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1.  The Fornix in Mild Cognitive Impairment and Alzheimer’s Disease 
The fornix is an integral white matter bundle located in the medial diencephalon and is part of the limbic structures. It serves a vital role in memory functions and as such has become the subject of recent research emphasis in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). As the characteristic pathological processes of AD progress, structural and functional changes to the medial temporal lobes and other regions become evident years before clinical symptoms are present. Though gray matter atrophy has been the most studied, degradation of white matter structures especially the fornix may precede these and has become detectable with use of diffusion tensor imaging (DTI) and other complimentary imaging techniques. Recent research utilizing DTI measurement of the fornix has shown good discriminability of diagnostic groups, particularly early and preclinical, as well as predictive power for incident MCI and AD. Stimulating and modulating fornix function by the way of DBS has been an exciting new area as pharmacological therapeutics has been slow to develop.
doi:10.3389/fnagi.2015.00001
PMCID: PMC4301006  PMID: 25653617
Alzheimer’s; MCI; fornix; DTI; DBS
2.  Moving Away from Amyloid Beta to Move on in Alzheimer Research 
doi:10.3389/fnagi.2015.00002
PMCID: PMC4302983  PMID: 25657623
Alzheimer’s disease; amyloid beta; bioenergetics; etiology; herpes simplex type 1
3.  Targeting Cholesterol Homeostasis to Fight Hearing Loss: A New Perspective 
Sensorineural hearing loss (SNHL) is a major pathology of the inner ear that affects nearly 600 million people worldwide. Despite intensive researches, this major health problem remains without satisfactory solutions. The pathophysiological mechanisms involved in SNHL include oxidative stress, excitotoxicity, inflammation, and ischemia, resulting in synaptic loss, axonal degeneration, and apoptosis of spiral ganglion neurons. The mechanisms associated with SNHL are shared with other neurodegenerative disorders. Cholesterol homeostasis is central to numerous pathologies including neurodegenerative diseases and cholesterol regulates major processes involved in neurons survival and function. The role of cholesterol homeostasis in the physiopathology of inner ear is largely unexplored. In this review, we discuss the findings concerning cholesterol homeostasis in neurodegenerative diseases and whether it should be translated into potential therapeutic strategies for the treatment of SNHL.
doi:10.3389/fnagi.2015.00003
PMCID: PMC4310297
sensorineural hearing loss; cholesterol homeostasis; liver X receptor; excitotoxicity; oxysterol
4.  Widespread Increase of Functional Connectivity in Parkinson’s Disease with Tremor: A Resting-State fMRI Study 
Parkinson’s disease (PD) is a clinically heterogeneous disease in the symptomatology dominated by tremor, akinesia, or rigidity. Focusing on PD patients with tremor, this study investigated their discoordination patterns of spontaneous brain activity by combining voxel-wise centrality, seed-based functional connectivity, and network efficiency methods. Sixteen patients and 20 matched healthy controls (HCs) were recruited and underwent structural and resting-state functional MRI scan. Compared with the HCs, the patients exhibited increased centrality in the frontal, parietal, and occipital regions while decreased centrality in the cerebellum anterior lobe and thalamus. Seeded at these regions, a distributed network was further identified that encompassed cortical (default mode network, sensorimotor cortex, prefrontal and occipital areas) and subcortical (thalamus and basal ganglia) regions and the cerebellum and brainstem. Graph-based analyses of this network revealed increased information transformation efficiency in the patients. Moreover, the identified network correlated with clinical manifestations in the patients and could distinguish the patients from HCs. Morphometric analyses revealed decreased gray matter volume in multiple regions that largely accounted for the observed functional abnormalities. Together, these findings provide a comprehensive view of network disorganization in PD with tremor and have important implications for understanding neural substrates underlying this specific type of PD.
