Treadmill exercise improves hippocampal neural plasticity and relieves cognitive deficits in a mouse model of epilepsy.
Neural regeneration research
Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited. Although regular exercise effectively improves learning and memory functions across multiple neurological diseases, its application in patients with epilepsy remains controversial. Here, we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy. Cognitive assays confirmed the improvement of object and spatial memory after endurance training, and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise. Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons, probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier. In summary, this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.
10.4103/1673-5374.377771
Chronic social defeat stress mouse model: Current view on its behavioral deficits and modifications.
Wang Wang,Liu Weizhen,Duan Dongxiao,Bai Hualong,Wang Ziliang,Xing Ying
Behavioral neuroscience
Stress is the main cause of mood disorders such as depression and posttraumatic stress disorder. Individuals respond to stress differently, as some develop depressive symptoms, whereas others successfully cope with adversity, but it remains unclear what makes some particularly vulnerable to stress. The chronic social defeat stress (CSDS) mouse model, an ethologically valid rodent model that exhibits long-term physiological and behavioral phenotypes similar to depression and anxiety, can imitate individual differences in stress responses in humans. In this review, we not only summarize various behavioral deficits of the CSDS mouse model that were reported since its establishment but also concentrate on modified CSDS mouse models that have been developed in recent years, aiming at providing useful information for future research and application of this model. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
10.1037/bne0000418
Anxiety and Alzheimer's disease: Behavioral analysis and neural basis in rodent models of Alzheimer's-related neuropathology.
Neuroscience and biobehavioral reviews
Alzheimer's disease (AD) pathology is commonly associated with cognitive decline but is also composed of neuropsychiatric symptoms including psychological distress and alterations in mood, including anxiety and depression. Emotional dysfunction in AD is frequently modeled using tests of anxiety-like behavior in transgenic rodents. These tests often include the elevated plus-maze, light/dark test and open field test. In this review, we describe prototypical behavioral paradigms used to examine emotional dysfunction in transgenic models of AD, specifically anxiety-like behavior. Next, we summarize the results of studies examining anxiety-like behavior in transgenic rodents, noting that the behavioral outcomes using these paradigms have produced inconsistent results. We suggest that future research will benefit from using a battery of tests to examine emotional behavior in transgenic AD models. We conclude by discussing putative, overlapping neurobiological mechanisms underlying AD-related neuropathology, stress and anxiety-like behavior reported in AD models.
10.1016/j.neubiorev.2021.05.005
Escitalopram Alleviates Alzheimer's Disease-Type Tau Pathologies in the Aged P301L Tau Transgenic Mice.
Wang Yan-Juan,Gong Wei-Gang,Ren Qing-Guo,Zhang Zhi-Jun
Journal of Alzheimer's disease : JAD
BACKGROUND:The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer's disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro. OBJECTIVE:In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. METHODS:Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. RESULTS:Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3β and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. CONCLUSION:The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3β signaling pathway.
10.3233/JAD-200401
Imbalance of multiple neurotransmitter pathways leading to depression-like behavior and cognitive dysfunction in the triple transgenic mouse model of Alzheimer disease.
