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

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

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

Dendritic excitation–inhibition balance shapes cerebellar output during motor behaviour

Feedforward excitatory and inhibitory circuits regulate cerebellar output, but how these circuits interact to shape the somatodendritic excitability of Purkinje cells during motor behaviour remains unresolved. Here we perform dendritic and somatic patch-clamp recordings in vivo combined with optogenetic silencing of interneurons to investigate how dendritic excitation and inhibition generates bidirectional (that is, increased or decreased) Purkinje cell output during self-paced locomotion. We find that granule cells generate a sustained depolarization of Purkinje cell dendrites during movement, which is counterbalanced by variable levels of feedforward inhibition from local interneurons. Subtle differences in the dendritic excitation–inhibition balance generate robust, bidirectional changes in simple spike (SSp) output. Disrupting this balance by selectively silencing molecular layer interneurons results in unidirectional firing rate changes, increased SSp regularity and disrupted locomotor behaviour. Our findings provide a mechanistic understanding of how feedforward excitatory and inhibitory circuits shape Purkinje cell output during motor behaviour

Analisando a problemática do risco em casais que vivem em situação de sorodiscordância Analyzing the risk problem in couples with serodiscordance

Este artigo relata um estudo feito com pessoas que vivem em situação de sorodiscordância - caracterizada pela parceria entre uma pessoa soropositiva para o HIV e outra não - e busca compreender de que modo elas convivem com essa condição que pode se apresentar como uma constante prática de risco. Foram realizadas, no Centro de Testagem e Aconselhamento do Hospital Escola São Francisco de Assis da Universidade Federal do Rio de Janeiro, quinze entrevistas com usuários que vivem em situação de sorodiscordância. O temor de transmitir o vírus HIV ao (à) parceiro (a) soronegativo (a) apareceu como uma constante. Além do medo, dificuldades para conversar sobre o assunto, planejar o futuro e manter uma vida sexual considerada satisfatória também se destacaram. O uso do preservativo não aparece como algo adotado facilmente. Os entrevistados apontam outros fatores em jogo no exercício das práticas sexuais com prevenção efetiva - para além do conhecimento sobre as formas de infecção pelo vírus. Tais fatores parecem depender mais diretamente das possibilidades de cada um dos parceiros em construir uma identidade do casal diante de uma nova realidade que traz risco. Paradoxalmente, o risco de infecção que está sempre num outro, neste caso, está num outro muito próximo, do qual depende, inclusive, a permanência do casal.<br>This article relates an investigation made with people who live in a situation of partner serodiscordance, shall say in partnerships in which one partner is HIV positive and the other is HIV negative. The study is aimed at understanding how these people deal with the constant risk this situation involves. Fifteen individuals living with serodiscordant partners were interviewed in the Testing and Counseling Center of the São Francisco de Assis School Hospital of the Federal University of Rio de Janeiro. The fear of transmitting the HIV to the seronegative partner is constant. Besides the fear, there are the difficulties to talk about the problem, to plan the future and to keep a satisfactory sexual life. Condom use does not seem to be an easily adopted practice. The interviewees point to other factors that need to be taken into consideration beyond safe sexual practices and knowledge of the forms of HIV transmission. Such factors seem to depend much more directly on the capacity of the partners to construct a new couple identity in face of a risk situation. The risk of infection always lies in another being. Paradoxically, in this case the risk of infection comes from someone so close that the continuation of the partnership itself depends on this other being