How repeated and unpredictable experiences turn into fear-memories

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A hitchhiker's guide to diffusion tensor imaging

Diffusion Tensor Imaging (DTI) studies are increasingly popular among clinicians and researchers as they provide unique insights into brain network connectivity. However, in order to optimize the use of DTI, several technical and methodological aspects must be factored in. These include decisions on: acquisition protocol, artifact handling, data quality control, reconstruction algorithm, and visualization approaches, and quantitative analysis methodology. Furthermore, the researcher and/or clinician also needs to take into account and decide on the most suited software tool(s) for each stage of the DTI analysis pipeline. Herein, we provide a straightforward hitchhiker's guide, covering all of the workflow's major stages. Ultimately, this guide will help newcomers navigate the most critical roadblocks in the analysis and further encourage the use of DTI.The work was supported by SwitchBox-FP7-HEALTH-2010-grant 259772-2. The authors acknowledge Nadine Santos for her help in editing the manuscript

Stress Transiently Affects Pavlovian-to-Instrumental Transfer

Stress has a strong impact in the brain, impairing decision-making processes as a result of changes in circuits involving the prefrontal and orbitofrontal cortices and the striatum. Given that these same circuits are key for action control and outcome encoding, we hypothesized that adaptive responses to which these are essential functions, could also be targeted by stress. To test this hypothesis we herein assessed the impact of chronic stress in a Pavlovian-to-instrumental transfer (PIT) paradigm, a model of an adaptive response in which a previously conditioned cue biases an instrumental goal-directed action. Data reveals that rats submitted to chronic unpredictable stress did not display deficits in pavlovian conditioning nor on the learning of the instrumental task, but were impaired in PIT; importantly, after a stress-free period the PIT deficits were no longer observed. These results are relevant to understand how stress biases multiple incentive processes that contribute to instrumental performance

BrainCAT: a tool for automated and combined functional magnetic resonance imaging and diffusion tensor imaging brain connectivity analysis

Multimodal neuroimaging studies have recently become a trend in the neuroimaging field and are certainly a standard for the future. Brain connectivity studies combining functional activation patterns using resting-state or task-related functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) tractography have growing popularity. However, there is a scarcity of solutions to perform optimized, intuitive, and consistent multimodal fMRI/DTI studies. Here we propose a new tool, brain connectivity analysis tool (Brain CAT), for an automated and standard multimodal analysis of combined fMRI/DTI data, using freely available tools. With a friendly graphical user interface, BrainCAT aims to make data processing easier and faster, implementing a fully automated data processing pipeline and minimizing the need for user intervention, which hopefully will expand the use of combined fMRI/DTI studies. Its validity was tested in an aging study of the default mode network (DMN) white matter connectivity. The results evidenced the cingulum bundle as the structural connector of the precuneus/posterior cingulate cortex and the medial frontal cortex, regions of the DMN. Moreover, mean fractional anisotropy (FA) values along the cingulum extracted with BrainCAT showed a strong correlation with FA values from the manual selection of the same bundle. Taken together, these results provide evidence that BrainCAT is suitable for these analyses.The authors thank the developers of all the software tools used by BrainCAT, namely, MRIcron, FSL, Diffusion Toolkit, and TrackVis. This work was supported by SwitchBox-FP7-HEALTH-2010-grant 259772-2

A novel risk-based decision-making paradigm

This paper presents a novel rodent decision-making task that explores uncertainty, independently of expectation and predictability. Using a 5-hole operating box, adult male Wistar rats were given choices between a small certain (safe) food reward and a large uncertain (risk) food reward. We found that animals strongly preferred the safe option when it had a fixed position or was cued with a light in a random placement scheme, but had no preference for safe or risk options when the latter were associated with light. Importantly, when the reward was manipulated animals could perceive alterations in the outcome value and biased their choice pattern to the most profitable option. In addition, we found that the D2/D3 agonist quinpirole biased all decisions toward risk in this paradigm. Finally, a c-fos analysis revealed that several brain areas known to be involved in decision-making mechanisms, including the medial prefrontal cortex, the orbitofrontal cortex, the nucleus accumbens and the striatum, were activated by the task. In summary, this paradigm is a useful and highly reliable tool to explore decision-making processes in contexts of uncertainty.Pedro Morgado is supported by a fellowship "SFRH/SINTD/60129/2009" funded by FCT-Foundation for Science and Technology. Supported by FEDER funds through Operational program for competitive factors-COMPETE and by national funds through FCT-Foundation for Science and Technology to project "PTDC/SAU-NSC/111814/2009.