Metabolic brain disease
Depression is among the most frequent psychiatric comorbid conditions in Alzheimer disease (AD). However, pharmacotherapy for depressive disorders in AD is still a big challenge, and the data on the efffcacy of current antidepressants used clinically for depressive symptoms in patients with AD remain inconclusive. Here we investigated the mechanism of the interactions between depression and AD, which we believe would aid in the development of pharmacological therapeutics for the comorbidity of depression and AD. Female APP/PS1/Tau triple transgenic (3×Tg-AD) mice at 24 months of age and age- and sex-matched wild-type (WT) mice were used. The shuttle-box passive avoidance test (PAT) were implemented to assess the abilities of learning and memory, and the open field test (OFT) and the tail suspension test (TST) were used to assess depression-like behavior. High-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used to detect the level of neurotransmitters related to depression in the hippocampus of mice. The data was identified by orthogonal projections to latent structures discriminant analysis (OPLS-DA). Most neurotransmitters exert their effects by binding to the corresponding receptor, so the expression of relative receptors in the hippocampus of mice was detected using Western blot. Compared to WT mice, 3×Tg-AD mice displayed significant cognitive impairment in the PAT and depression-like behavior in the OFT and TST. They also showed significant decreases in the levels of L-tyrosine, norepinephrine, vanillylmandelic acid, 5-hydroxytryptamine, and acetylcholine, in contrast to significant increases in 5-hydroxyindoleacetic acid, L-histidine, L-glutamine, and L-arginine in the hippocampus. Moreover, the expression of the alpha 1a adrenergic receptor (ADRA1A), serotonin 1 A receptor (5HT1A), and γ-aminobutyric acid A receptor subunit alpha-2 (GABRA2) was significantly downregulated in the hippocampus of 3×Tg-AD mice, while histamine H3 receptor (H3R) expression was significantly upregulated. In addition, the ratio of phosphorylated cAMP-response element-binding protein (pCREB) and CREB was significantly decreased in the hippocampus of 3×Tg-AD mice than WT mice. We demonstrated in the present study that aged female 3×Tg-AD mice showed depression-like behavior accompanied with cognitive dysfunction. The complex and diverse mechanism appears not only relevant to the imbalance of multiple neurotransmitter pathways, including the transmitters and receptors of the monoaminergic, GABAergic, histaminergic, and cholinergic systems, but also related to the changes in L-arginine and CREB signaling molecules.
10.1007/s11011-023-01242-2
Apathy-like behaviour in tau mouse models of Alzheimer's disease and frontotemporal dementia.
Behavioural brain research
Apathy is the most common behavioural and psychological symptom in Alzheimer's disease (AD) and other neurodegenerative diseases including frontotemporal dementia (FTD) and Parkinson's disease (PD). In patients, apathy can include symptoms of loss of motivation, initiative, and interest, listlessness, and indifference, flattening of emotions, absence of drive and passion. Researchers have later refined this to a reduction in goal direct behaviours. In animals, specific symptoms of apathy-like behaviour have been modelled including goal directed or nest-building behaviour which are seen as indicative of proxies for motivation and daily activities. In the present study a nest-building protocol was established using four different inbred mouse strains (CD1, BALB/c, C57Bl/6J, C3H) before assessing AD and FTD tau transgenic mice of Line 1 (L1) and Line 66 (L66) in this paradigm. Female mice aged 5 - 6 months were assessed in the home cage over a period of 7 days with nest-building behaviour scored by three independent experimenters at intervals of 1-, 2- and 7-days post nestlet introduction. Inbred mouse strains displayed different levels of nesting behaviour. BALB/c mice were more proficient than CD1 and C3H mice, while all strains displayed similar nest-building behaviour by day 7. In the tau mouse models, L66 presented with impaired nesting compared to wild-type on days 1 and 2 (not day 7), whereas L1 performed like wild-type on all days. Anhedonia measured in a sucrose preference test was only observed in L66. Anhedonia and low nesting scores in L66 mice are indicative of apathy-like phenotypes. Differences evident between the L1 and L66 tau transgenic mouse models are likely due to the different human tau species expressed in these mice.
10.1016/j.bbr.2023.114707
Early Cognitive and Behavioral Deficits in Mouse Models for Tauopathy and Alzheimer's Disease.
Samaey Celine,Schreurs An,Stroobants Stijn,Balschun Detlef
Frontiers in aging neuroscience
Neurocognitive disorders, among which Alzheimer's disease (AD), have become one of the major causes of death in developed countries. No effective disease-modifying therapy is available, possibly because current treatments are administered too late to still be able to intervene in the disease progress. AD is characterized by a gradual onset with subclinical neurobiological and behavioral changes that precede diagnosis with years to even decades. The earlier the diagnosis, the earlier potential treatments can be tested and started. Mouse models are valuable to study the possible causes underlying early phases of neuropathology and their reflection in behavior and other biomarkers, to help improve preclinical detection and diagnosis of AD. Here, we assessed cognitive functioning and social behavior in transgenic mice expressing tau pathology only (Tau-P301L) or a combination of amyloid and tau pathology [amyloid precursor protein (APP)-V717I × Tau-P301L]. The mice were subjected to a variety of behavioral tasks at an age of 3-6 months, i.e., at an early phase of their AD-like pathology. We hypothesized that compared to age-matched wild-type controls, transgenic mice would show specific impairments in both cognitive and non-cognitive tasks. In line with our expectations, transgenic mice showed decreased cognitive flexibility in the Morris water maze, decreased exploratory behavior, decreased performance in a nesting task, and increased anxiety-like behavior. In accordance with the amyloid-cascade hypothesis, some of the behavioral measures showed more severe deficits in APP-V717I × Tau-P301L compared to Tau-P301L mice, indicating an exacerbation of disease processes due to the co-occurrence of amyloid and tau pathology. Our study supports the use of behavioral markers as early indicators of ongoing AD pathology during the preclinical phase.