doi:10.3389/fnagi.2015.00006
PMCID: PMC4315047
Parkinson’s disease; tremor; connectome; centrality; resting functional connectivity
5.  Self-reported physical activity and objective aerobic fitness: differential associations with gray matter density in healthy aging 
Aerobic fitness (AF) and self-reported physical activity (srPA) do not represent the same construct. However, many exercise and brain aging studies interchangeably use AF and srPA measures, which may be problematic with regards to how these metrics are associated with brain outcomes, such as morphology. If AF and PA measures captured the same phenomena, regional brain volumes associated with these measures should directly overlap. This study employed the general linear model to examine the differential association between objectively-measured AF (treadmill assessment) and srPA (questionnaire) with gray matter density (GMd) in 29 cognitively unimpaired community-dwelling older adults using voxel based morphometry. The results show significant regional variance in terms of GMd when comparing AF and srPA as predictors. Higher AF was associated with greater GMd in the cerebellum only, while srPA displayed positive associations with GMd in occipito-temporal, left perisylvian, and frontal regions after correcting for age. Importantly, only AF level, and not srPA, modified the relationship between age and GMd, such that higher levels of AF were associated with increased GMd in older age, while decreased GMd was seen in those with lower AF as a function of age. These results support existing literature suggesting that both AF and PA exert beneficial effects on GMd, but only AF served as a buffer against age-related GMd loss. Furthermore, these results highlight the need for use of objective PA measurement and comparability of tools across studies, since results vary dependent upon the measures used and whether these are objective or subjective in nature.
doi:10.3389/fnagi.2015.00005
PMCID: PMC4315095
physical activity; aerobic fitness; voxel based morphometry; healthy aging; MRI; gray matter density
6.  Fornix White Matter is Correlated with Resting-State Functional Connectivity of the Thalamus and Hippocampus in Healthy Aging but Not in Mild Cognitive Impairment – A Preliminary Study 
In this study, we wished to examine the relationship between the structural connectivity of the fornix, a white matter (WM) tract in the limbic system, which is affected in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease, and the resting-state functional connectivity (FC) of two key related subcortical structures, the thalamus, and hippocampus. Twenty-two older healthy controls (HC) and 18 older adults with aMCI underwent multi-modal MRI scanning. The fornix was reconstructed using constrained-spherical deconvolution-based tractography. The FC between the thalamus and hippocampus was calculated using a region-of-interest approach from which the mean time series were exacted and correlated. Diffusion tensor imaging measures of the WM microstructure of the fornix were correlated against the Fisher Z correlation values from the FC analysis. There was no difference between the groups in the fornix WM measures, nor in the resting-state FC of the thalamus and hippocampus. We did however find that the relationship between functional and structural connectivity differed significantly between the groups. In the HCs, there was a significant positive association between linear diffusion (CL) in the fornix and the FC of the thalamus and hippocampus, however, there was no relationship between these measures in the aMCI group. These preliminary findings suggest that in aMCI, the relationship between the functional and structural connectivity of regions of the limbic system may be significantly altered compared to healthy ageing. The combined use of diffusion weighted imaging and functional MRI may advance our understanding of neural network changes in aMCI, and elucidate subtle changes in the relationship between structural and functional brain networks.
doi:10.3389/fnagi.2015.00010
PMCID: PMC4318417
diffusion MRI; tractography; functional connectivity; fornix; mild cognitive impairment (MCI); hippocampus; thalamus
7.  Cochlear Injury and Adaptive Plasticity of the Auditory Cortex 
Growing evidence suggests that cochlear stressors as noise exposure and aging can induce homeostatic/maladaptive changes in the central auditory system from the brainstem to the cortex. Studies centered on such changes have revealed several mechanisms that operate in the context of sensory disruption after insult (noise trauma, drug-, or age-related injury). The oxidative stress is central to current theories of induced sensory-neural hearing loss and aging, and interventions to attenuate the hearing loss are based on antioxidant agent. The present review addresses the recent literature on the alterations in hair cells and spiral ganglion neurons due to noise-induced oxidative stress in the cochlea, as well on the impact of cochlear damage on the auditory cortex neurons. The emerging image emphasizes that noise-induced deafferentation and upward spread of cochlear damage is associated with the altered dendritic architecture of auditory pyramidal neurons. The cortical modifications may be reversed by treatment with antioxidants counteracting the cochlear redox imbalance. These findings open new therapeutic approaches to treat the functional consequences of the cortical reorganization following cochlear damage.
