Unexpected awakenings in severe dementia from case reports to laboratory.

OBJECTIVE: Case report notions of unexpected memory retrieval in patients with severe dementia near to death are starting to alter the central "irreversible" paradigm of dementia and locate dementia as a problem of memory retrieval, not consolidation. We suggest that the most likely central tenet of this paradoxical memory retrieval is the fluctuation of neuromodulators projecting from the brain stem to the medial prefrontal cortex and the hippocampus. The neuromodulation-centric explanation of this phenomenon aims to open the "irreversible" paradigm of dementia up for discussion and suggest a plausible treatment strategy by questioning how the devastating process of death fluctuates memory performance in severe dementia. BACKGROUND: Supporting demented patients, who are mostly unresponsive, without making demands or asking a question and regarding them as valuable human beings unexpectedly improve their memory performance around the time of death. NEW LUCIDITY HYPOTHESIS: Around the time of death, neurological signs (hyper-arousal and -attention) of demented people point out that neurotransmitter discharges are dramatically changed. Relatively resistant neuromodulator circuits to neurodegeneration can maintain optimal levels of arousal and attention for memory processing. In this way, unexpected episodes of lucidity can be triggered. Also, corticotropin-releasing peptides might increase mental clarity by increasing the excitability of the neuromodulator circuits. The science of memory retrieval is more complicated and nuanced than retrieval observations in case reports, but the rapid development of new techniques holds promise for future understanding of lucidity in severe dementia. MAJOR CHALLENGE FOR THE MODEL: There is no an animal or human model to test this hypothesis; however, the similarities between neurological signs (instantaneous cognitive fluctuations) of delirium and paradoxical lucidity could provide a unique window to understand neural events of terminal lucidity on a modified animal model of delirium. Likewise, similarities between unexpected consciousness signs of terminal lucidity and lucid dreaming suggest that lucid dreaming episodes might be considered a human model for terminal lucidity research.

Optogenetic stimulation of serotonin nuclei retrieve the lost memory in Alzheimer's disease.

How are memories stored and retrieved? It was one of the most discussed questions in the past century by neuroscientists. Leading studies of the period brought two different explanations to this question: The first statement considers memory as a physiological change in the brain and suggest that the retrieval of memory is only occurred by the same physiologic changes observed during the memory formation, while the second suggests that memory is a psychic mood stored in mind and the retrieval of memory is occurred by mystical energy fluctuations. Although the exact reason and the pathogenesis of Alzheimer's disease have not yet been fully understood, the approaches that centered the retrieval strategy of lost memory constitutes the basis of the treatment strategies in Alzheimer's disease today. The majority of treatment studies has based on the manipulation of the cholinergic system; however, although serotonin has mnemonic effects, its role in the pathogenesis of Alzheimer's disease has not been investigated as much as the cholinergic system. Here we show how serotonin affects the pathogenesis of Alzheimer's disease in a comprehensive perspective and we suggest that the optogenetics manipulation of serotonin nuclei retrieve the lost memory by closing the inward-rectifier potassium channel Kir2 on the memory engram cells. Also, we raise the possible effects of serotonin on the memory engram cells and the interactions between the amyloid-centric hypothesis of Alzheimer's disease and the memory engram hypothesis to explain the pathophysiology of memory loss in Alzheimer's disease.

An update on memory formation and retrieval: An engram-centric approach.

