Daniela Ferreira

The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling.

The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.

Chronic stress disrupts neural coherence between cortico-limbic structures

Chronic stress impairs cognitive function, namely on tasks that rely on the integrity of cortico-limbic networks. To unravel the functional impact of progressive stress in cortico-limbic networks we measured neural activity and spectral coherences between the ventral hippocampus (vHIP) and the medial prefrontal cortex (mPFC) in rats subjected to short term stress (STS) and chronic unpredictable stress (CUS). CUS exposure consistently disrupted the spectral coherence between both areas for a wide range of frequencies, whereas STS exposure failed to trigger such effect. The chronic stress-induced coherence decrease correlated inversely with the vHIP power spectrum, but not with the mPFC power spectrum, which supports the view that hippocampal dysfunction is the primary event after stress exposure. Importantly, we additionally show that the variations in vHIP-to-mPFC coherence and power spectrum in the vHIP correlated with stress-induced behavioral deficits in a spatial reference memory task. Altogether, these findings result in an innovative readout to measure, and follow, the functional events that underlie the stress-induced reference memory impairments.

Absence of ataxin-3 leads to cytoskeletal disorganization and increased cell death.

Ataxin-3 (ATXN3) is a widely expressed protein that binds to ubiquitylated proteins, has deubiquitylating activity in vitro and is thought to modulate substrate degradation through the ubiquitin-proteasome pathway. Expansion of a polyglutamine tract in ATXN3 causes Machado-Joseph disease, a late-onset neurodegenerative disorder characterized by ubiquitin-positive aggregate formation and specific neuronal death. Although ATXN3 has been involved in transcriptional repression and in the ubiquitin-proteasome pathway, its biological function is still unknown. In this work, we show that depletion of ATXN3 using small-interference RNA (siRNA) causes a prominent phenotype in both human and mouse cell lines. A mild increase in ubiquitylation occurs and cells exhibit ubiquitin-positive foci, which is consistent with ATXN3 putative function as a deubiquitylating enzyme. In addition, siATXN3-silenced cells exhibit marked morphological changes such as rounder shape and loss of adhesion protrusions. At a structural level, the microtubule, microfilament and intermediate filament networks are severely compromised and disorganized. This cytoskeletal phenotype is reversible and dependent on ATXN3 levels. Cell-extracellular matrix connection is also affected in ATXN3-depleted cells as talin expression is reduced in the focal adhesions and lower levels of alpha-1 integrin subunit are expressed at their surface. Although the cytoskeletal and adhesion problems do not originate any major change in the cell cycle of siATXN3-depleted cells, cell death is increased in siATXN3 cultures compared to controls. In summary, in this work we show that the absence of ATXN3 leads to an overt cytoskeletal/adhesion defect raising the possibility that this protein may play a role in the cytoskeleton.

Age effects on EEG correlates of the Wisconsin Card Sorting Test

Body and brain undergo several changes with aging. One of the domains in which these changes are more remarkable relates with cognitive performance. In the present work, electroencephalogram (EEG) markers (power spectral density and spectral coherence) of age‐related cognitive decline were sought whilst the subjects performed the Wisconsin Card Sorting Test (WCST). Considering the expected age‐related cognitive deficits, WCST was applied to young, mid‐age and elderly participants, and the theta and alpha frequency bands were analyzed. From the results herein presented, higher theta and alpha power were found to be associated with a good performance in the WCST of younger subjects. Additionally, higher theta and alpha coherence were also associated with good performance and were shown to decline with age and a decrease in alpha peak frequency seems to be associated with aging. Additionally, inter‐hemispheric long‐range coherences and parietal theta power were identified as age‐independent EEG correlates of cognitive performance. In summary, these data reveals age‐dependent as well as age‐independent EEG correlates of cognitive performance that contribute to the understanding of brain aging and related cognitive deficits.

Pulmonary arterial hypertension – Experience of Centro Hospitalar de Vila Nova de Gaia

INTRODUCTIONnPulmonary arterial hypertension (PAH) is a serious and progressive disease, potentially fatal in a few years. Until the 1990s the only effective treatment for this disease was pulmonary/cardiopulmonary transplant. Over the last few years several drugs have emerged that have modified the course of the disease.nnnAIMSnTo characterise patients with PAH followed at Centro Hospitalar de V.N.Gaia between 2000 and 2006. To raise awareness of this entity.nnnMATERIAL AND METHODSnRetrospective analysis of all patients with PAH or chronic thromboembolic pulmonary hypertension (CTEPH) followed at our Hospital.nnnRESULTSnIn this period 11 patients were observed, 7 women and 4 men, with a mean age of 43 y. Five patients had idiopathic PAH, three had CTEPH, two had PAH associated with interauricular communication and one had PAH associated with CREST Syndrome. At the time of diagnosis most patients were in NYHA/ /WHO Functional Class III/IV, mean systolic pulmonary artery pressure was 98+/-32 mm Hg and mean distance walked in the 6-minute walk test was 401 m. Initial treatment: Three patients had inhaled iloprost, two subcutaneous treprostinil, three oral bosentan, one oral sildenafil and two patients under- went surgery. Mean follow-up time was 28.1 months. Five patients recovered, three are stable, one worsened and two died.nnnCONCLUSIONSnPAH is a serious illness which requires a multidisciplinary approach with the need for complex and expensive therapies. Diagnosis in initial sta- ges is essential for an effective treatment.

Aging and attentional set shifting on WCST: An event-related EEG study

As the brain ages, it suffers several neurochemical, structural and functional changes. These deficits are primarily reflected on daily memory tasks. In the present work, we use the Wisconsin Card Sorting Task (WCST) task to assess P300 component of the event-related potential (ERP) as a marker for aging. Considering age-related effects, WCST was applied to young, middle-aged and elder participants. Early-late trial analysis tested the attentional set shifting and working memory updating hypothesis for the mechanisms behind WCST. The results suggest that, as people age, P3b peak latency highly correlates with age on both early and late trials, increasing as people gets older. P3b peak amplitude significantly distinguished between early and late trials regardless the subjects age, while there were no differences on P300 peak latency.

Identification of performance-related EEG phenotypes for neurofeedback training

With aging the body and the brain undergoes several changes. One of these changes is the loss of neuroplasticity, which leads to the decrease of cognitive abilities. Hence the necessity of stopping or reversing these changes is of utmost importance to contemporary society. In the present work, using electroencephalogram and the Wisconsin card sorting test (WCST) we try to understand which are the performance-related EEG phenotypes. The test was applied to young and elderly subjects due to the expected cognitive deficits with increasing age. The results showed that parietal theta desynchronization and the increase of the inter-frontal and intra-hemispheric coherence was associated to the group of good performers in the WCST. The implementation of an algorithm for low-resolution brain electromagnetic tomography (LORETA) showed that the WCST is not a specific test of the pre-frontal cortex. The identified performance-related EEG features have potential application on neurofeedback training protocols intended to hinder age-related cognitive decline.