doi:10.3389/fnagi.2015.00008
PMCID: PMC4318425
presbycusis; noise-induced hearing loss; auditory cortex; pyramidal neurons; oxidative stress
8.  Assessing the emergence and reliability of cognitive decline over the life span in Fisher 344 rats using the spatial water maze 
The spatial water maze is routinely used to investigate hippocampal-dependent spatial memory and the biological mechanisms that underlie variability in cognitive decline during aging. The utility of the task for repeated testing in order to examine the trajectory of cognitive decline and to prescreen animals prior to therapeutic interventions maybe limited due to carryover effects of repeated training. The current study examines the role of carryover effects, as well as the reliability of individual differences, in determining age-related impairment on episodic and reference memory versions of the water maze task. Results indicate that impaired acquisition of episodic spatial information emerges in middle-age and the propensity for impairment increases with advancing age. While learning was variable across animals, acquisition deficits for episodic information were reliable across training sessions in middle-age and aged rats. A significant impairment in the 24~h retention of episodic spatial information was observed in aged animals. When animals were trained to the same location (i.e., reference memory), an impairment was limited to the rate of acquisition in aged animals. However, with continued training, all aged animals were able to acquire a reference memory and no age differences were observed in the 24~h retention of a spatial reference memory. Together, the results point to a progressive impairment in episodic spatial memory with advancing age and suggest that tests of episodic spatial memory are reliable and more sensitive than reference memory for detecting cognitive decline.
doi:10.3389/fnagi.2014.00002
PMCID: PMC3896816  PMID: 24478698
aging; F344 rats; hippocampus; episodic memory; reference memory; learning and memory; spatial water maze
9.  Environmental enrichment strengthens corticocortical interactions and reduces amyloid-β oligomers in aged mice 
Brain aging is characterized by global changes which are thought to underlie age-related cognitive decline. These include variations in brain activity and the progressive increase in the concentration of soluble amyloid-β (Aβ) oligomers, directly impairing synaptic function and plasticity even in the absence of any neurodegenerative disorder. Considering the high social impact of the decline in brain performance associated to aging, there is an urgent need to better understand how it can be prevented or contrasted. Lifestyle components, such as social interaction, motor exercise and cognitive activity, are thought to modulate brain physiology and its susceptibility to age-related pathologies. However, the precise functional and molecular factors that respond to environmental stimuli and might mediate their protective action again pathological aging still need to be clearly identified. To address this issue, we exploited environmental enrichment (EE), a reliable model for studying the effect of experience on the brain based on the enhancement of cognitive, social and motor experience, in aged wild-type mice. We analyzed the functional consequences of EE on aged brain physiology by performing in vivo local field potential (LFP) recordings with chronic implants. In addition, we also investigated changes induced by EE on molecular markers of neural plasticity and on the levels of soluble Aβ oligomers. We report that EE induced profound changes in the activity of the primary visual and auditory cortices and in their functional interaction. At the molecular level, EE enhanced plasticity by an upward shift of the cortical excitation/inhibition balance. In addition, EE reduced brain Aβ oligomers and increased synthesis of the Aβ-degrading enzyme neprilysin. Our findings strengthen the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes.
doi:10.3389/fnagi.2014.00001
PMCID: PMC3899529  PMID: 24478697
environmental enrichment; aging; cross-correlation; EEG; vGluT-1; vGAT; neprilysin; amyloid-β oligomers
10.  Increased Bilateral Interactions in Middle-Aged Subjects 
A hallmark of the age-related neural reorganization is that old versus young adults execute typical motor tasks by a more diffuse neural activation pattern including stronger ipsilateral activation during unilateral tasks. Whether such changes in neural activation are present already at middle age and affect bimanual interactions is unknown. We compared the amount of associated activity, i.e., muscle activity and force produced by the non-task hand and motor evoked potentials (MEPs) produced by magnetic brain stimulation between young (mean 24 years, n = 10) and middle-aged (mean 50 years, n = 10) subjects during brief unilateral (seven levels of % maximal voluntary contractions, MVCs) and bilateral contractions (4 × 7 levels of % MVC combinations), and during a 120-s-long MVC of sustained unilateral index finger abduction. During the force production, the excitability of the ipsilateral (iM1) or contralateral primary motor cortex (cM1) was assessed. The associated activity in the “resting” hand was ~2-fold higher in middle-aged (28% of MVC) versus young adults (11% of MVC) during brief unilateral MVCs. After controlling for the background muscle activity, MEPs in iM1 were similar in the two groups during brief unilateral contractions. Only at low (bilateral) forces, MEPs evoked in cM1 were 30% higher in the middle-aged versus young adults. At the start of the sustained contraction, the associated activity was higher in the middle-aged versus young subjects and increased progressively in both groups (30 versus 15% MVC at 120 s, respectively). MEPs were greater at the start of the sustained contraction in middle-aged subjects but increased further during the contraction only in young adults. Under these experimental conditions, the data provide evidence for the reorganization of neural control of unilateral force production as early as age 50. Future studies will determine if the altered neural control of such inter-manual interactions are of functional significance.
