Animals can use a range of strategies to recall important locations. These include simple stimulus–response strategies and more complex spatial (place) strategies, which are thought to have distinct ...neural substrates. The hippocampus—and NMDA receptor activation therein—is considered to be crucial for spatial, but not response strategies. The medial prefrontal cortex has also been implicated in memory retrieval; however, evidence concerning its specific role is equivocal. Both hippocampal and prefrontal regions have been associated with flexible behavioural responding (e.g. when task demands change). Here, we investigated the use of spatial and non‐spatial strategies in the Morris water maze and their associated brain areas in rats using immediate early gene (IEG) imaging of Zif268 and c‐Fos. Specifically, we charted the involvement of hippocampal and prefrontal subregions during retrieval of spatial and non‐spatial memories. Behavioural flexibility was also examined using intact and partial cue configurations during recall. Results indicated that regions of both the hippocampus (area CA3) and prefrontal cortex (anterior cingulate cortex) were preferentially engaged in spatial memory recall compared to response learning. In addition, both spatial and non‐spatial memories were dependent on NMDA receptor activation. MK801 impaired recall performance across all groups and reduced IEG activation across hippocampal and prefrontal regions. Finally, IEG results revealed divergent patterns of Zif268 and c‐Fos activity and support the suggestion that Zif268 plays a functional role in the recall of long‐term memories.
We examined the role of hippocampal and prefrontal subregions in spatial and non‐spatial memory retrieval in rodents using immediate early gene imaging (Zif268 and c‐Fos). Hippocampal area CA3 and the anterior cingulate cortex were preferentially engaged in spatial memory recall. MK801 impaired recall and reduced Zif268 activation across all regions, indicating that spatial and non‐spatial memories were NMDA receptor‐dependent.
•NMDAR blockade alters basal levels of c-Fos expression in a region specific manner.•Inhibition of NMDARs, but not AMPARs, disrupts spatial memory encoding.•Inhibition of NMDARs attenuates expression ...of Zif268 but not c-Fos in area CA1.•AMPAR blockade has no effect on spatial memory acquisition or IEG expression.•Zif268 and c-Fos expression are not coordinated during spatial memory formation.
The objective of this study was to examine the effects of NMDAR and AMPAR antagonism on the expression of Zif268 and c-Fos in the hippocampus and medial prefrontal cortex during spatial memory encoding in rats trained in the Morris water maze. NMDAR inhibition impaired navigation and significantly attenuated expression of Zif268, but not c-Fos, in area CA1. AMPAR channel blockade had little effect on learning or IEG expression. Overall, Zif268 and c-Fos displayed markedly different patterns of hippocampal and prefrontal expression, with Zif268 being more closely linked to spatial learning.
The centrosome is the main microtubule‐organizing centre. It also organizes a local network of actin filaments. However, the precise function of the actin network at the centrosome is not well ...understood. Here, we show that increasing densities of actin filaments at the centrosome of lymphocytes are correlated with reduced amounts of microtubules. Furthermore, lymphocyte activation resulted in disassembly of centrosomal actin and an increase in microtubule number. To further investigate the direct crosstalk between actin and microtubules at the centrosome, we performed in vitro reconstitution assays based on (i) purified centrosomes and (ii) on the co‐micropatterning of microtubule seeds and actin filaments. These two assays demonstrated that actin filaments constitute a physical barrier blocking elongation of nascent microtubules. Finally, we showed that cell adhesion and cell spreading lead to lower densities of centrosomal actin, thus resulting in higher microtubule growth. We therefore propose a novel mechanism, by which the number of centrosomal microtubules is regulated by cell adhesion and actin‐network architecture.
Synopsis
Centrosomes, the main interphase microtubule‐organizing centers of the cell, also nucleate local actin filament networks, which are now found to form a physical barrier blocking microtubule elongation.
Activation of B lymphocytes is associated with reduction of centrosomal actin and increase in the number of microtubules.
The amount of centrosomal actin is negatively correlated to the amount of microtubules.
In vitro reconstitutions show negative correlation between the amount of centrosomal actin and the number of microtubules.
Cell spreading proportionally affects the amount of centrosomal actin and the number of centrosomal microtubules.
Increasing density of F‐actin nucleating from the main interphase microtubule‐organizing center creates a physical barrier for nascent microtubules in lymphocytes and in vitro.