10.3389/fnagi.2019.00335
A tau fragment links depressive-like behaviors and cognitive declines in Alzheimer's disease mouse models through attenuating mitochondrial function.
Frontiers in aging neuroscience
Introduction:Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-β peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear. Methods:Depressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-δ). Further behavioral studies investigated the role of Tau N368-PPAR-δ interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS. Results:We found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-δ, repressing PPAR-δ-mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-δ. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-δ effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice. Conclusion:These results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-δ, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer's disease.
10.3389/fnagi.2023.1293164
Moving Beyond Depression: Mood Symptoms Across the Spectrum Relate to Tau Pathology in Older Women at Risk for Alzheimer's Disease.
International journal of aging & human development
We examined how symptoms across the mood spectrum relate to Alzheimer's disease (AD) biomarkers in older women at high risk for AD. Participants included 25 women aged 65+ with mild cognitive deficits and elevated AD genetic risk. The Profile of Mood States Questionnaire measured mood symptoms and a total mood disturbance (TMD) score. Tau burden in the meta-temporal region of interest was measured using MK-6240 Tau positron emission tomography (PET) imaging. A subset ( = 12) also had p-Tau181, and Aß40/42 levels measured in plasma. Higher TMD scores related to higher tau PET standardized uptake value ratio (SUVR). Greater negative mood symptoms correlated with higher tau PET SUVR, while greater vigor correlated with lower SUVR. Similar results were seen with plasma p-Tau181 levels, but not with Aβ40/42 levels. In conclusion, positive and negative mood symptoms related to tau pathology in older women at high risk for AD, highlighting a role of mental well-being in AD risk.
10.1177/00914150241253257
Altered depression-related behavior and neurochemical changes in serotonergic neurons in mutant R406W human tau transgenic mice.
Egashira Nobuaki,Iwasaki Katsunori,Takashima Akihiko,Watanabe Takuya,Kawabe Hideyuki,Matsuda Tomomi,Mishima Kenichi,Chidori Shozo,Nishimura Ryoji,Fujiwara Michihiro
Brain research
Mutant R406W human tau was originally identified in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and causes a hereditary tauopathy that clinically resembles Alzheimer's disease (AD). In the current study, we examined the performance of R406W transgenic (Tg) mice in the forced swimming test, a test with high predictivity of antidepressant efficacy in human depression, and found an enhancement of the immobility time. In contrast, the motor function and anxiety-related emotional response of R406W Tg mice were normal. Furthermore, a selective serotonin reuptake inhibitor (SSRI), fluvoxamine (100 mg/kg, p.o.), significantly reduced this enhancement of the immobility time, whereas a noradrenaline reuptake inhibitor, desipramine, had no effect. In an in vivo microdialysis study, R406W Tg mice exhibited a significantly decreased extracellular 5-hydroxyindoleacetic acid (5-HIAA) level in the frontal cortex and also exhibited a tendency toward a decreased extracellular 5-hydroxytryptamine (5-HT) level. Moreover, fluvoxamine, which reduced the enhancement of the immobility time, significantly increased the extracellular 5-HT level in R406W Tg mice. These results suggest that R406W Tg mice exhibit changes in depression-related behavior involving serotonergic neurons and provide an animal model for investigating AD with depression.
10.1016/j.brainres.2005.08.004