OBJECTIVE: We explore here that memory loss observed in the early stage of Alzheimer's disease (AD) is a disorder of memory retrieval, instead of a storage impairment. This engram-centric explanation aims to enlarge the conceptual frame of memory as an emergent behavior of the brain and to propose a new treatment strategy for memory retrieval in dementia-AD. BACKGROUND: The conventional memory hypothesis suggests that memory is stored as multiple traces in hippocampal neurons but recent evidence indicates that there are specialized memory engrams responsible for the storage and the retrieval of different memory types. UPDATED MEMORY HYPOTHESIS: There are specialized memory engram neurons for each memory type and when information will be stored as a memory arrives in the hippocampus through afferent neurons finds its neuron according to the excitability states of engram neurons. The excitability level in engram neurons seems like a code canalizing the interactions between engrams and information. Therefore, to enhance the excitability of memory engram neurons improves memory loss observed in AD. In addition, we suggest that the hippocampus creates an index for information stored in memory engram cells in specialized regions for different types of memory, instead of storing all information; and different anatomic locations of engram cells and their roles in memory retrieval point out that memory could be an emergent behavior of the brain, and the interaction between serotonin fluctuation and engram neurons could be neural underpinnings of terminal lucidity. MAJOR CHALLENGES FOR THE MODEL: The major challenge for this engram-centric memory retrieval model is the translation from bench to patient, specifically the delivery of optogenetic tools in patients. Engram neurons can be specifically activated by optogenetic tools, but optogenetics is an invasive technique which requires optic fiber implantation into the brain. In addition, light can overheat the tissue and thus induce damage in tissue. Furthermore, light is a foreign object and its direct implantation into the brain may cause neuroinflammation, the main trigger of neurodegenerative diseases. Therefore, to test the engram hypothesis in human, new tools to allow specific engram activation should be discovered.

Assessment of the effect of laser irradiations at different wavelengths (660, 810, 980, and 1064 nm) on autophagy in a rat model of mucositis.

It is known that high-dose radiation has an effect on tissue healing, but tissue healing does not occur when low dose radiation is applied. To clarify this issue, we compare the treatment success of low dose radiation with programmed cell death mechanisms on wounded tissue. In this study, we aimed to investigate the interactions of low and high-dose radiation using an autophagic mechanism. We included 35 adult Wistar-Albino rats in this study. All animals were injected with 100 mg/kg of 5-fluorouracil (5-FU) on the first day and 65 mg/kg of 5-FU on the third day. The tips of 18-gauge needles were used to develop a superficial scratching on the left cheek pouch mucosa by dragging in a linear movement on third and fifth days. After mucositis formation was clinically detected, animals were divided into five groups (n = 7). Different wavelengths of laser irradiations (1064 nm, Fidelis Plus, Fotona, Slovenia; 980 nm, FOX laser, A.R.C., Germany; 810 nm, Fotona XD, Fotona, Slovenia; 660 nm, HELBO, Medizintechnik GmbH, Wels, Austria) were performed on four groups once daily for 4 days. The laser irradiation was not performed on the control group. To get the tissue from the left cheek at the end of fourth day from all animals, oval excisional biopsy was performed. Molecular analysis assessments of pathological and normal tissue taken were performed. For this purpose, the expression analysis of autophagy genes was performed. The results were evaluated by normalization and statistics analysis. We found that Ulk1, Beclin1, and Atg5 expression levels were increased in the rats when the Nd:YAG laser was applied. This increase showed that a 1064-nm laser is needed to activate the autophagic mechanism. However, in the diode applications, we found that Beclin1, Atg10, Atg5, and Atg7 expressions numerically decreased. Atg5 is responsible for the elongation of autophagosome. Becn1 is a control gene in the control mechanism of autophagy. The reduction of the expression of these genes leads us to think that it may depend on the effect of drug (5-FU) used to form model. Expressions of therapeutic genes increase to ensure hemostasis, but in our study, expressions were found to decrease. More detailed studies are needed.

Editorial.

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Nigella sativa, Anthemis hyaline and Citrus sinensis extracts reduce SARS-CoV-2 replication by fluctuating Rho GTPase, PI3K-AKT, and MAPK/ERK pathways in HeLa-CEACAM1a cells.

