Behavioral and Neurophysiological Implications of Pathological Human Tau Expression in Serotonin Neurons

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(5), С. 932 - 943

Опубликована: Фев. 20, 2024

Alzheimer's disease (AD) is a progressive degenerative disorder that results in severe loss of brain cells and irreversible cognitive decline. Memory problems are the most recognized symptoms AD. However, approximately 90% patients diagnosed with AD suffer from behavioral symptoms, including mood changes social impairment years before dysfunction. Recent evidence indicates dorsal raphe nucleus (DRN) among initial regions show tau pathology, which hallmark feature The DRN harbors serotonin (5-HT) neurons, critically involved mood, social, regulation. Serotonergic early process may contribute to mechanisms underlying vulnerability contribution 5-HT system progression remain unknown. Here, we performed electrophysiological characterizations mice expressing phosphorylation-prone form human (hTauP301L) neurons. We found pathological expression neurons induces anxiety-like behavior alterations stress-coping strategies female male mice. Female also exhibited disinhibition mild response neuron-specific hTauP301L expression. Behavioral were accompanied by disrupted neuron physiology exacerbated excitability disruption females only. These data provide mechanistic insights into systems impaired progression, critical for intervention.

Язык: Английский

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An Honest Reckoning With the Amygdala and Mental Illness

American Journal of Psychiatry, Год журнала: 2024, Номер 181(12), С. 1059 - 1075

Опубликована: Дек. 1, 2024

Anxiety disorders are a leading source of human misery, morbidity, and premature mortality. Existing treatments far from curative for many, underscoring the need to clarify underlying neural mechanisms. Although many brain regions contribute, amygdala has received most intense scientific attention. Over past several decades, this scrutiny yielded detailed understanding function, but it failed produce new clinical assays, biomarkers, or cures. Rising urgent public health challenge demands an honest reckoning with functional-neuroanatomical complexity shift theories anchored on "the amygdala" models centered specific nuclei cell types. This review begins by examining evidence studies rodents, monkeys, humans "canonical model," idea that plays central role in fear- anxiety-related states, traits, disorders. Next, authors selectively highlight work indicating canonical model, while true, is overly simplistic fails adequately capture actual state evidentiary record, breadth amygdala-associated functions illnesses, amygdala's functional architecture. The describe implications these facts basic neuroimaging research. concludes some general recommendations grappling accelerating efforts understand more effectively treat amygdala-related psychopathology.

Язык: Английский

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Pathological and neurochemical correlates of locus coeruleus functional network activity

Biological Psychology, Год журнала: 2024, Номер 192, С. 108847 - 108847

Опубликована: Июль 20, 2024

The locus coeruleus (LC) produces the neuromodulators norepinephrine and dopamine, projects widely to subcortical cortical brain regions. LC has been a focus of neuroimaging biomarker development for early detection Alzheimer's disease (AD) since it was identified as one earliest regions develop tau pathology. Our recent research established use positron emission tomography (PET) measure catecholamine synthesis capacity in cognitively unimpaired older adults. We extend this work by investigating possible influence pathology neurochemical function on network activity using functional magnetic resonance imaging (fMRI). In separate sessions, participants underwent PET ([18F]Fluoro-m-tyrosine), ([18F]Flortaucipir), amyloid-β ([11C]Pittsburgh compound B), fMRI at rest. Consistent with growing body aging preclinical AD, we find that higher is associated burden individuals risk developing AD (amyloid-β positive). Critically, relationships between tau) were moderated capacity. High levels reduced Broadly, these findings support view individual differences are shaped interactions neuromodulator function, point systems potential therapeutic targets.

Язык: Английский

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Implementation and Assessment of Tau Thresholds in Non-Demented Individuals as Predictors of Cognitive Decline in Tau Imaging Studies

Journal of Alzheimer s Disease, Год журнала: 2024, Номер 100(s1), С. S75 - S92

Опубликована: Авг. 9, 2024

Tau accumulation in Alzheimer's disease is associated with short term clinical progression and faster rates of cognitive decline individuals high amyloid-β deposition. Defining an optimal threshold tau predictive remains a challenge.

Язык: Английский

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Tell me why: the missing w in episodic memory’s what, where, and when

Cognitive Affective & Behavioral Neuroscience, Год журнала: 2024, Номер 25(1), С. 6 - 24

Опубликована: Окт. 25, 2024

Язык: Английский

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BLA-involved circuits in neuropsychiatric disorders

Ageing Research Reviews, Год журнала: 2024, Номер 99, С. 102363 - 102363

Опубликована: Июнь 4, 2024

Язык: Английский

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Causal Associations Between Imaging-derived Phenotypes and Risk of Alzheimer's Disease and Other Neurodegenerative Disorders:A Mendelian Randomization Study

