Ultrastructural and transcriptional profiling of neuropathological misregulation of CREB function

We compare here the neurodegenerative processes observed in the hippocampus of bitransgenic mice with chronically altered levels of cAMP-response element-binding protein (CREB) function. The combination of genome-wide transcriptional profiling of degenerating hippocampal tissue with microscopy analyses reveals that the sustained inhibition of CREB function in A-CREB mice is associated with dark neuron degeneration, whereas its strong chronic activation in VP16-CREB mice primarily causes excitotoxic cell death and inflammation. Furthermore, the meta-analysis with gene expression profiles available in public databases identifies relevant common markers to other neurodegenerative processes and highlights the importance of the immune response in neurodegeneration. Overall, these analyses define the ultrastructural and transcriptional signatures associated with these two forms of hippocampal neurodegeneration, confirm the importance of fine-tuned regulation of CREB-dependent gene expression for CA1 neuron survival and function, and provide novel insight into the function of CREB in the etiology of neurodegenerative processes. © 2010 Macmillan Publishers Limited All rights reserved.The work at AB and LMV laboratory was supported by the European Commission Coordination Action ENINET (contract number LSHM-CT-2005-19063), the Spanish Ministry of Science and Innovation grants BFU2005-00286, CSD2007-00023, and SAF2008-00611, the Generalitat Valenciana grant GVPRE/2008/365, and the Fundació La Marató de TV3 grant 063510. The work at RL laboratory was supported by the Spanish Ministry of Science and Innovation grant BFU2006-01896 and the Junta de Comunidades de Castilla-La Mancha grant PAI08-0174-6967.Peer Reviewe

Do Economic Crises Always Undermine Trust in Others? The Case of Generalized, Interpersonal, and In-Group Trust

After the global economic collapse triggered by the Great Recession, there has been an increased interest in the potential psychological implications of periods of economic decline. Recent evidence suggests that negative personal experiences linked to the economic crisis may lead to diminished generalized trust (i.e., the belief that most of the people of the society are honest and can be trusted). Adding to the growing literature on the psychological consequences of the economic crisis, we propose that the perceived personal impact of the economic crisis not only would undermine generalized trust but also may lead to increased interpersonal trust (i.e., directed to specific and close people) and depersonalized in-group trust [i.e., directed to individuals who, while strangers, belong to the same group (e.g., social class)]. Across three studies (N = 1379), we tested these central hypotheses and ascertained whether the perceived personal impact of the crisis would predict these types of trust (assessed using questionnaire and behavioral measures) independent of individuals’ socioeconomic status. Non-experimental data from Study 1 revealed that a higher perceived personal impact of the crisis is related to lower levels of generalized trust and higher levels of interpersonal trust. These effects were independent of participants’ socioeconomic status. Non-experimental data from Study 2 replicated the findings obtained in Study 1 and also showed a positive association between the perceived personal impact of the crisis and depersonalized in-group trust.This research was supported by the Spanish Ministry of Economy and Competitiveness [Ref. PSI2014-59659-R and Ref. PSI- 2017-83966-R (MINECO/AEI/FEDER/UE)] and by a Grant (FPU13/02478) from the FPU Program of the Spanish Ministry of Education, Culture, and Sport

CREB Regulates Distinct Adaptive Transcriptional Programs in Astrocytes and Neurons

The cyclic AMP response element binding protein (CREB) is a primary hub of a activity-driven genetic programs in neurons controlling plasticity, neurogenesis and survival. By contrast, the gene networks coordinated by CREB in astrocytes are Unknown despite the fact that the astrocytic CREB is a also activity-driven and neuroprotective. Herein we identified the transcriptional programs regulated by CREB in astrocytes as compared to neurons using, as study materials, transcriptome databases of astrocyte exposed to weII-known activators of CREB-dependent transcription as well as publidy available transcriptomes of neuronal cultures. Functional CREB signatures were extracted from the transcriptomes using Gene Ontology, adult-brain gene lists generated by Translating Ribosome Affinity Purification (TRAP) and CREB-target gene repositories. We found minimal overlap between CREB signatures in astrocytes and neurons. In astrocytes, the top triad of functions regulated by CREB consists of'Gene expression', 'Mitochondria', and 'Signa Iling', while in neurons it is 'Neurotransmission', 'Signalling' and 'Gene expression', the latter being represented by different genes from those in astrocytes. The newly gene rated data bases Will provide a tool to explore novel means whereby CREB impinges on brain functions requiring adaptive, long-lasting changes by coordinating transcriptionaI cascades in astrocytes

