Proteolysis of proBDNF Is a Key Regulator in the Formation of Memory

It is essential to understand the molecular processes underlying long-term memory to provide therapeutic targets of aberrant memory that produce pathological behaviour in humans. Under conditions of recall, fully-consolidated memories can undergo reconsolidation or extinction. These retrieval-mediated memory processes may rely on distinct molecular processes. The cellular mechanisms initiating the signature molecular events are not known. Using infusions of protein synthesis inhibitors, antisense oligonucleotide targeting brain-derived neurotrophic factor (BDNF) mRNA or tPA-STOP (an inhibitor of the proteolysis of BDNF protein) into the hippocampus of the awake rat, we show that acquisition and extinction of contextual fear memory depended on the increased and decreased proteolysis of proBDNF (precursor BDNF) in the hippocampus, respectively. Conditions of retrieval that are known to initiate the reconsolidation of contextual fear memory, a BDNF-independent memory process, were not correlated with altered proBDNF cleavage. Thus, the processing of BDNF was associated with the acquisition of new information and the updating of information about a salient stimulus. Furthermore, the differential requirement for the processing of proBDNF by tPA in distinct memory processes suggest that the molecular events actively engaged to support the storage and/or the successful retrieval of memory depends on the integration of ongoing experience with past learning

Happy Aged People Are All Alike, While Every Unhappy Aged Person Is Unhappy in Its Own Way

Aging of the world's population represents one of the most remarkable success stories of medicine and of humankind, but it is also a source of various challenges. The aim of the collaborative cross-cultural European study of adult well being (ESAW) is to frame the concept of aging successfully within a causal model that embraces physical health and functional status, cognitive efficacy, material security, social support resources, and life activity. Within the framework of this project, we show here that the degree of heterogeneity among people who view aging in a positive light is significantly lower than the degree of heterogeneity of those who hold a negative perception of aging. We base this conclusion on our analysis of a survey involving 12,478 people aged 50 to 90 from six West European countries. We treat the survey database as a bipartite network in which individual respondents are linked to the actual answers they provide. Taking this perspective allows us to construct a projected network of respondents in which each link indicates a statistically validated similarity of answers profile between the connected respondents, and to identify clusters of individuals independently of demographics. We show that mental and physical well-being are key factors determining a positive perception of aging. We further observe that psychological aspects, like self-esteem and resilience, and the nationality of respondents are relevant aspects to discriminate among participants who indicate positive perception of aging

For whom is a health-promoting intervention effective? Predictive factors for performing activities of daily living independently

BACKGROUND: Health-promoting interventions tailored to support older persons to remain in their homes, so-called "ageing in place" is important for supporting or improving their health. The health-promoting programme "Elderly Persons in the Risk Zone," (EPRZ) was set up for this purpose and has shown positive results for maintaining independence in activities of daily living for older persons 80 years and above at 1- and 2 year follow-ups. The aim of this study was to explore factors for maintaining independence in the EPRZ health-promoting programme.METHODS: Total of 459 participants in the original trial was included in the analysis; 345 in the programme arm and 114 in the control arm. Thirteen variables, including demographic, health, and programme-specific indicators, were chosen as predictors for independence of activities of daily living. Logistic regression was performed separately for participants in the health promotion programme and in the control arm.RESULTS: In the programme arm, being younger, living alone and self-rated lack of tiredness in performing mobility activities predicted a positive effect of independence in activities of daily living at 1-year follow-up (odds ratio [OR] 1.18, 1.73, 3.02) and 2-year, (OR 1.13, 2.01, 2.02). In the control arm, being less frail was the only predictor at 1-year follow up (OR 1.6 1.09, 2.4); no variables predicted the outcome at the 2-year follow-up.CONCLUSIONS: Older persons living alone - as a risk of ill health - should be especially recognized and offered an opportunity to participate in health-promoting programmes such as "Elderly Persons in the Risk Zone". Further, screening for subjective frailty could form an advantageous guiding principle to target the right population when deciding to whom health-promoting intervention should be offered.TRIAL REGISTRATION: The original clinical trial was registered at ClinicalTrials.gov. Identifier: NCT00877058 , April 6, 2009