Adults with attention‐deficit/hyperactivity disorder (ADHD) have been described as having altered resting‐state electroencephalographic (EEG) spectral power and theta/beta ratio (TBR). However, a ...recent review (Pulini et al. 2018) identified methodological errors in neuroimaging, including EEG, ADHD classification studies. Therefore, the specific EEG neuromarkers of adult ADHD remain to be identified, as do the EEG characteristics that mediate between genes and behaviour (mediational endophenotypes). Resting‐state eyes‐open and eyes‐closed EEG was measured from 38 adults with ADHD, 45 first‐degree relatives of people with ADHD and 51 unrelated controls. A machine learning classification analysis using penalized logistic regression (Elastic Net) examined if EEG spectral power (1–45 Hz) and TBR could classify participants into ADHD, first‐degree relatives and/or control groups. Random‐label permutation was used to quantify any bias in the analysis. Eyes‐open absolute and relative EEG power distinguished ADHD from control participants (area under receiver operating characteristic = 0.71–0.77). The best predictors of ADHD status were increased power in delta, theta and low‐alpha over centro‐parietal regions, and in frontal low‐beta and parietal mid‐beta. TBR did not successfully classify ADHD status. Elevated eyes‐open power in delta, theta, low‐alpha and low‐beta distinguished first‐degree relatives from controls (area under receiver operating characteristic = 0.68–0.72), suggesting that these features may be a mediational endophenotype for adult ADHD. Resting‐state EEG spectral power may be a neuromarker and mediational endophenotype of adult ADHD. These results did not support TBR as a diagnostic neuromarker for ADHD. It is possible that TBR is a characteristic of childhood ADHD.
Machine learning classification analysis with penalized logistic regression revealed specific eyes‐open resting‐state EEG spectral power neuromarkers for adults with attention‐deficit/hyperactivity disorder (ADHD). These can be developed and integrated into complementary assessment/prognostic tools for adult ADHD diagnostics. We also found specific EEG characteristics that mediate between genes and behaviour. Our results did not support theta/beta ratio as a diagnostic neuromarker for adult ADHD.
Summary
Our study aimed to examine the role of perceptual load in eyewitness memory and susceptibility to misinformation and establish whether trait‐based memory specificity protects against ...misinformation. Participants (n = 264) viewed a video depicting a crime and completed a memory questionnaire immediately afterwards and 1 week later. Memory specificity was measured using the Autobiographical Memory Test (AMT). Higher AMT scores were associated with better memory accuracy. Performance was worse in the high load compared to the low load condition at immediate recall. However, this effect was not seen for every question and load did not influence eyewitness identifications. To test the possibility that load effects were not fully captured by the questionnaire in experiment 1, we conducted a second experiment (n = 120) where we systematically manipulated misinformation about central and peripheral details. We found no effects. Our findings suggest that high perceptual load enhances eyewitness suggestibility, while specific autobiographical memory protects against misinformation.
Recent studies have suggested a link between particulate matter (PM) exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases; accumulating evidences point ...to a new role for air pollution in CNS diseases. The purpose of our study is to investigate PM10sum effects on lungs and extra pulmonary tissues. Milano PM10sum has been intratracheally instilled into BALB/c mice. Broncho Alveolar Lavage fluid, lung parenchyma, heart and brain were screened for markers of inflammation (cell counts, cytokines, ET-1, HO-1, MPO, iNOS), cytotoxicity (LDH, ALP, Hsp70, Caspase8-p18, Caspase3-p17) for a putative pro-carcinogenic marker (Cyp1B1) and for TLR4 pathway activation. Brain was also investigated for CD68, TNF-α, GFAP. In blood, cell counts were performed while plasma was screened for endothelial activation (sP-selectin, ET-1) and for inflammation markers (TNF-α, MIP-2, IL-1β, MPO). Genes up-regulation (HMOX1, Cyp1B1, IL-1β, MIP-2, MPO) and miR-21 have been investigated in lungs and blood. Inflammation in the respiratory tract of PM10sum-treated mice has been confirmed in BALf and lung parenchyma by increased PMNs percentage, increased ET-1, MPO and cytokines levels. A systemic spreading of lung inflammation in PM10sum-treated mice has been related to the increased blood total cell count and neutrophils percentage, as well as to increased blood MPO. The blood-endothelium interface activation has been confirmed by significant increases of plasma ET-1 and sP-selectin. Furthermore PM10sum induced heart endothelial activation and PAHs metabolism, proved by increased ET-1 and Cyp1B1 levels. Moreover, PM10sum causes an increase in brain HO-1 and ET-1. These results state the translocation of inflammation mediators, ultrafine particles, LPS, metals associated to PM10sum, from lungs to bloodstream, thus triggering a systemic reaction, mainly involving heart and brain. Our results provided additional insight into the toxicity of PM10sum and could facilitate shedding light on mechanisms underlying the development of urban air pollution related diseases.