Stress affects theta activity in limbic networks and impairs novelty-induced exploration and familiarization

Exposure to a novel environment triggers the response of several brain areas that regulate emotional behaviors. Here, we studied theta oscillations within the hippocampus (HPC)-amygdala (AMY)-medial prefrontal cortex (mPFC) network in exploration of a novel environment and subsequent familiarization through repeated exposures to that same environment; in addition, we assessed how concomitant stress exposure could disrupt this activity and impair both behavioral processes. Local field potentials (LFP) were simultaneously recorded from dorsal and ventral hippocampus (dHPC and vHPC, respectively), basolateral amygdala (BLA) and mPFC in freely behaving rats while they were exposed to a novel environment, then repeatedly re-exposed over the course of 3 weeks to that same environment and, finally, on re-exposure to a novel unfamiliar environment. A longitudinal analysis of theta activity within this circuit revealed a reduction of vHPC and BLA theta power and vHPC-BLA theta coherence through familiarization which was correlated with a return to normal exploratory behavior in control rats. In contrast, a persistent over-activation of the same brain regions was observed in stressed rats that displayed impairments in novel exploration and familiarization processes. Importantly, we show that stress also affected intra-hippocampal synchrony and heightened the coherence between vHPC and BLA. In summary, we demonstrate that modulatory theta activity in the aforementioned circuit, namely in the vHPC and BLA, is correlated with the expression of anxiety in novelty-induced exploration and familiarization in both normal and pathological conditions.Luis R. Jacinto was supported by the Portuguese Foundation for Science and Technology (FCT) under grant SFRH/BD/40459/2007. This work was supported by FCT and FEDER funds through Programa Operacional Factores de Competitividade (COMPETE) with project references FCOMP-01-0124-FEDER-021145 (FCT/PTDC/SAU-ENB/118383/2010) and FCOMP-01-0124-FEDER-022674; ADI Project "DoIT-Desenvolvimento e Operacionalizacao da Investigacao de Translacao" ("MyHealth-PPS4"; project no 13853); and a BIAL Foundation Grant (138/2008 to Joao J. Cerqueira)

Telephone-based screening tools for mild cognitive impairment and dementia in aging studies : a review of validated instruments

The decline of cognitive function in old age is a great challenge for modern society. The simultaneous increase in dementia and other neurodegenerative diseases justifies a growing need for accurate and valid cognitive assessment instruments. Although in-person testing is considered the most effective and preferred administration mode of assessment, it can pose not only a research difficulty in reaching large and diverse population samples, but it may also limit the assessment and follow-up of individuals with either physical or health limitations or reduced motivation. Therefore, telephone-based cognitive screening instruments can be an alternative and attractive strategy to in-person assessments. In order to give a current view of the state of the art of telephone-based tools for cognitive assessment in aging, this review highlights some of the existing instruments with particular focus on data validation, cognitive domains assessed, administration time and instrument limitations and advantages. From the review of the literature, performed using the databases EBSCO, Science Direct and PubMed, it was possible to verify that while telephone-based tools are useful in research and clinical practice, providing a promising approach, the methodologies still need refinement in the validation steps, including comparison with either single instruments or neurocognitive test batteries, to improve specificity and sensitivity to validly detect subtle changes in cognition that may precede cognitive impairment.This work was funded by the European Commission (FP7): "SwitchBox" (Contract HEALTH-F2-2010-259772). Teresa C. Castanho and Liliana Amorim are recipients of doctoral fellowships from the Fundacao para a Ciencia e Tecnologia (FCT, Portugal) and the MyHealth project (Contract DoIT-13853), respectively. Nadine C. Santos is a recipient of a postdoctoral fellowship by the Switchbox project

Perceived stress in obsessive-compulsive disorder is related with obsessive but not cmpulsive symptoms

