Age and Environment Influences on Mouse Prion Disease Progression: Behavioral Changes and Morphometry and Stereology of Hippocampal Astrocytes

Because enriched environment (EE) and exercise increase and aging decreases immune response, we hypothesized that environmental enrichment and aging will, respectively, delay and increase prion disease progression. Mice dorsal striatum received bilateral stereotaxic intracerebral injections of normal or ME7 prion infected mouse brain homogenates. After behavior analysis, animals were euthanized and their brains processed for astrocyte GFAP immunolabeling. Our analysis related to the environmental influence are limited to young adult mice, whereas age influence refers to aged mice raised on standard cages. Burrowing activity began to reduce in ME7-SE two weeks before ME7-EE, while no changes were apparent in ME7 aged mice (ME7-A). Object placement recognition was impaired in ME7-SE, NBH-A, and ME7-A but normal in all other groups. Object identity recognition was impaired in ME7-A. Cluster analysis revealed two morphological families of astrocytes in NBH-SE animals, three in NBH-A and ME7-A, and four in NBH-EE, ME7-SE, and ME7-EE. As compared with control groups, astrocytes from DG and CA3 prion-diseased animals show significant numerical and morphological differences and environmental enrichment did not reverse these changes but induced different morphological changes in GFAP+ hippocampal astroglia. We suggest that environmental enrichment and aging delayed hippocampal-dependent behavioral and neuropathological signs of disease progression.

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Limbic Encephalitis Brain Damage Induced by Cocal Virus in Adult Mice Is Reduced by Environmental Enrichment: Neuropathological and Behavioral Studies

Viruses ◽

10.3390/v13010048 ◽

2020 ◽

Vol 13 (1) ◽

pp. 48

Author(s):

Priscilla dos Santos Lieuthier Freitas ◽

Ana Victória de Lima Lima ◽

Karina Glazianne Barbosa Carvalho ◽

Tatyane da Silva Cabral ◽

Alexandre Maia de Farias ◽

...

Keyword(s):

Disease Progression ◽

Environmental Enrichment ◽

Limbic Encephalitis ◽

Morphological Changes ◽

Experimental Models ◽

Behavioral Changes ◽

Cytokine Concentration ◽

Morphological Response ◽

Viral Antigens ◽

Adult Mice

We previously demonstrated, using the Piry virus model, that environmental enrichment promotes higher T-cell infiltration, fewer microglial changes, and faster central nervous system (CNS) virus clearance in adult mice. However, little is known about disease progression, behavioral changes, CNS cytokine concentration, and neuropathology in limbic encephalitis in experimental models. Using Cocal virus, we infected C57Bl6 adult mice and studied the neuroanatomical distribution of viral antigens in correlation with the microglial morphological response, measured the CNS cytokine concentration, and assessed behavioral changes. C57Bl6 adult mice were maintained in an impoverished environment (IE) or enriched environment (EE) for four months and then subjected to the open field test. Afterwards, an equal volume of normal or virus-infected brain homogenate was nasally instilled. The brains were processed to detect viral antigens and microglial morphological changes using selective immunolabeling. We demonstrated earlier significant weight loss and higher mortality in IE mice. Additionally, behavioral analysis revealed a significant influence of the environment on locomotor and exploratory activity that was associated with less neuroinvasion and a reduced microglial response. Thus, environmental enrichment was associated with a more effective immune response in a mouse model of limbic encephalitis, allowing faster viral clearance/decreased viral dissemination, reduced disease progression, and less CNS damage.

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Maternal care and environmental enrichment influences on serotonin knockout mice with implications for a gene x stress model of autism

10.32469/10355/72196 ◽

2019 ◽

Author(s):

◽

Briana M. Kille

Keyword(s):

Serotonin Transporter ◽

Maternal Care ◽

Environmental Enrichment ◽

Environmental Influence ◽

Repetitive Behavior ◽

Critical Time ◽

University Of Missouri ◽

Time Period ◽

Maternal Genotype ◽

The University

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Previous research has shown a genetic variant in the serotonin transporter gene (Slc6a4) can increase the severity of a person's reaction to stress. This variant interacts with environmental stressors resulting in poorer health outcomes. Previous studies have also found that stressing pregnant mothers who carry the variant can result in an increased likelihood of autism diagnosis for the child. This maternal genotype x prenatal stress interaction has been modeled in the serotonin transporter knockout (SERT KO) mouse--dams genetically modified to mimic humans carrying the short allele were stressed during pregnancy resulting in offspring showing altered social behavior, repetitive behavior, and anxiety behavior. The first study included in this dissertation attempted to replicate this model while using a foster dam paradigm to avoid potential maternal care confounds. Surprisingly, the results showed that equalizing maternal care equalized several group differences in behavior. It is theorized that this is due to elimination of the neonatal insult from poor maternal care that would correspond to a human prenatal insult during a previously identified critical time period. The second study explored the potential effects environmentally enriched home cages on anxiety like behaviors of SERT KO mice. The study showed that all animals, regardless of genotype, showed fewer anxiety like behaviors in the open field assay. Together, these studies expand on our understanding of environmental influence on SERT KO mice used in translational studies.