A hippocampal Cdk5 pathway regulates extinction of contextual fear

Treatment of emotional disorders involves the promotion of extinction processes, which are defined as the learned reduction of fear. The molecular mechanisms underlying extinction have only begun to be elucidated. By employing genetic and pharmacological approaches in mice, we show here that extinction requires downregulation of Rac-1 and cyclin-dependent kinase 5 (Cdk5), and upregulation of p21 activated kinase-1 (PAK-1) activity. This is physiologically achieved by a Rac-1–dependent relocation of the Cdk5 activator p35 from the membrane to the cytosol and dissociation of p35 from PAK-1. Moreover, our data suggest that Cdk5/p35 activity prevents extinction in part by inhibition of PAK-1 activity in a Rac-1–dependent manner. We propose that extinction of contextual fear is regulated by counteracting components of a molecular pathway involving Rac-1, Cdk5 and PAK-1. Our data suggest that this pathway could provide a suitable target for therapeutic treatment of emotional disorders.National Institutes of Health (U.S.) (Grant NS051874)Alexander von Humboldt-Stiftung (German Research Foundation Fellowship)European Neuroscience Institute Goettinge

Context-Dependent Encoding of Fear and Extinction Memories in a Large-Scale Network Model of the Basal Amygdala

The basal nucleus of the amygdala (BA) is involved in the formation of context-dependent conditioned fear and extinction memories. To understand the underlying neural mechanisms we developed a large-scale neuron network model of the BA, composed of excitatory and inhibitory leaky-integrate-and-fire neurons. Excitatory BA neurons received conditioned stimulus (CS)-related input from the adjacent lateral nucleus (LA) and contextual input from the hippocampus or medial prefrontal cortex (mPFC). We implemented a plasticity mechanism according to which CS and contextual synapses were potentiated if CS and contextual inputs temporally coincided on the afferents of the excitatory neurons. Our simulations revealed a differential recruitment of two distinct subpopulations of BA neurons during conditioning and extinction, mimicking the activation of experimentally observed cell populations. We propose that these two subgroups encode contextual specificity of fear and extinction memories, respectively. Mutual competition between them, mediated by feedback inhibition and driven by contextual inputs, regulates the activity in the central amygdala (CEA) thereby controlling amygdala output and fear behavior. The model makes multiple testable predictions that may advance our understanding of fear and extinction memories

The CB1 receptor antagonist AM251 impairs reconsolidation of pavlovian fear memory in the rat basolateral amygdala

We have investigated the requirement for signaling at CB1 receptors in the reconsolidation of a previously consolidated auditory fear memory, by infusing the CB1 receptor antagonist AM251, or the FAAH inhibitor URB597, directly into the basolateral amygdala (BLA) in conjunction with memory reactivation. AM251 disrupted memory restabilization, but only when administered after reactivation. URB597 produced a small, transient enhancement of memory restabilization when administered after reactivation. The amnestic effect of AM251 was rescued by coadministration of the GABAA receptor antagonist bicuculline at reactivation, indicating that the disruption of reconsolidation was mediated by altered GABAergic transmission in the BLA. These data show that the endocannabinoid system in the BLA is an important modulator of fear memory reconsolidation and that its effects on memory are mediated by an interaction with the GABAergic system. Thus, targeting the endocannabinoid system may have therapeutic potential to reduce the impact of maladaptive memories in neuropsychiatric disorders such as posttraumatic stress disorder.This work was conducted within the Behavioural and Clinical Neuroscience Institute, a joint initiative funded by the Wellcome Trust and the UK Medical Research Council, in the Department of Psychology at the University of Cambridge. This work was funded by a UK Medical Research Council programme grant (no. G1002231) awarded to BJE and ALM. PR was supported by a Department of Physiology and Pharmacology Fellowship at the Sapienza University of Rome, and an Italian Society of Pharmacology Fellowship. ALM is the Ferreras-Willetts Fellow in Neuroscience at Downing College, Cambridge. The manuscript was partly prepared while ALM was an Erskine Visiting Cambridge Fellow at the University of Canterbury, Christchurch, New Zealand