Traditional remedies have long utilized Anthemis hyaline, Nigella sativa, and Citrus sinensis peel extracts as treatments for microbial infections. This study aimed to investigate the influence of Anthemis hyaline, Nigella sativa, and Citrus sinensis extracts on coronavirus replication and apoptosis-related pathways. HeLa-CEACAM1a cells were exposed to mouse hepatitis virus-A59. After viral inoculation, the mRNA levels of 36 genes were quantified using a Fluidigm Dynamic Array nanofluidic chip. IL-8 level and intracellular Ca2+ concentration was measured, and viral titer was assessed by the TCID50/ml assay to detect the extent of infection. Treatment with Nigella sativa extract surged the inflammatory cytokine IL-8 level at both 24 and 48-hour. Changes in gene expression were notable for RHOA, VAV3, ROCK2, CFL1, RASA1, and MPRIP genes following treatment with any of the extracts. The addition of Anthemis hyaline, Nigella sativa, or Citrus sinensis extracts to coronavirus-infected cells reduced viral presence, with Anthemis hyaline extract leading to a virtually undetectable viral load at 6- and 8-hours after infection. While all treatments influenced IL-8 production and viral levels, Anthemis hyaline extract displayed the most pronounced reduction in viral load. Consequently, Anthemis hyaline extract emerges as the most promising agent, harboring potential therapeutic compounds.

Connectivity between Gut Microbiota and Terminal Awakenings in Alzheimer's Disease.

Memory is empirically described as a brain function that connects the past to the present. This reductionist approach has focused on memory function within neurons and synapses, leading to an understanding that memory loss in dementia is caused by irreversible neuronal damage. However, recent palliative case reports and the Human Connectome Project have challenged the "irreversible" paradigm by indicating that some demented patients are able to retrieve supposed 'lost' memories and cognitive functions near death. The serotonin-centric hypothesis and the lifelong oligodendrocyte differentiation capacity may explain terminal awakening symptoms in these patients. Furthermore, an increased rate of serotonin-secreting and oligodendrocyte precursor cell-triggering gut bacteria near death temporally correlates with lucid improvements in demented patients. These findings may shift the context of terminal memory retrieval from a purely neuronal to a systemic idea that bridges terminal lucidity and gut microbiota. In this review, we take the systemic approach further and point out a temporal correlation between the gut microbiome and terminal lucid episodes in Alzheimer's patients.

Local myelin damage in the hippocampus fluctuates gut microbiome profile and memory.

The concept of the gut-brain axis has focused research on how gut dysbiosis affects myelin biology in the brain. However, this axis has not been tested to determine whether it conveys the effects of myelin damage on the gut microbiome profile. Therefore, we aimed to investigate how myelin biology is correlated with gut microbiome profile. The impact of local myelin damage in the hippocampus on gut microbiome profile was investigated with 16S rRNA metagenomic sequence and molecular analysis of myelin biology-associated proteins, and its reflections on memory performance were tested with behavioral tests. Local myelin damage in the hippocampus triggered severe gut dysbiosis, p < .05, changed memory performance, p < .05, and deviated emotional responses. Moreover, myelin treatment with clemastine improved gut dysbiosis and behavioral deviations. Our study provides animal-based evidence on the direct interaction between glial biology in the hippocampus and gut microbiome profile. This study proposes a framework for generating new hypotheses bridging different systems to the gut-brain axis.

Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes.

Meningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain. 3D T2-Fluid Attenuated Inversion Recovery magnetic resonance imaging relies on internal signals of protein rich lymphatic fluid rather than contrast media and is used in the present study to visualize the major human dural lymphatic structures. Moreover we detect direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes. We also identify age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain.

Profiling of Autophagy-Associated microRNAs in the Osteosarcoma Cell Line of U2OS.