doi:10.3389/fnagi.2014.00005
PMCID: PMC3901301  PMID: 24478699
fatigue; associated muscle activity; middle-aged; bimanual interactions; ipsilateral corticospinal excitability
11.  Aspirin Promotes Oligodendrocyte Precursor Cell Proliferation and Differentiation after White Matter Lesion 
Cerebral white matter lesion (WML) is one of the main causes for cognitive impairment and is often caused by chronic cerebral hypoperfusion. A line of evidence has shown that aspirin has neuroprotective effects and produces some benefits in long-term outcome and survival for ischemic stroke patients. However, whether aspirin exerts a protective effect against WML is still largely unknown. Here, we showed that aspirin could promote oligodendrocyte precursor cell (OPC) proliferation and differentiation into oligodendrocytes after WML. Male Sprague-Dawley rats were subjected to permanent bilateral common carotid artery occlusion, a well-established model for WML. Four weeks later, Morris water maze test showed an impairment of learning and memory ability of rat while aspirin treatment improved behavioral performance. Low dose of aspirin (25 mg/kg) was found to elevate the number of OPCs while relatively high doses (100–200 mg/kg) increased that of oligodendrocytes, and ameliorated WML-induced the thinning of myelin, as revealed by the electron microscope. Similarly, our in vitro study also showed that relatively low and high doses of aspirin enhanced OPC proliferation and differentiation into oligodendrocytes, respectively. Furthermore, we revealed that aspirin enhanced extracellular signal-related kinase (ERK) but inhibited RhoA activities. In summary, we provided the first evidence that aspirin can promote oligodendrogenesis and oligodendrocyte myelination after WML, which may involve ERK and RhoA pathways.
doi:10.3389/fnagi.2014.00007
PMCID: PMC3902474  PMID: 24478700
aspirin; oligodendrocytes; oligodendrocyte precursor cells; white matter lesion; extracellular signal-related kinase; RhoA
12.  Memory loss in Alzheimer's disease: are the alterations in the UPR network involved in the cognitive impairment? 
doi:10.3389/fnagi.2014.00008
PMCID: PMC3906588  PMID: 24523695
Alzheimer's disease; UPR signaling pathways; memory; ER stress; memory impairment
13.  Exercise enhances memory consolidation in the aging brain 
Exercise has been shown to reduce age-related losses in cognitive function including learning and memory, but the mechanisms underlying this effect remain poorly understood. Memory formation occurs in stages that include an initial acquisition phase, an intermediate labile phase, and then a process of consolidation which leads to long-term memory formation. An effective way to examine the mechanism by which exercise improves memory is to introduce the intervention (exercise), post-acquisition, making it possible to selectively examine memory storage and consolidation. Accordingly we evaluated the effects of post-trial exercise (10 min on a treadmill) on memory consolidation in aged canines both right after, an hour after, and 24 h after acute exercise training in concurrent discrimination, object location memory (OLM), and novel object recognition tasks. Our study shows that post-trial exercise facilitates memory function by improving memory consolidation in aged animals in a time-dependent manner. The improvements were significant at 24 h post-exercise and not right after or 1 h after exercise. Aged animals were also tested following chronic exercise (10 min/day for 14 consecutive days) on OLM or till criterion were reached (for reversal learning task). We found improvements from a chronic exercise design in both the object location and reversal learning tasks. Our studies suggest that mechanisms to improve overall consolidation and cognitive function remain accessible even with progressing age and can be re-engaged by both acute and chronic exercise.
doi:10.3389/fnagi.2014.00003
PMCID: PMC3910002  PMID: 24550824
exercise; memory consolidation; aging; concurrent discrimination; object location; novel object recognition; reversal learning; dogs
14.  Dietary Mineral Intake and Risk of Mild Cognitive Impairment: The PATH through Life Project 
Background: Higher dietary intake of potassium, calcium, and magnesium is protective against ischemic strokes while also being associated with a decreased risk of all-cause dementia. The effect of dietary iron intake on cerebral function is less clear but iron is also implicated in Alzheimer neuropathology. The aim of this study was to investigate whether dietary intake of these minerals was also associated with increased risk of mild cognitive impairment (MCI, amnestic) and other mild cognitive disorders (MCD).
Methods: Associations between dietary mineral intake and risk of MCI/MCD were assessed in cognitively healthy individuals (n = 1406, 52% female, mean age 62.5 years) living in the community, who were followed up over 8 years. Relative risk was assessed with Cox hazard ratios (HRs) after controlling for health and socio-demographic covariates.