Oxidative stress, pulmonary and systemic inflammation, endothelial cell dysfunction, atherosclerosis and cardiac autonomic dysfunction have been linked to urban particulate matter exposure. The ...chemical composition of airborne pollutants in Milano is similar to those of other European cities though with a higher PM2.5 fraction. Milano winter fine particles (PM2.5win) are characterized by the presence of nitrate, organic carbon fraction, with high amount of polycyclic aromatic hydrocarbons and elements such as Pb, Al, Zn, V, Fe, Cr and others, with a negligible endotoxin presence. In BALB/c mice, we examined, at biochemical and transcriptomic levels, the adverse effects of repeated Milano PM2.5win exposure in lung and heart. We found that ET-1, Hsp70, Cyp1A1, Cyp1B1 and Hsp-70, HO-1, MPO respectively increased within lung and heart of PM2.5win-treated mice. The PM2.5win exposure had a strong impact on global gene expression of heart tissue (181 up-regulated and 178 down-regulated genes) but a lesser impact on lung tissue (14 up-regulated genes and 43 down-regulated genes). Focusing on modulated genes, in lung we found two- to three-fold changes of those genes related to polycyclic aromatic hydrocarbons exposure and calcium signalling. Within heart the most striking aspect is the twofold to threefold increase in collagen and laminin related genes as well as in genes involved in calcium signaling. The current study extends our previous findings, showing that repeated instillations of PM2.5win trigger systemic adverse effects. PM2.5win thus likely poses an acute threat primarily to susceptible people, such as the elderly and those with unrecognized coronary artery or structural heart disease. The study of genomic responses will improve understanding of disease mechanisms and enable future clinical testing of interventions against the toxic effects of air pollutant.
Cells going through mitosis undergo precisely timed changes in cell shape and organisation, which serve to ensure the fair partitioning of cellular components into the two daughter cells. These ...structural changes are driven by changes in actin filament and microtubule dynamics and organisation. While most evidence suggests that the two cytoskeletal systems are remodelled in parallel during mitosis, recent work in interphase cells has implicated the centrosome in both microtubule and actin nucleation, suggesting the potential for regulatory crosstalk between the two systems. Here, by using both in vitro and in vivo assays to study centrosomal actin nucleation as cells pass through mitosis, we show that mitotic exit is accompanied by a burst in cytoplasmic actin filament formation that depends on WASH and the Arp2/3 complex. This leads to the accumulation of actin around centrosomes as cells enter anaphase and to a corresponding reduction in the density of centrosomal microtubules. Taken together, these data suggest that the mitotic regulation of centrosomal WASH and the Arp2/3 complex controls local actin nucleation, which may function to tune the levels of centrosomal microtubules during passage through mitosis.
Synopsis
Centrosomes, the main interphase microtubule‐organizing centers, were recently found to also nucleate actin filaments. Here, local actin nucleation is observed in anaphase, tuning centrosomal microtubule nucleation as cells passage through mitosis.
Centrosomes function as both actin‐ and microtubule‐organizing centers during mitotic exit.
Actin transiently accumulates around centrosomes at early anaphase.
In vitro reconstitution assays with isolated centrosomes show a burst in actin filament formation at early anaphase.
Anaphase actin filament formation depends on Arp2/3 and WASH complex activity.
The anaphase actin burst around centrosomes is accompanied by reduction in microtubule density suggesting cross‐talk between the two systems.
Centrosomes organize both microtubule and actin filaments during mitosis, with a transient burst of actin nucleation in anaphase correlating with reduced microtubule density.
The adenosine monophosphate activated kinase protein (AMPK) is an evolutionary-conserved protein important for cell survival and organismal longevity through the modulation of energy homeostasis. ...Several studies suggested that AMPK activation may improve energy metabolism and protein clearance in the brains of patients with vascular injury or neurodegenerative disease. However, in Huntington's disease (HD), AMPK may be activated in the striatum of HD mice at a late, post-symptomatic phase of the disease, and high-dose regiments of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide may worsen neuropathological and behavioural phenotypes. Here, we revisited the role of AMPK in HD using models that recapitulate the early features of the disease, including Caenorhabditis elegans neuron dysfunction before cell death and mouse striatal cell vulnerability. Genetic and pharmacological manipulation of aak-2/AMPKα shows that AMPK activation protects C. elegans neurons from the dysfunction induced by human exon-1 huntingtin (Htt) expression, in a daf-16/forkhead box O-dependent manner. Similarly, AMPK activation using genetic manipulation and low-dose metformin treatment protects mouse striatal cells expressing full-length mutant Htt (mHtt), counteracting their vulnerability to stress, with reduction of soluble mHtt levels by metformin and compensation of cytotoxicity by AMPKα1. Furthermore, AMPK protection is active in the mouse brain as delivery of gain-of-function AMPK-γ1 to mouse striata slows down the neurodegenerative effects of mHtt. Collectively, these data highlight the importance of considering the dynamic of HD for assessing the therapeutic potential of stress-response targets in the disease. We postulate that AMPK activation is a compensatory response and valid approach for protecting dysfunctional and vulnerable neurons in HD.
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