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 10, 2024

ABSTRACT Background Accumulating observational studies have suggested associations between imaging-derived phenotypes (IDPs) and common neurodegenerative disorders, especially Alzheimer’s disease (AD). The goal of this study is to evaluate the causal structural functional IDPs 4 including AD, Parkinson’s (PD), Amyotrophic lateral sclerosis (ALS), Multiple (MS). Methods Bidirectional two-sample Mendelian randomization (MR) were conducted using summary statistics obtained from genome-wide association 3909 UK biobank disorders. Results Forward MR analysis showed that volume cerebral white matter in left hemisphere was associated with increased risk ALS (odds ratio [OR] = 1.15, 95% confidence interval [CI] 1.09-1.22, P 3.52 x 10 -6 ). In reverse analysis, we revealed genetically determined AD MS multiple (all < 1.28 -5 [0.05/3909], 9 MS). For example, causally reduced gray right ventral striatum (OR 0.95, CI 0.93-0.97, 4.68 -7 ) lower rfMRI amplitudes several nodes (ICA25 node 9, ICA25 8, ICA100 11). Additionally, putamen 0.97, 0.97-0.98, 4.47 orientation dispersion index hippocampus 1.03, 1.01-1.04, 2.02 Conclusions Our plausible NDDs brain IDPs. These findings might hold promise for identifying new mechanisms developing novel preventative therapies at imaging levels.

Язык: Английский

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Causal Associations Between Imaging-derived Phenotypes and Risk of Alzheimer’s Disease and Other Neurodegenerative Disorders: A Mendelian Randomization Study

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Сен. 11, 2024

Background Accumulating observational studies have suggested associations between imaging-derived phenotypes (IDPs) and common neurodegenerative disorders, especially Alzheimer’s disease (AD). The goal of this study is to evaluate the causal structural functional IDPs 4 including AD, Parkinson’s (PD), Amyotrophic lateral sclerosis (ALS), Multiple (MS).Methods Bidirectional two-sample Mendelian randomization (MR) were conducted using summary statistics obtained from genome-wide association 3909 UK biobank disorders.Results Forward MR analysis showed that volume cerebral white matter in left hemisphere was associated with increased risk ALS (odds ratio [OR] = 1.15, 95% confidence interval [CI] 1.09–1.22, P 3.52 x 10^{− 6}). In reverse analysis, we revealed genetically determined AD MS multiple (all < 1.28 5[0.05/3909], 9 MS). For example, causally reduced gray right ventral striatum (OR 0.95, CI 0.93–0.97, 4.68 7) lower rfMRI amplitudes several nodes (ICA25 node 9, ICA25 8, ICA100 11). Additionally, putamen 0.97, 0.97–0.98, 4.47 orientation dispersion index hippocampus 1.03, 1.01–1.04, 2.02 6).Conclusions Our plausible NDDs brain IDPs. These findings might hold promise for identifying new mechanisms developing novel preventative therapies at imaging levels.

Язык: Английский

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Co-administration of coenzyme Q10 and curcumin mitigates cognitive deficits and exerts neuroprotective effects in aluminum chloride-induced Alzheimer's disease in aged mice

Experimental Gerontology, Год журнала: 2024, Номер 199, С. 112659 - 112659

Опубликована: Дек. 19, 2024

Aluminum chloride (AlCl3), a known neurotoxic and Alzheimerogenic metal disrupts redox homeostasis which plays pivotal role in pathophysiology of neurodegenerative disorders, particularly cognitive decline. The current study was designed to unveil the long-term neuroprotective outcomes efficacy CoQ10 curcumin low dose (100 mg/kg each) combination 18-months old geriatric male Balb/c mice subjected AlCl3-prompted memory derangements (200 water bottles) for 28 days. properties driven by antioxidant mechanisms were assessed via observing cellular pathology key-memory related brain regions including cornuammonis (CA3 DG) cortex 2/3 layer. Our revealed that AlCl3 exposure significantly reduced spatial learning memory. In contrast, combinatorial regime markedly mitigated deficits Vs. individual high-dose AlCl3-treated animals as demonstrated their improved performance neurobehavioral tests such Y-maze, novel object recognition, passive avoidance Morris-water maze test. Additionally, co-administration restored balance reducing levels oxidative stressor (MDA) increasing anti-oxidant capacity (SOD,GPx). AchE is an enzyme involved acetylcholine breakdown negatively impacts function. elevated brains vs. treatment. This neurochemical alteration notably reversed dual-treatment group. Furthermore, ameliorated AlCl3-induced neurotoxicity preserving neuronal cytoarchitecture both cortical hippocampal regions. conclusion, might attenuate loss induced AlCl3-intoxication restoring aberrant activity, enhanced defenses salvaging deleterious damage.

Язык: Английский

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Limbic and cerebellar effects in Alzheimer-Perusini’s disease: A physics-inspired approach

Biomedical Signal Processing and Control, Год журнала: 2024, Номер 103, С. 107355 - 107355

Опубликована: Дек. 30, 2024

Язык: Английский

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