Results: Higher magnesium intake was associated with a reduced risk of developing MCI/MCD (MCI: HR 0.07, 95% confidence interval (CI) 0.01–0.56, p = 0.013; MCD: HR 0.47, 95% CI 0.22–0.99, p = 0.046) in multivariate analyses. Higher intake of potassium (MCI: HR 1.09, 95% CI 1.01–1.17, p = 0.028; MCD: HR 1.05, 95% CI 0.99–1.10, p = 0.107) and iron (MCI: HR 1.54, 95% CI 1.03–2.29, p = 0.034) was associated with an increased risk of developing MCI/MCD.
Conclusion: These findings suggest that dietary intake of minerals known to be implicated in biological processes associated with vascular and Alzheimer’s pathology may contribute to disease progression earlier in the disease process and require further attention.
doi:10.3389/fnagi.2014.00004
PMCID: PMC3912433  PMID: 24550825
magnesium; potassium; calcium; iron; dementia
15.  Relative power and coherence of EEG series are related to amnestic mild cognitive impairment in diabetes 
Objective: Diabetes is a risk factor for dementia and mild cognitive impairment. The aim of this study was to investigate whether some features of resting-state EEG (rsEEG) could be applied as a biomarker to distinguish the subjects with amnestic mild cognitive impairment (aMCI) from normal cognitive function in type 2 diabetes.
Materials and Methods: In this study, 28 patients with type 2 diabetes (16 aMCI patients and 12 controls) were investigated. Recording of the rsEEG series and neuropsychological assessments were performed. The rsEEG signal was first decomposed into delta, theta, alpha, beta, gamma frequency bands. The relative power of each given band/sum of power and the coherence of waves from different brain areas were calculated. The extracted features from rsEEG and neuropsychological assessments were analyzed as well.
Results: The main findings of this study were that: (1) compared with the control group, the ratios of power in theta band [P(theta)] vs. power in alpha band [P(alpha)] [P(theta)/P(alpha)] in the frontal region and left temporal region were significantly higher for aMCI, and (2) for aMCI, the alpha coherences in posterior, fronto-right temporal, fronto-posterior, right temporo-posterior were decreased; the theta coherences in left central-right central (LC-RC) and left posterior-right posterior (LP-RP) regions were also decreased; but the delta coherences in left temporal-right temporal (LT-RT) region were increased.
Conclusion: The proposed indexes from rsEEG recordings could be employed to track cognitive function of diabetic patients and also to help in the diagnosis of those who develop aMCI.
doi:10.3389/fnagi.2014.00011
PMCID: PMC3912457  PMID: 24550827
resting-state EEG; amnestic mild cognitive impairment; diabetes; relative power; coherence
16.  Network-Based Biomarkers in Alzheimer’s Disease: Review and Future Directions 
By 2050 it is estimated that the number of worldwide Alzheimer’s disease (AD) patients will quadruple from the current number of 36 million people. To date, no single test, prior to postmortem examination, can confirm that a person suffers from AD. Therefore, there is a strong need for accurate and sensitive tools for the early diagnoses of AD. The complex etiology and multiple pathogenesis of AD call for a system-level understanding of the currently available biomarkers and the study of new biomarkers via network-based modeling of heterogeneous data types. In this review, we summarize recent research on the study of AD as a connectivity syndrome. We argue that a network-based approach in biomarker discovery will provide key insights to fully understand the network degeneration hypothesis (disease starts in specific network areas and progressively spreads to connected areas of the initial loci-networks) with a potential impact for early diagnosis and disease-modifying treatments. We introduce a new framework for the quantitative study of biomarkers that can help shorten the transition between academic research and clinical diagnosis in AD.