BACKGROUND: Autophagy is a cellular process that plays a role in the destruction of proteins and organelles. It has been shown that impaired autophagic flux triggers canceration, infectious disease, and neurodegenerative diseases. It has been suggested that tumor formation is inhibited by autophagy that reduces oxidative stress and recycles damaged organelles. microRNAs are 17-25 bp in length, single-stranded, and noncoding small RNAs that play roles in the regulation of metabolic gene expression at the post-transcriptional level. Osteosarcoma is an aggressive bone cancer that affects mainly children and adolescents. OBJECTIVE: The current article aims to profile autophagy-associated miRNAs in osteosarcoma cell lines and to examine the therapeutical potentials of these miRNAs by suppressing their expressions with Adriamycin and Rapamycin. METHODS: We used fluidigm dynamic array nanofluidic chip 96.96 for mRNA expression assay in osteosarcoma cell line U2OS. RESULTS: It was probed that after the suppression of autophagy-associated miRNAs by adriamycin and rapamycin, while most of the miRNAs were down-regulated in osteosarcoma cell lines, some miRNAs' expressions, such as miR-3141, miR-4296, miR-133b, and miR-720, were strikingly increased. Rapamycin and adriamycin, mTOR inhibitors, stir autophagic machinery, which results in decreased cell survival. CONCLUSION: Together, we propose that the expressions of miR-3141, miR-4296, miR-133b, and miR-720 might exacerbate the pathogenesis of osteosarcoma; therefore, the suppression of these miRNAs with the loss-offunction approaches could be an appropriate strategy that is worth testing in osteosarcoma.

Investigation of Cytotoxic Effects of Oxymetazoline on Lungs in a Rat Model of Rhinitis Medicamentosa.

BACKGROUND: Rhinitis medicamentosa, also known as 'rebound congestion,' is inflammation of the nasal mucosa caused by the overuse of topical nasal decongestants. Although local decongestants resolve the initial nasal obstruction, the overuse causes rebound obstruction. However, how the overuse of the decongestant causes rhinitis medicamentosa is not known. OBJECTIVES: Here, we show the intracellular effects of oxymetazoline, commonly used a local decongestant, on the cell death pathways. We also investigated the antioxidative effects of erdosteine suspension (175 mg/5mL), an antioxidative agent. METHODS: Thirty Wistar-albino rats were used to form the rhinitis medicamentosa model. After rhinitis medicamentosa was clinically detected, we removed the whole lungs of animals to perform the molecular analyses of cell death pathways. RESULTS: We found a statistically significant decrease in the expression levels of Atg5 (p=0.021), Atg7 (p=0.013) and Ulk1 (p=0.036) in the oxymetazoline group compared to the control group (p<0.05); however, Caspase 3 expression level was recorded to be significantly increased in the oxymetazoline group, and the expression level of Beclin1 recorded to be substantially increased in the erdosteine group (p=0.001). CONCLUSION: Based on these grounds, we suggest that vasoconstriction in capillary vessels caused by oxymetazoline could lead to a decrease in the blood supply, which triggers autophagy to ensure cellular homeostasis.

Temporal Correlation Between Neurological and Gastrointestinal Symptoms of SARS-CoV-2.

Severe Acute Respiratory Syndrome Coronavirus-2 (SAR-CoV-2) has been shown to invade brain tissue. Based on the evolutionary similarity with SARS-CoV, researchers propose that SARS-CoV-2 can invade the olfactory bulb and gastrointestinal (GI) system through angiotensin-converting enzyme 2. However, how SARS-CoV-2 causes neurological or GI symptoms is not clear. Many suggested intestinal and neural inflammations, caused by viral invasion, as the most likely reason for the GI and neurological symptoms; however, the patients with coronavirus disease 2019 (COVID-19) without neurological or GI symptoms indicate that this is not the case. The gut-brain axis could explain the reason for why some with COVID-19 do not have these symptoms. COVID-19 patients mostly show respiratory distress first, then diarrhea, anorexia, stroke, or loss of consciousness comes into view. Obviously, GI invasion is a mechanical process that begins with oral invasion and, therefore, most probably exists before the brain invasion, as indicated in case reports. However, when the GI tract is invaded, the virus may enter the central nervous system through vascular and lymphatic systems or the vagal nerve. SARS-CoV-2 can infect leukocytes and migrate with them into the brain, or the viral particles can be directly transported across the blood-brain barrier to the brain. Also, more recent research has revealed that SARS-CoV-2 can invade the peripheral lymphatic vessels connecting with the glymphatic system of the brain. The temporal correlation between neurological and gastrointestinal symptoms suggests the lymph vessels around the GI tract, the vascular system, or the gut-brain axis (enteric nervous system) as the most likely entry route for SARS-CoV-2 to the brain.

