Transgenic inhibition of neuronal calcineurin activity in the forebrain facilitates fear conditioning, but inhibits the extinction of contextual fear memories

It is unclear whether protein phosphatases, which counteract the actions of protein kinases, play a beneficial role in the formation and extinction of previously acquired fear memories. In this study, we investigated the role of the calcium/calmodulin dependent phosphatase 2B, also known as calcineurin (CaN) in the formation of contextual fear memory and extinction of previously acquired contextual fear. We used a temporally regulated transgenic approach, that allowed us to selectively inhibit neuronal CaN activity in the forebrain either during conditioning or only during extinction training leaving the conditioning undisturbed. Reducing CaN activity through the expression of a CaN inhibitor facilitated contextual fear conditioning, while it impaired the extinction of previously formed contextual fear memory. These findings give the first genetic evidence that neuronal CaN plays an opposite role in the formation of contextual fear memories and the extinction of previously formed contextual fear memories. (C) 2007 Elsevier Inc. All rights reserved

Status Of The FAIR Synchrotron Projects SIS18 And SIS100

A large fraction of the program to upgrade the existingheavy ion synchrotron SIS18 as injector for the FAIR synchrotron SIS100 has been successfully completed. With the achieved technical status, a major increase of theaccelerated number of heavy ions could be reached. Thenow available performance especially demonstrates thefeasibility of high intensity beams of medium charge stateheavy ions with a sufficient control of the dynamicvacuum and connected charge exchange loss. Two furtherupgrade measures, the installation of additional magneticalloy (MA) acceleration cavities and the exchange of themain dipole power converter, are presently beingimplemented. For the FAIR synchrotron SIS100, theprocurement of all major components with longproduction times has been started. With the delivery andtesting of several pre-series components, the phase ofoutstanding technical reserach and developments could becompleted and the readiness for series productionachieved

The old second messenger cAMP teams up with novel cell death mechanisms:Potential translational therapeutical benefit for Alzheimer's disease and Parkinson's disease

Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent neurodegenerative disorders severely impacting life expectancy and quality of life of millions of people worldwide. AD and PD exhibit both a very distinct pathophysiological disease pattern. Intriguingly, recent researches, however, implicate that overlapping mechanisms may underlie AD and PD. In AD and PD, novel cell death mechanisms, encompassing parthanatos, netosis, lysosome-dependent cell death, senescence and ferroptosis, apparently rely on the production of reactive oxygen species, and seem to be modulated by the well-known, "old" second messenger cAMP. Signaling of cAMP via PKA and Epac promotes parthanatos and induces lysosomal cell death, while signaling of cAMP via PKA inhibits netosis and cellular senescence. Additionally, PKA protects against ferroptosis, whereas Epac1 promotes ferroptosis. Here we review the most recent insights into the overlapping mechanisms between AD and PD, with a special focus on cAMP signaling and the pharmacology of cAMP signaling pathways.</p

The effects of social environment on AD-related pathology in hAPP-J20 mice and tau-P301L mice

In humans, social factors (e.g., loneliness) have been linked to the risk of developing Alzheimer's Disease (AD). To date, AD pathology is primarily characterized by amyloid-β plaques and tau tangles. We aimed to assess the effect of single- and group-housing on AD-related pathology in a mouse model for amyloid pathology (J20, and WT controls) and a mouse model for tau pathology (P301L) with and without seeding of synthetic human tau fragments (K18). Female mice were either single housed (SH) or group housed (GH) from the age of 6-7 weeks onwards. In 12-week-old P301L mice, tau pathology was induced through seeding by injecting K18 into the dorsal hippocampus (P301L K18), while control mice received a PBS injection (P301L PBS). P301L mice were sacrificed at 4 months of age and J20 mice at 10 months of age. In all mice brain pathology was histologically assessed by examining microglia, the CA1 pyramidal cell layer and specific AD pathology: analysis of plaques in J20 mice and tau hyperphosphorylation in P301L mice. Contrary to our expectation, SH-J20 mice interestingly displayed fewer plaques in the hippocampus compared to GH-J20 mice. However, housing did not affect tau hyperphosphorylation at Ser202/Thr205 of P301L mice, nor neuronal cell death in the CA1 region in any of the mice. The number of microglia was increased by the J20 genotype, and their activation (based on cell body to cell size ratio) in the CA1 was affected by genotype and housing condition (interaction effect). Single housing of P301L mice was linked to the development of stereotypic behavior (i.e. somersaulting and circling behavior). In P301L K18 mice, an increased number of microglia were observed, among which were rod microglia. Taken together, our findings point to a significant effect of social housing conditions on amyloid plaques and microglia in J20 mice and on the development of stereotypic behavior in P301L mice, indicating that the social environment can modulate AD-related pathology. </p