doi:10.3389/fnagi.2014.00012
PMCID: PMC3912507  PMID: 24550828
Alzheimer’s disease; network degeneration hypothesis; network-based biomarkers; default-mode network DMN; resting-state functional connectivity
17.  The impact of age on load-related dorsolateral prefrontal cortex activation 
Healthy aging is accompanied by working memory-related functional cerebral changes. Depending on performance accuracy and the level of working memory demands, older adults show task-related patterns of either increased or decreased activation compared to younger adults. Controversies remain concerning the interpretation of these changes and whether they already manifest in earlier decades of life. To address these issues, functional magnetic resonance imaging (fMRI) was used to examine brain activation during spatial working memory retrieval in 45 healthy individuals between 20 and 68 years of age. Participants performed a modified version of the Corsi Block-Tapping test (CBT). The CBT requires the storage and subsequent reproduction of spatial target sequences and allows modulating working memory load by a variation of sequence length. Results revealed that activation intensity at the lowest CBT load level increased with increasing age and positively correlated with the number of errors. At higher CBT load levels, activation intensity decreased with increasing age together with a disproportional accuracy decline on the behavioral level. Moreover, results suggests that younger individuals showed higher activation intensity at high CBT load than at low CBT load switching to the opposite pattern at an age of about 40 years. Consistent with the assumptions of the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH), the present results reveal specific age-related alterations in left dorsolateral prefrontal cortex activation in response to increasing task load. Specifically, the results point toward increasing neural inefficiency with age at low task load and a progressive limitation of resources with age at higher task load. The present findings argue for an increasing functional cerebral dysfunction over a time span of 50 years that may partly be compensated on the behavioral level until a resource ceiling is approached.
doi:10.3389/fnagi.2014.00009
PMCID: PMC3913830  PMID: 24550826
aging; CRUNCH; functional magnetic resonance imaging; prefrontal cortex; dorsolateral prefrontal cortex; spatial working memory; executive functioning; Corsi
18.  Development and Decline of Upright Gait Stability 
Upright gait is a peculiar characteristic of humans that requires the ability to manage upper body dynamic balance while walking, despite the perturbations that are generated by movements of the lower limbs. Most of the studies on upright gait stability have compared young adults and the elderly to determine the effects of aging. In other studies, the comparison was between healthy subjects and patients to examine specific pathologies. Fewer researches have also investigated the development of upright gait stability in children. This review discusses these studies in order to provide an overview of this relevant aspect of human locomotion. A clear trend from development to decline of upright gait stability has been depicted across the entire lifespan, from toddlers at first steps to elderly. In old individuals, even if healthy, the deterioration of skeletal muscle, combined with sensorial and cognitive performance, reduces the ability to maintain an upright trunk during walking, increasing the instability and the risk of falls. Further, the pathological causes of altered development or of a sudden loss of gait stability, as well as the environmental influence are investigated. The last part of this review is focused on the control of upper body accelerations during walking, a particularly interesting topic for the recent development of low-cost wearable accelerometers.
doi:10.3389/fnagi.2014.00014
PMCID: PMC3913994  PMID: 24550829
locomotion; walking; balance; falls; accelerometry; motor control; aging; neuromuscular diseases
19.  Retinoic acid modulates intrahippocampal levels of corticosterone in middle-aged mice: consequences on hippocampal plasticity and contextual memory 
It is now established that vitamin A and its derivatives, retinoic acid (RA), are required for cognitive functions in adulthood. RA hyposignaling and hyperactivity of glucocorticoid (GC) pathway appear concomitantly during aging and would contribute to the deterioration of hippocampal synaptic plasticity and functions. Furthermore, recent data have evidenced counteracting effects of retinoids on GC signaling pathway. In the present study, we addressed the following issue: whether the stimulation of RA pathway could modulate intrahippocampal corticosterone (CORT) levels in middle-aged mice and thereby impact on hippocampal plasticity and cognitive functions. We firstly investigated the effects of vitamin A supplementation and RA treatment in middle-aged mice, on contextual serial discrimination task, a paradigm which allows the detection of early signs of age-related hippocampal-dependent memory dysfunction. We then measured intrahippocampal CORT concentrations by microdialysis before and after a novelty-induced stress. Our results show that both RA treatment and vitamin A supplementation improve “episodic-like” memory in middle-aged mice but RA treatment appears to be more efficient. Moreover, we show that the beneficial effect of RA on memory is associated to an increase in hippocampal PSD-95 expression. In addition, intrahippocampal CORT levels are reduced after novelty-induced stress in RA-treated animals. This effect cannot be related to a modulation of hippocampal 11β-HSD1 expression. Interestingly, RA treatment induces a modulation of RA receptors RARα and RARβ expression in middle-aged mice, a finding which has been correlated with the amplitude of intrahippocampal CORT levels after novelty-induced stress. Taken together, our results suggest that the preventive action of RA treatment on age-related memory deficits in middle-aged mice could be, at least in part, due to an inhibitory effect of retinoids on GC activity.
