME/CFS_ICC than in ME/CFS_Fukuda patients. In ME/CFS_Fukuda patients, we detected positive correlations between fatigue and hippocampus subfield volumes and a negative correlation between sleep disturbance score and the right CA1 body volume.

In ME/CFS_ICC patients, we detected a strong negative relationship between fatigue and left hippocampus tail volume. Strong negative relationships were also detected between pain and SF36 physical scores and two hippocampal subfield volumes (left: GC-ML-DG head and CA4 head).

Our study demonstrated that volumetric differences in hippocampal subfields have strong statistical inference for patients meeting the ME/CFS_ICC case definition and confirms hippocampal involvement in the cognitive and memory problems of ME/CFS_ICC patients.

Source: Thapaliya K, Staines D, Marshall-Gradisnik S, Su J, Barnden L. Volumetric differences in hippocampal subfields and associations with clinical measures in myalgic encephalomyelitis/chronic fatigue syndrome. J Neurosci Res. 2022 Mar 31. doi: 10.1002/jnr.25048. Epub ahead of print. PMID: 35355311. https://onlinelibrary.wiley.com/doi/10.1002/jnr.25048 (Full study)

The role of the hippocampus in the pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe acquired illness characterized by a profound sensation of fatigue, not ameliorated by rest and resulting in a substantial decrease in the amount and quality of occupational, social and recreational activities.

Despite intense research, the aetiology and pathogenesis of ME/CFS is still unknown and no conclusive biological markers have been found. As a consequence, an accepted curative treatment is still lacking and rehabilitation programmes are not very effective, as few patients recover. Increased knowledge of the mechanisms leading to the emergence and maintenance of the illness is called for.

In this study, I will put forth an alternative hypothesis to explain some of the pathologies associated with ME/CFS, by concentrating on one of the major strategic organs of the brain, the hippocampus. I will show that the ME/CFS triggering factors also impact the hippocampus, leading to neurocognitive deficits and disturbances in the regulation of the stress system and pain perception. These deficits lead to a substantial decrease in activity and to sleep disorders, which, in turn, impact the hippocampus and initiate a vicious circle of increased disability.

Source: Saury JM. The role of the hippocampus in the pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Med Hypotheses. 2016 Jan;86:30-8. doi: 10.1016/j.mehy.2015.11.024. Epub 2015 Nov 27. https://www.ncbi.nlm.nih.gov/pubmed/26804593

Resveratrol improves hippocampal atrophy in chronic fatigue mice by enhancing neurogenesis and inhibiting apoptosis of granular cells

Abstract:

Neuroimaging evidence showed structural and/or functional abnormalities existing in the central nervous system, especially the hippocampus, in chronic fatigue syndrome (CFS) patients. However, its pathophysiologic mechanisms are unclear in part due to the lack of an applicable animal model. We established a chronic fatigue murine model by six repeated injections of Brucella abortus antigen to mice, which was manifested as reduced daily running activity and hippocampal atrophy. Thereafter, resveratrol, a polyphenolic activator of sirtuin 1, was used for treatment in this model. Daily running activity was increased by more than 20%, and the hippocampus was enlarged after 4-week resveratrol therapy.

Furthermore, resveratrol inhibited neuronal apoptosis and expression of hippocampal acetylated p53 in the fatigue mice. Resveratrol also improved neurogenesis and expression of brain-derived neurotrophic factor mRNA in the hippocampus. We concluded that repeated injection of B. abortus antigen could induce hypoactivity and hippocampal atrophy in mice. Resveratrol may be effective for improving fatigue symptoms and enlarging the atrophic hippocampus by repressing apoptosis and promoting neurogenesis.

Source: Moriya J, Chen R, Yamakawa J, Sasaki K, Ishigaki Y, Takahashi T. Resveratrol improves hippocampal atrophy in chronic fatigue mice by enhancing neurogenesis and inhibiting apoptosis of granular cells. Biol Pharm Bull. 2011;34(3):354-9. https://www.jstage.jst.go.jp/article/bpb/34/3/34_3_354/_article (Full article)