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Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.796635 ◽

2021 ◽

Vol 15 ◽

Author(s):

Eduard Bentea ◽

Laura De Pauw ◽

Lise Verbruggen ◽

Lila C. Winfrey ◽

Lauren Deneyer ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Proteasome Inhibition ◽

Cell Loss ◽

Redox Balance ◽

Nigrostriatal Pathway ◽

Knock Out ◽

Aged Mice ◽

Adult Mice ◽

Age Related ◽

Nigrostriatal Degeneration

The astrocytic cystine/glutamate antiporter system xc– (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson’s disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT–/–) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT+/+) littermates. Contrary to adult mice, aged xCT–/– mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT+/+ littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT–/– mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice (Bentea et al., 2015a), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT–/– mice when compared to age-matched xCT+/+ littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT–/– mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system xc– in mechanisms of dopaminergic cell loss and its interaction with aging.

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Abstract TP78: Combination of Neuroprotective Drug and Neural Stem Cells Benefits Aged Stroke Mice with Delayed Tissue Plasminogen Activator Treatment

Stroke ◽

10.1161/str.48.suppl_1.tp78 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Auston Eckert ◽

Milton H Hamblin ◽

Jean-Pyo Lee

Keyword(s):

Stem Cells ◽

Young Adult ◽

Neural Stem Cells ◽

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Inflammatory Drug ◽

Aged Mice ◽

Post Stroke ◽

Adult Mice ◽

Tissue Plasminogen

Background: Presently, tissue plasminogen activator (tPA) is the sole FDA-approved antithrombotic treatment available for stroke. However, tPA’s harmful side effects within the central nervous system can exacerbate blood-brain barrier (BBB) damage and increase mortality. Patients should receive tPA less than 4.5 hours post-stroke. Although age alone is not an impediment for tPA treatment, the harmful effects of delayed tPA (>4.5h), particularly on aged stroke animals, have not been well studied. We reported that intracranial transplantation of neural stem cells (hNSCs) ameliorates BBB damage caused by ischemic stroke. In this study, we examined the combined effects of minocycline (a neuroprotective and anti-inflammatory drug) and hNSC transplantation on the mortality of delayed tPA-treated aged mice within 48h post-stroke. Methods and Results: We utilized the middle cerebral artery occlusion stroke mouse model to induce focal cerebral ischemia followed by reperfusion (MCAO/R). 6h post-MCAO, we administered tPA intravenously. Minocycline was administered intraperitoneally at various time points prior to tPA injection. One day post-stroke, we injected hNSCs intracranially. Previously, we reported that hNSCs (both human and mouse) transplanted into the brain 24h post-stroke rapidly improve neurological outcome in young-adult mice (4-5mo). In our current study, tPA administered within 4.5h did not increase mortality in either young-adult or aged mice. However, we found delayed tPA treatment (6h post-stroke) significantly increased the mortality of aged mice (13-18 mo) but not in young-adult mice. Here, we report that by combining minocycline prior to tPA significantly reduced mortality. Furthermore, transplanting hNSCs in minocycline-treated mice further ameliorated the pathophysiology caused by delayed tPA. Conclusions: Our findings implicate that administering the anti-apototic and anti-inflammatory drug prior to tPA injection, and then post-treating with multipotent neuroprotective hNSCs might expand the time window of tPA and reduce reperfusion injury.

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S15-2Effects of environmental enrichment upon ethanol-induced conditioned place preference and BDNF levels in adolescent and adult mice

Alcohol and Alcoholism ◽

10.1093/alcalc/agx075.56 ◽

2017 ◽

Vol 52 (suppl_1) ◽

pp. i4-i30

Author(s):

R Camarini ◽

A.B. Suárez ◽

L.B. Hoffmann ◽

A.V. Rueda ◽

M.B. Rae ◽

...

Keyword(s):

Conditioned Place Preference ◽

Environmental Enrichment ◽

Place Preference ◽

Adult Mice

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Aging Influences the Metabolic and Inflammatory Phenotype in an Experimental Mouse Model of Acute Lung Injury

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa248 ◽

2020 ◽

Author(s):

Kevin W Gibbs ◽

Chia-Chi Chuang Key ◽

Lanazha Belfield ◽

Jennifer Krall ◽

Lina Purcell ◽

...