doi:10.3389/fnagi.2014.00006
PMCID: PMC3917121  PMID: 24570662
vitamin A; retinoic acid; corticosterone; memory; hippocampal plasticity
20.  Chronic cerebral hypoperfusion causes decrease of O-GlcNAcylation, hyperphosphorylation of tau and behavioral deficits in mice 
Chronic cerebral hypoperfusion (CCH) is one of the causes of vascular dementia (VaD) and is also an etiological factor for Alzheimer’s disease (AD). However, how CCH causes cognitive impairment and contributes to Alzheimer’s pathology is poorly understood. Here we produced a mouse model of CCH by unilateral common carotid artery occlusion (UCCAO) and studied the behavioral changes and brain abnormalities in mice 2.5 months after UCCAO. We found that CCH caused significant short-term memory deficits and mild long-term spatial memory impairment, as well as decreased level of protein O-GlcNAcylation, increased level of tau phosphorylation, dysregulated synaptic proteins and insulin signaling, and selective neurodegeneration in the brain. These findings provide mechanistic insight into the effects of CCH on memory and cognition and the likely link between AD and VaD.
doi:10.3389/fnagi.2014.00010
PMCID: PMC3918671  PMID: 24575038
chronic cerebral hypoperfusion; Alzheimer’s disease; cognitive impairment; O-GlcNAcylation; tau phosphorylation; synaptic plasticity markers; brain insulin signaling; neurodegeneration
21.  Increased metal content in the TDP-43A315T transgenic mouse model of frontotemporal lobar degeneration and amyotrophic lateral sclerosis 
Disrupted metal homeostasis is a consistent feature of neurodegenerative disease in humans and is recapitulated in mouse models of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and neuronal ceriod lipofuscinosis. While the definitive pathogenesis of neurodegenerative disease in humans remains to be fully elucidated, disease-like symptoms in the mouse models are all driven by the presence or over-expression of a putative pathogenic protein, indicating an in vivo relationship between expression of these proteins, disrupted metal homeostasis and the symptoms of neuronal failure. Recently it was established that mutant TAR DNA binding protein-43 (TDP-43) is associated with the development of frontotemporal lobar degeneration and ALS. Subsequent development of transgenic mice that express human TDP-43 carrying the disease-causing A315T mutation has provided new opportunity to study the underlying mechanisms of TDP-43-related neurodegenerative disease. We assessed the cognitive and locomotive phenotype of TDP-43 A315T mice and their wild-type littermates and also assessed bulk metal content of brain and spinal cord tissues. Metal levels in the brain were not affected by the expression of mutant TDP-43, but zinc, copper, and manganese levels were all increased in the spinal cords of TDP-43 A315T mice when compared to wild-type littermates. Performance of the TDP-43 A315T mice in the Y-maze test for cognitive function was not significantly different to wild-type mice. By contrast, performance of the TDP-43 A315T in the rotarod test for locomotive function was consistently worse than wild-type mice. These preliminary in vivo data are the first to show that expression of a disease-causing form of TDP-43 is sufficient to disrupt metal ion homeostasis in the central nervous system. Disrupted metal ion homeostasis in the spinal cord but not the brain may explain why the TDP-43 A315T mice show symptoms of locomotive decline and not cognitive decline.
doi:10.3389/fnagi.2014.00015
PMCID: PMC3920072  PMID: 24575040
amyotrophic lateral sclerosis (ALS); frontotemporal lobar degeneration (FTLD); TAR DNA binding protein-43 (TDP-43); copper (Cu); zinc (Zn); manganese (Mn); neurodegenerative disease
22.  Aged rats are hypo-responsive to acute restraint: implications for psychosocial stress in aging 
Cognitive processes associated with prefrontal cortex and hippocampus decline with age and are vulnerable to disruption by stress. The stress/stress hormone/allostatic load hypotheses of brain aging posit that brain aging, at least in part, is the manifestation of life-long stress exposure. In addition, as humans age, there is a profound increase in the incidence of new onset stressors, many of which are psychosocial (e.g., loss of job, death of spouse, social isolation), and aged humans are well-understood to be more vulnerable to the negative consequences of such new-onset chronic psychosocial stress events. However, the mechanistic underpinnings of this age-related shift in chronic psychosocial stress response, or the initial acute phase of that chronic response, have been less well-studied. Here, we separated young (3 month) and aged (21 month) male F344 rats into control and acute restraint (an animal model of psychosocial stress) groups (n = 9–12/group). We then assessed hippocampus-associated behavioral, electrophysiological, and transcriptional outcomes, as well as blood glucocorticoid and sleep architecture changes. Aged rats showed characteristic water maze, deep sleep, transcriptome, and synaptic sensitivity changes compared to young. Young and aged rats showed similar levels of distress during the 3 h restraint, as well as highly significant increases in blood glucocorticoid levels 21 h after restraint. However, young, but not aged, animals responded to stress exposure with water maze deficits, loss of deep sleep and hyperthermia. These results demonstrate that aged subjects are hypo-responsive to new-onset acute psychosocial stress, which may have negative consequences for long-term stress adaptation and suggest that age itself may act as a stressor occluding the influence of new onset stressors.