Obsessive–compulsive disorder (OCD) is achronic psychiatric disorder characterized by recurrent intrusive thoughts and/or repetitive compulsory behaviors. This psychiatric disorder is known to be stress responsive, as symptoms increase during periods of stress but also because stressful events may precede the onset of OCD. However, only a few and inconsistent reports have been published about the stress perception and the stress-response in these patients. Herein, we have characterized the correlations of OCD symptoms with basal serum cortisol levels and scores in a stress perceived questionnaire (PSS-10). The present data reveals that cortisol levels and the stress scores in the PSS-10 were significantly higher in OCD patients that in controls. Moreover, stress levels self-reported by patients using the PSS-10 correlated positively with OCD severity in the Yale–Brown Obsessive–Compulsive Scale (Y–BOCS). Interestingly, PSS-10 scores correlated with the obsessive component, but not with the compulsive component, of Y–BOCS. These results confirm that stress is relevant in the context of OCD, particularly for the obsessive symptomatology.Pedro Morgado is supported by a fellowship “SFRH/SINTD/60129/2009” funded by FCT – Foundation for Science and Technology. Supported by FEDER funds through Operational program for competitive factors – COMPETE and by national funds through FCT –Foundation for Science and Technology to project “PTDC/SAU-NSC/111814/2009.

Variable delay-to-signal: a fast paradigm for assessment of aspects of impulsivity in rats

Testing impulsive behavior in rodents is challenging and labor-intensive. We developed a new behavioral paradigm-the Variable Delay-to-Signal (VDS) test-that provides rapid and simultaneous assessment of response and decision impulsivity in rodents. Presentation of a light at variable delays signals the permission for action (nose poke) contingent with a reward. 2 blocks of 25 trials at 3 s delay flank a block of 70 trials in which light is presented with randomly selected 6 or 12 s delays. Exposure to such large delays boosts the rate of premature responses when the delay drops to 3 s in the final block, an effect that is blunted by an acute methamphetamine challenge and that correlates with the delay-discounting (DD) paradigm (choice impulsivity). Finally, as expected, treatment with the NMDA antagonist MK-801 caused a generalized response increase in all VDS blocks. The pharmacological validation, particularly with methamphetamine which has a well established dual effect on response and decision impulsivity, and the correlations between the impulsive behavior in the DD and VDS paradigms, suggests that the later is able to provide, in a single session, a multi-dimensional assessment of impulsive behavior.The work wa ssupported by a fellowship “SFRH/BPD/80118/2011” funded by FCT—Portuguese Foundation for Science and Technology and by FEDER funds through Operational program for competitivity factors—COMPETE and by national funds through FCT—Foundation for Science and Technology to projects PTDC/SAU-NEU/108557/2008 and PTDC/SAUNSC/111814/2009

The path from the choroid plexus to the subventricular zone: go with the flow!

In adult mammals, under physiological conditions, neurogenesis, the process of generating new functional neurons from precursor cells, occurs mainly in two brain areas: the subgranular zone in the dentate gyrus of the hippocampus, and the subventricular zone (SVZ) lining the walls of the brain lateral ventricles. Taking into account the location of the SVZ and the cytoarchitecture of this periventricular neural progenitor cell niche, namely the fact that the slow dividing primary progenitor cells (type B cells) of the SVZ extend an apical primary cilium toward the brain ventricular space which is filled with cerebrospinal fluid (CSF), it becomes likely that the composition of the CSF can modulate both self-renewal, proliferation and differentiation of SVZ neural stem cells. The major site of CSF synthesis is the choroid plexus (CP); quite surprisingly, however, it is still largely unknown the contribution of molecules specifically secreted by the adult CP as modulators of the SVZ adult neurogenesis. This is even more relevant in light of recent evidence showing the ability of the CP to adapt its transcriptome and secretome to various physiologic and pathologic stimuli. By giving particular emphasizes to growth factors and axonal guidance molecules we will illustrate how CP-born molecules might play an important role in the SVZ niche cell population dynamics.Ana M. Falcão and Ashley Novais are recipients of Ph.D.Fellowships from the Fundação para a Ciência e Tecnologia (FCT,Portugal).Fernanda Marques is a recipiente of post docToral fellowship from the Fundação para a Ciência e Tecnologia (FCT,Portugal).This work is supported by a grant from FCT (PTDC/SAU-OSM/104475/2008