Positioning Europe for the EPITRANSCRIPTOMICS challenge

The genetic alphabet consists of the four letters: C, A, G, and T in DNA and C,A,G, and U in RNA. Triplets of these four letters jointly encode 20 different amino acids out of which proteins of all organisms are built. This system is universal and is found in all kingdoms of life. However, bases in DNA and RNA can be chemically modified. In DNA, around 10 different modifications are known, and those have been studied intensively over the past 20 years. Scientific studies on DNA modifications and proteins that recognize them gave rise to the large field of epigenetic and epigenomic research. The outcome of this intense research field is the discovery that development, ageing, and stem-cell dependent regeneration but also several diseases including cancer are largely controlled by the epigenetic state of cells. Consequently, this research has already led to the first FDA approved drugs that exploit the gained knowledge to combat disease. In recent years, the ~150 modifications found in RNA have come to the focus of intense research. Here we provide a perspective on necessary and expected developments in the fast expanding area of RNA modifications, termed epitranscriptomics.SCOPUS: no.jinfo:eu-repo/semantics/publishe

Hippocampal gene profiling: Toward a systems biology of the hippocampus

Transcriptomics and proteomics approaches give a unique perspective for understanding brain and hippocampal functions but also pose unique challenges because of the singular complexity of the nervous system. The proliferation of genome-wide expression studies during the last decade has provided important insight into the molecular underpinnings of brain anatomy, neural plasticity, and neurological diseases. Microarray technology has dominated transcriptomics research, but this situation is rapidly changing with the recent technological advances in high-throughput sequencing. The full potential of transcriptomics in the neurosciences will be achieved as a result of its integration with other >-omics> disciplines as well as the development of novel analytical bioinformatics and systems biology tools for meta-analysis. Here, we review some of the most relevant advances in the gene profiling of the hippocampus, its relationship with proteomics approaches, and the promising perspectives for the future. © 2010 Wiley Periodicals, Inc.Grant sponsor: Spanish Ministry of Science and Innovation Grants; Grant number: BFU2008–00611, SAF2008–03194-E, and CSD2007–00023; Grant sponsor: Fundación Ramón Areces and Fundació la Marató de TV3Peer Reviewe

Transcription, epigenetics and ameliorative strategies in huntington’s disease: A genome-wide perspective

This article is distributed under the terms of the Creative Commons Attribution License.Transcriptional dysregulation in Huntington's disease (HD) is an early event that shapes the brain transcriptome by both the depletion and ectopic activation of gene products that eventually affect survival and neuronal functions. Disruption in the activity of gene expression regulators, such as transcription factors, chromatin-remodeling proteins, and noncoding RNAs, accounts for the expression changes observed in multiple animal and cellular models of HD and in samples from patients. Here, I review the recent advances in the study of HD transcriptional dysregulation and its causes to finally discuss the possible implications in ameliorative strategies from a genome-wide perspective. To date, the use of genome-wide approaches, predominantly based on microarray platforms, has been successful in providing an extensive catalog of differentially regulated genes, including biomarkers aimed at monitoring the progress of the pathology. Although still incipient, the introduction of combined next-generation sequencing techniques is enhancing our comprehension of the mechanisms underlying altered transcriptional dysregulation in HD by providing the first genomic landscapes associated with epigenetics and the occupancy of transcription factors. In addition, the use of genome-wide approaches is becoming more and more necessary to evaluate the efficacy and safety of ameliorative strategies and to identify novel mechanisms of amelioration that may help in the improvement of current preclinical therapeutics. Finally, the major conclusions obtained from HD transcriptomics studies have the potential to be extrapolated to other neurodegenerative disorders.I thank the Spanish Ministry of Economy and Competitiveness for the economic support (Ramón Cajal contract and grant SAF2011-22506).Peer reviewe

Epigenetic-based therapies in the preclinical and clinical treatment of Huntington's disease

The study of epigenetics is providing novel insights about the functional and developmental complexity of the nervous system. In neuropathology, therapies aimed at correcting epigenetic dysregulation have been extensively documented in a large variety of models for neurodegenerative, neurodevelopmental and psychiatric disorders. Taking the treatment of Huntington's disease as a paradigm for the study of these ameliorative strategies, this review updates the main conclusions derived from the use of epigenetic drugs at the preclinical and clinical stages, including actions beyond epigenetics.I thank to the Spanish Ministry of Economy and Competitiveness for the economic support (Ramón y Cajal contract and grant SAF2011-22506). The Instituto de Neurociencias is a Center of Excellence Severo Ochoa.Peer reviewe

What's wrong with epigenetics in Huntington's disease?