doi:10.3389/fnagi.2014.00013
PMCID: PMC3921565  PMID: 24575039
psychosocial stress; aging; cognition; hippocampus; bioinformatics; sleep stages
23.  Cognitive decline due to excess synaptic Zn2+ signaling in the hippocampus 
Zinc is an essential component of physiological brain function. Vesicular zinc is released from glutamatergic (zincergic) neuron terminals and serves as a signal factor (Zn2+ signal) in both the intracellular (cytosol) compartment and the extracellular compartment. Synaptic Zn2+ signaling is dynamically linked to neurotransmission and is involved in processes of synaptic plasticity such as long-term potentiation and cognitive activity. On the other hand, the activity of the hypothalamic–pituitary–adrenal (HPA) axis, i.e., glucocorticoid secretion, which can potentiate glutamatergic neuron activity, is linked to cognitive function. HPA axis activity modifies synaptic Zn2+ dynamics at zincergic synapses. An increase in HPA axis activity, which occurs after exposure to stress, may induce excess intracellular Zn2+ signaling in the hippocampus, followed by hippocampus-dependent memory deficit. Excessive excitation of zincergic neurons in the hippocampus can contribute to cognitive decline under stressful and/or pathological conditions. This paper provides an overview of the ``Hypothesis and Theory'' of Zn2+-mediated modification of cognitive activity.
doi:10.3389/fnagi.2014.00026
PMCID: PMC3936311  PMID: 24578691
Zn2+ signal; hippocampus; cognition; glucocorticoid; glutamate
24.  Age-related impairments in active learning and strategic visual exploration 
Old age could impair memory by disrupting learning strategies used by younger individuals. We tested this possibility by manipulating the ability to use visual-exploration strategies during learning. Subjects controlled visual exploration during active learning, thus permitting the use of strategies, whereas strategies were limited during passive learning via predetermined exploration patterns. Performance on tests of object recognition and object-location recall was matched for younger and older subjects for objects studied passively, when learning strategies were restricted. Active learning improved object recognition similarly for younger and older subjects. However, active learning improved object-location recall for younger subjects, but not older subjects. Exploration patterns were used to identify a learning strategy involving repeat viewing. Older subjects used this strategy less frequently and it provided less memory benefit compared to younger subjects. In previous experiments, we linked hippocampal-prefrontal co-activation to improvements in object-location recall from active learning and to the exploration strategy. Collectively, these findings suggest that age-related memory problems result partly from impaired strategies during learning, potentially due to reduced hippocampal-prefrontal co-engagement.
doi:10.3389/fnagi.2014.00019
PMCID: PMC3924049  PMID: 24592236
active learning; memory; aging; age-related memory impairment; vicarious trial-and-error behavior; hippocampus; prefrontal cortex; revisitation
25.  Hijacking PrPc-dependent signal transduction: when prions impair Aβ clearance 
The cellular prion protein PrPc is the normal counterpart of the scrapie prion protein PrP Sc, the main component of the infectious agent of transmissible spongiform encephalopathies. The recent discovery that PrP c can serve as a receptor for the amyloid beta (Aβ) peptide and relay its neurotoxicity is sparking renewed interest on this protein and its involvement in signal transduction processes. Disease-associated PrP Sc shares with Aβ the ability to hijack PrP c-dependent signaling cascades, and thereby instigate pathogenic events. Among these is an impairment of Aβ clearance, uncovered in prion-infected neuronal cells. These findings add another facet to the intricate interplay between PrP c and Aβ. Here, we summarize the connection between PrP-mediated signaling and Aβ clearance and discuss its pathological implications.
doi:10.3389/fnagi.2014.00025
PMCID: PMC3938157  PMID: 24592237
cellular prion protein; prion infection; Aβ clearance; signal transduction; Alzheimer’s disease

Results 1-25 (561)