DC trains and Pc3s : source effects in mid-lattitude geomagnetic transfer functions

Magnetotelluric (MT) data from two sites 150 and 300 km southeast of San Francisco, California (geomagnetic dipole latitude: 43 degrees, L approximately 1.9) show that the usual MT assumption of spatially uniform external magnetic fields is violated to a significant degree in the period range 10-30 s. Inter-station transfer functions exhibit large systematic temporal variations which are consistent with a combination of two distinct sources: electromagnetic noise due to the San Francisco Bay Area Rapid Transit (BART) DC electric railway, and Pc3 geomagnetic pulsations. There is a suggestion in the data that some of the Pc activity may actually be excited by BART

Social health and prevention of dementia:Integration of human and mice studies

Objectives: Prevention of dementia is considered a healthcare priority. We aimed to identify potentially modifiable risk factors and mechanisms within the social health domain to find novel avenues to prevent cognitive decline and dementia. Design: We integrated the results of eight sub-studies of the Social Health in Mice and Men (SHiMMy) project that were separately published in specialized journals, but not yet jointly considered. We followed the integrative methodology of Whittemore and Knafl, using the conceptual framework for social health to structure and integrate the results of human epidemiological and qualitative studies and experimental mice studies. This is a novel multi-method approach. Participants: Participants of the population-based longitudinal cohort Rotterdam study were included in the epidemiolocal studies (ranging from N = 1259 to N = 3.720) and in the qualitative study (n = 17). Mice intervention studies were performed using a transgenic mouse model for Alzheimer's pathology and matched controls, under group and single housed conditions.Measurements: Epidemiological studies include social health markers (loneliness, perceived social support, marital status) and magnetic resonance imaging of the brain. The semi-structured qualitative study used an interview guide. The mice study assessed behavioral and histological markers. Results: In human and mice studies, we identified several similar potentially modifiable risk (e.g. marital status, social group size) and protective (e.g. perceived social support, behavioral responses) factors. This alignment of findings showing that social health may impact brain health lend further support to our social health hypothesis. Conclusion: These results allow us to propose evidence-based social health targets for preventive interventions.</p

Distinct immune responses in people living with HIV following SARS-CoV-2 recovery

Background SARS-CoV-2 infection results in greater disease severity among immunocompromised individuals compared to healthy individuals. However, there is conflicting information about the impact of chronic HIV infection on immune responses to SARS-CoV-2 infection and vaccination. Method We used a combination of machine learning approaches and network analysis to explore 56 immune markers and comprehensively profile humoral and cellular immunity in a cross-sectional observational cohort of people without HIV (PWOH; n = 216) and people living with HIV (PLWH; n = 43) who recovered from SARS-CoV-2 infection (13–131 days since SARS-COV-2 diagnosis) early in the pandemic. Results PLWH recovered from symptomatic outpatient COVID-19 exhibit lower humoral and B cell responses to SARS-CoV-2 vs. PWOH but, surprisingly, both symptomatic outpatient and hospitalized PLWH have higher anti-endemic coronavirus antibody responses compared to PWOH counterparts and asymptomatic PLWH. The latter observation suggests that this was not strictly due to broadly elevated levels of anti-endemic coronavirus antibodies in PLWH. Moreover, correlation-based analysis reveals that while different compartments of the immune response to SARS-CoV-2 infection are positively correlated in PWOH recovered from symptomatic outpatient COVID-19, these correlations are weaker in PLWH. Conclusion Our analyses reveal significant differences in the coordinated immune responses elicited by infection in PLWH compared to PWOH

The continued need for animals to advance brain research

Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised