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The impact of age on load-related dorsolateral prefrontal cortex activation.

ABSTRACT: 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.

SUBMITTER: Toepper M

PROVIDER: S-EPMC3913830 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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The impact of age on load-related dorsolateral prefrontal cortex activation.

Toepper Max M Gebhardt Helge H Bauer Eva E Haberkamp Anke A Beblo Thomas T Gallhofer Bernd B Driessen Martin M Sammer Gebhard G

Frontiers in aging neuroscience 20140205

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 act ...[more]

PMID: 24550826

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Project description:BackgroundMethamphetamine (MA), is an extremely addictive stimulant that adversely affects the central nervous system. Accumulating evidence indicates that molecular mechanisms such as oxidative stress, apoptosis, and autophagy are involved in the toxicity of MA. Considering experimental animal studies exhibiting MA-induced neurotoxicity, the relevance of these findings needs to be evidently elucidated in human MA users. It is generally assumed that multiple chemical substances released in the brain following MA-induced metabolic activation are primary factors underlying damage of neural cells. Hence, this study aimed to investigate the role of autophagy and apoptosis as well as oxidative stress in the brain of postmortem MA-induced toxicity.Materials and methodsIn this study, we determine the gene expression of autophagy and apoptosis, including BECN1, MAP1ALC3, CASP8, TP53, and BAX genes in ten healthy controls and ten chronic users of MA postmortem dorsolateral prefrontal cortex (DLPFC) by real-time polymerase chain reaction. Also, we applied immunohistochemistry in formalin-fixed and paraffin-embedded human brain samples to analyze brain-derived neurotrophic factor (BDNF). Also, spectrophotometry was performed to measure glutathione (GSH) content.ResultsThe expression level of apoptotic and autophagic genes (BECN1, MAP1ALC3, CASP8, TP53, and BAX) were significantly elevated, while GSH content and BDNF showed substantial reductions in DLPFC of chronic MA users. Discussion: Our data showed that MA addiction provokes transduction pathways, namely apoptosis and autophagy, along with oxidative mechanisms in DLPFC. Also, MA induces multiple functional and structural perturbations in the brain, determining its toxicity and possibly contributing to neurotoxicity.DiscussionOur study showed BDNF-positive cells as well as GSH amount, displayed significant declines in DLPFC of MA user. MA addiction provokes transduction pathways, namely apoptosis and autophagy, along with oxidative mechanisms in DLPFC. However, further investigations are needed to throw light on the cellular and molecular mechanisms that act in the various regions of the addicted brain, especially in DLPFC.

Project description:In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in gamma-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex- and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD(67)) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA(A) receptor subunits (alpha1, alpha4, beta3, gamma2 and delta). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD(67), SST and alpha1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCK-containing subpopulations of GABA neurons and in the signaling via certain GABA(A) receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.

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The impact of age on load-related dorsolateral prefrontal cortex activation.

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The impact of age on load-related dorsolateral prefrontal cortex activation.

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