Keyword(s):

Acute Lung Injury ◽

Fatty Acid ◽

Lung Injury ◽

Whole Body ◽

Acid Oxidation ◽

Aged Mice ◽

Protein Levels ◽

Adult Mice ◽

Age Related ◽

Before And After

Abstract Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 months) and aged (18–20 months) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO on survival from acute severe stress and suggesting that adult mice have increased resilience to FAO inhibition. Skeletal muscles from aged ALI mice had increased transcription of key fatty acid metabolizing enzymes, CPT-1b, LCAD, MCAD, FATP1 and UCP3. Additionally, aged mice had increased protein levels of CPT-1b at baseline and after lung injury. Surprisingly, CPT-1b in isolated skeletal muscle mitochondria had decreased activity in aged mice compared to adults. The distinct phenotype of aged ALI mice has similar characteristics to the adverse age-related outcomes of ARDS. This model may be useful to examine and augment immunologic and metabolic abnormalities unique to the critically ill aged population.

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BACE1 partial deletion induces synaptic plasticity deficit in adult mice

Scientific Reports ◽

10.1038/s41598-019-56329-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Sylvia Lombardo ◽

Martina Chiacchiaretta ◽

Andrew Tarr ◽

WonHee Kim ◽

Tingyi Cao ◽

...

Keyword(s):

Synaptic Plasticity ◽

Long Term Potentiation ◽

Axonal Guidance ◽

Knock Out ◽

App Processing ◽

Aged Mice ◽

Adult Mice ◽

Term Potentiation ◽

Partial Depletion

AbstractBACE1 is the first enzyme involved in APP processing, thus it is a strong therapeutic target candidate for Alzheimer’s disease. The observation of deleterious phenotypes in BACE1 Knock-out (KO) mouse models (germline and conditional) raised some concerns on the safety and tolerability of BACE1 inhibition. Here, we have employed a tamoxifen inducible BACE1 conditional Knock-out (cKO) mouse model to achieve a controlled partial depletion of BACE1 in adult mice. Biochemical and behavioural characterization was performed at two time points: 4–5 months (young mice) and 12–13 months (aged mice). A ~50% to ~70% BACE1 protein reduction in hippocampus and cortex, respectively, induced a significant reduction of BACE1 substrates processing and decrease of Aβx-40 levels at both ages. Hippocampal axonal guidance and peripheral nerve myelination were not affected. Aged mice displayed a CA1 long-term potentiation (LTP) deficit that was not associated with memory impairment. Our findings indicate that numerous phenotypes observed in germline BACE1 KO reflect a fundamental role of BACE1 during development while other phenotypes, observed in adult cKO, may be absent when partially rather than completely deleting BACE1. However, we demonstrated that partial depletion of BACE1 still induces CA1 LTP impairment, supporting a role of BACE1 in synaptic plasticity in adulthood.

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Environmental enrichment is associated with rapid volumetric brain changes in adult mice

NeuroImage ◽

10.1016/j.neuroimage.2015.01.027 ◽

2015 ◽

Vol 109 ◽

pp. 190-198 ◽

Cited By ~ 41

Author(s):

Jan Scholz ◽

Rylan Allemang-Grand ◽

Jun Dazai ◽

Jason P. Lerch

Keyword(s):

Environmental Enrichment ◽

Adult Mice ◽

Brain Changes

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Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1525474113 ◽

2016 ◽

Vol 113 (28) ◽

pp. E4061-E4068 ◽

Cited By ~ 52

Author(s):

Reitaro Tokumasu ◽

Kosuke Yamaga ◽

Yuji Yamazaki ◽

Hiroyuki Murota ◽

Koya Suzuki ◽

...

Keyword(s):

Atopic Dermatitis ◽

Morphological Changes ◽

Contact Hypersensitivity ◽

Expression Level ◽

Barrier Functions ◽

Knock Out ◽

Macrophage Recruitment ◽

Adult Mice ◽

Dose Dependent

Atopic dermatitis (AD) is a chronic inflammatory skin disease in humans. It was recently noted that the characteristics of epidermal barrier functions critically influence the pathological features of AD. Evidence suggests that claudin-1 (CLDN1), a major component of tight junctions (TJs) in the epidermis, plays a key role in human AD, but the mechanism underlying this role is poorly understood. One of the main challenges in studying CLDN1's effects is that Cldn1 knock-out mice cannot survive beyond 1 d after birth, due to lethal dehydration. Here, we established a series of mouse lines that express Cldn1 at various levels and used these mice to study Cldn1’s effects in vivo. Notably, we discovered a dose-dependent effect of Cldn1’s expression in orchestrating features of AD. In our experimental model, epithelial barrier functions and morphological changes in the skin varied exponentially with the decrease in Cldn1 expression level. At low Cldn1 expression levels, mice exhibited morphological features of AD and an innate immune response that included neutrophil and macrophage recruitment to the skin. These phenotypes were especially apparent in the infant stages and lessened as the mice became adults, depending on the expression level of Cldn1. Still, these adult mice with improved phenotypes showed an enhanced hapten-induced contact hypersensitivity response compared with WT mice. Furthermore, we revealed a relationship between macrophage recruitment and CLDN1 levels in human AD patients. Our findings collectively suggest that CLDN1 regulates the pathogenesis, severity, and natural course of human AD.

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