Neuromodulation of Memory Formation and Extinction.

Memory retrieval is mediated by discharges of acetylcholine, glutamate, gammaaminobutyric acid, norepinephrine, and serotonin/5-hydroxytryptamine circuits. These projections and memory interact through engram circuits, neurobiological traces of memory. Increased excitability in engram circuits of the medial prefrontal cortex and hippocampus results in remote and recent memory retrievals, respectively. However, due to degenerated neurotransmitter projections, the excitability state of engram circuits is decreased in the patient with dementia; and thus, acquired- memory cannot be retrieved by natural cues. Here, we suggest that artificial neuropharmacological stimulations of the acquired-memory with an excitation potential higher than a natural cue can excite engram circuits in the medial prefrontal cortex, which results in the retrieval of lost memories in dementia. The neuropharmacological foundations of engram cell-mediated memory retrieval strategy in severe dementia, in line with this has also been explained. We particularly highlighted the close interactions between periaqueductal gray, locus coeruleus, raphe nuclei, and medial prefrontal cortex and basolateral amygdala as treatment targets for memory loss. Furthermore, the engram circuits projecting raphe nuclei, locus coeruleus, and pontomesencephalic tegmentum complex could be significant targets of memory editing and memory formation in the absence of experience, and a well-defined study of the neural events underlying the interaction of brain stem and memory will be relevant for such developments. We anticipate our perspective to be a starting point for more sophisticated in vivo models for neuropharmacological modulations of memory retrieval in Alzheimer's dementia.

Endocannabinoid Signaling for GABAergic-Microglia (Mis)Communication in the Brain Aging.

The aging brain seems to be characterized by neuronal loss leading to cognitive decline and progressively worsening symptoms related to neurodegeneration. Also, pro-inflammatory states, if prolonged, may increase neuronal vulnerability via excessive activation of microglia and their pro-inflammatory by-products, which is seen as individuals increase in age. Consequently, microglial activity is tightly regulated by neuron-microglia communications. The endocannabinoid system (ECS) is emerging as a regulator of microglia and the neuronal-microglia communication system. Recently, it has been demonstrated that cannabinoid 1 (CB1) receptor signaling on GABAergic interneurons plays a crucial role in regulating microglial activity. Interestingly, if endocannabinoid signaling on GABAergic neurons are disturbed, the phenotypes mimic central nervous system insult models by activating microglia and leading to accelerated brain aging. Investigating the endocannabinoid receptors, ligands, and genetic deletions yields the potential to understand the communication system and mechanism by which the ECS regulates glial cells and aspects of aging. While there remains much to discover with the ECS, the information gathered and identified already could lead to the development of cell-specific therapeutic interventions that help in reducing the effects of age-related pro-inflammatory states and neurodegeneration.

An update on the interactions between Alzheimer's disease, autophagy and inflammation.

An update on pathogenesis of Alzheimer's disease, the present document describes the crosstalk between autophagy and inflammation in Alzheimer's disease progression by assessing key findings and identifying gaps in the current knowledge. Inflammation mediators can disrupt the clearance of misfolded proteins. It is well defined that misfolded protein accumulation and aberrant level of inflammatory mediators in the brain can trigger Alzheimer's disease. Studies indicated that restoring the inflammatory and autophagy mediators improves Alzheimer's disease. This presents a problem: How inflammation interacts with the protein clearance system, autophagy, in the brain. Here, we describe an update on the link between inflammation and autophagy pathways. Some of the vital challenges for the presented link included investigation of the questions: What is the role of inflammation mediators in the brain under various conditions; and how altered level of inflammatory mediators affects the performance of autophagy at molecular level.