Huntington's disease (HD) can be considered the paradigm of epigenetic dysregulation in neurodegenerative disorders. In this review, we attempted to compile the evidence that indicates, on the one hand, that several epigenetic marks (histone acetylation, methylation, ubiquitylation, phosphorylation and DNA modifications) are altered in multiple models and in postmortem patient samples, and on the other hand, that pharmacological treatments aimed to reverse such alterations have beneficial effects on HD phenotypic and biochemical traits. However, the working hypotheses regarding the biological significance of epigenetic dysregulation in this disease and the mechanisms of action of the tested ameliorative strategies need to be refined. Understanding the complexity of the epigenetics in HD will provide useful insights to examine the role of epigenetic dysregulation in other neuropathologies, such as Alzheimer's or Parkinson's diseases.LMV's research is supported by a Ramón Cajal contract and grant SAF2011-22506 from the Spanish Ministry of Economy and Competitiveness. DG is supported by a predoctoral fellowship (JAE-pre) from the Program “Junta para la Ampliación de Estudios” co-funded by the Fondo Social Europeo (FSE) and grants from the Fundació Gent per Gent and the Spanish Ministry of Economy and Competitiveness (SAF2011-22855).Peer reviewe

cAMP response element-binding protein is a primary hub of activity-driven neuronal gene expression

Long-lasting forms of neuronal plasticity require de novo gene expression, but relatively little is known about the events that occur genome-wide in response to activity in a neuronal network. Here, we unveil the gene expression programs initiated in mouse hippocampal neurons in response to different stimuli and explore the contribution of four prominent plasticity-related transcription factors (CREB, SRF, EGR1, and FOS) to these programs. Our study provides a comprehensive view of the intricate genetic networks and interactions elicited by neuronal stimulation identifying hundreds of novel downstream targets, including novel stimulus-associated miRNAs and candidate genes that may be differentially regulated at the exon/promoter level. Our analyses indicate that these four transcription factors impinge on similar biological processes through primarily non-overlapping gene-expression programs. Meta-analysis of the datasets generated in our study and comparison with publicly available transcriptomics data revealed the individual and collective contribution of these transcription factors to different activity-driven genetic programs. In addition, both gain-and loss-of-function experiments support a pivotal role for CREB in membrane-to-nucleus signal transduction in neurons. Our data provide a novel resource for researchers wanting to explore the genetic pathways associated with activity-regulated neuronal functions. © 2011 the authors.Research at the Barco laboratory is supported by Spanish Ministry of Science and Innovation Grants BFU2008-00611, CSD2007-00023, and SAF2008-03194-E (part of the coordinated ERA-Net NEURON project Epitherapy). E.B. had a Gobierno Vasco fellowship, and L.M.V. has a Ramón y Cajal contract given by the Spanish Ministry of Science and Innovation.Peer Reviewe

Inhibition of cAMP response element-binding protein reduces neuronal excitability and plasticity, and triggers neurodegeneration

The cAMP-responsive element-binding protein (CREB) pathway has been involved in 2 major cascades of gene expression regulating neuronal function. The first one presents CREB as a critical component of the molecular switch that controls long-lasting forms of neuronal plasticity and learning. The second one relates CREB to neuronal survival and protection. To investigate the role of CREB-dependent gene expression in neuronal plasticity and survival in vivo, we generated bitransgenic mice expressing A-CREB, an artificial peptide with strong and broad inhibitory effect on the CREB family, in forebrain neurons in a regulatable manner. The expression of A-CREB in hippocampal neurons impaired L-LTP, reduced intrinsic excitability and the susceptibility to induced seizures, and altered both basal and activity-driven gene expression. In the long-term, the chronic inhibition of CREB function caused severe loss of neurons in the CA1 subfield as well as in other brain regions. Our experiments confirmed previous findings in CREB-deficient mutants and revealed new aspects of CREB-dependent gene expression in the hippocampus supporting a dual role for CREB-dependent gene expression regulating intrinsic and synaptic plasticity and promoting neuronal survival.European Commission grants (MEXT-CT-2003-509550 and MIRG-CT2005-016343), Spanish MEC Grants (BFU2005-00286 and CSD2007-00023), and grants from Fundació La Marató de TV3 and Fundacioón Ramón Areces supported research at A.B.’s lab.Peer Reviewe