Forced treadmill exercise prevents oxidative stress and memory deficits following chronic cerebral hypoperfusion in the rat

Physical activity impacts functional recovery following stroke in humans, however its effects in experimental animals submitted to chronic cerebral hypoperfusion have not been investigated. The aim of this study was to evaluate the therapeutic potential of exercise, as assessed by cognitive activity in the Morris water maze and the brain oxidative status, through measurement of macromolecules damage, TBARS levels and total cellular thiols, as well as antioxidant enzymes in hippocampus, striatum and cerebral cortex. Adult male Wistar rats were submitted to the modified permanent bilateral occlusion of the common carotid arteries (2VO) method, with right common carotid artery being first occluded, and tested 3 months after the ischemic event. The effects of three different exercise protocols were examined: pre-ischemia, post-ischemia and pre+post-ischemia. Physical exercise consisted of sessions of 20-min, 3 times per week during 12 weeks (moderate intensity). Rats were submitted to cognitive assessment, in both reference and working spatial memory and after the last testing session were sacrificed to have oxidative stress parameters determined. Hypoperfusion caused a significant cognitive deficit in both spatial water maze tasks and this effect was reversed in rats receiving exercise protocol post and pre+post the ischemic event. Moreover, forced regular treadmill exercise regulated oxidative damage and antioxidant enzyme activity in the hippocampus. These results suggest that physical exercise protects against cognitive and biochemical impairments caused by chronic cerebral hypoperfusion.     

Co-variation between graphic pattern stability and attentional cost: A clue for the difficulty to produce handwritten traces

Attentional cost incurred for generating handwritten graphic patterns was investigated using a classic dual-task procedure, in which a concurrent reaction time (RT) task was used as an index of the attentional cost incurred by the primary graphic task. Eight right-handed adults had to trace graphic patterns, characterized by a 0°, 45°, 90°, 135° or 180° relative phase and corresponding to shapes ranging from lines to ellipses to circles, while responding by a key press as fast as possible to an auditory signal. The results evidenced a strong and significant correlation between the stability of the produced pattern and the associated attentional cost. The amplitude of the minor and major axes of the produced ellipsoids decreased with the increase of movement frequency, as expected by nonlinear models of oscillatory pattern generation. These findings pave the way to the study for the (coordinative) processes for letter (mal)formation in cursive handwriting.     

Psychoanalytic process and thought: Convergence of Bion and Matte‐Blanco1

Using the convergence between Bion and Matte‐Blanco, in this article the author attempts to stress the view of the psychoanalytical method as promoter of expansion of the ability of the patient to think his emotional experiences. After a brief résumé of the ideas of both Bion and Matte‐Blanco, certain points of congruence between the two are emphasised: the way of perceiving the range of phenomena observed by psychoanalysis, intuition as a method for observing this field, the feelings as the raw material for thinking, and the importance of the concept of infinity in psychoanalysis. The way in which the ideas of Matte‐Blanco assist in the understanding of Bion's propositions is highlighted. Following these correlations, the author discusses certain questions pertinent to the psychoanalytical method and proposes a model in which the analyst acts as a mediator/catalyst in the process of revision of the ways in which the patient has organised his emotional experiences and the theories constructed to support these hypotheses. Samples of clinical material are presented.     

Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice

Activation of the N-methyl-d-aspartate receptor (NMDAR) glycine site has been shown to accelerate adaptive forms of learning that may benefit psychopathologies involving cognitive and perseverative disturbances. In this study, the effects of increasing the brain levels of the endogenous NMDAR glycine site agonist D-serine, through the genetic inactivation of its catabolic enzyme D-amino acid oxidase (DAO), were examined in behavioral tests of learning and memory. In the Morris water maze task (MWM), mice carrying the hypofunctional Dao1^G181R mutation demonstrated normal acquisition of a single platform location but had substantially improved memory for a new target location in the subsequent reversal phase. Furthermore, Dao1^G181R mutant animals exhibited an increased rate of extinction in the MWM that was similarly observed following pharmacological administration of D-serine (600 mg/kg) in wild-type C57BL/6J mice. In contextual and cued fear conditioning, no alterations were found in initial associative memory recall; however, extinction of the contextual fear memory was facilitated in mutant animals. Thus, an augmented level of D-serine resulting from reduced DAO activity promotes adaptive learning in response to changing conditions. The NMDAR glycine site and DAO may be promising therapeutic targets to improve cognitive flexibility and inhibitory learning in psychiatric disorders such as schizophrenia and anxiety syndromes.The N-methyl-d-aspartate receptor (NMDAR) has an important role in excitatory neurotransmission and contributes to numerous brain processes, including synaptic plasticity, learning, and memory formation (Nicoll 2003). Activation of NMDARs requires membrane depolarization in addition to concurrent binding of glutamate to NMDAR2 (NR2) and glycine to the NMDAR1 (NR1) subunit (Johnson and Ascher 1987; Clements and Westbrook 1991). D-serine has also been shown to be an endogenous co-agonist for the NR1 glycine site, acting with high selectivity and a potency similar to or greater than that of glycine (Matsui et al. 1995). In the brain, the localization of D-serine closely resembles that of NMDARs (Schell et al. 1997), and D-serine has been reported to be the predominant physiologic co-agonist for the maintenance of NMDAR-mediated currents in the hippocampus, retina, and hypothalamus (Mothet et al. 2000; Yang et al. 2003). Moreover, in vivo studies have demonstrated that the NMDAR glycine site is not saturated at the synapses of several brain regions (Fuchs et al. 2005). Consequently, increasing D-serine levels may modulate neurotransmission and behavioral responses reliant on NMDAR activity.The NMDAR glycine site has been implicated in the pathophysiology and treatment of a number of psychiatric conditions (Coyle and Tsai 2004; Millan 2005). Blockade of the NMDAR with noncompetitive antagonists like phencyclidine results in the production and exacerbation of schizophrenic-like symptoms in humans and animals (Javitt and Zukin 1991; Krystal et al. 1994). Genetic studies have associated genes that mediate D-serine synthesis and degradation with a vulnerability to schizophrenia, and levels of D-serine are decreased in the CSF and serum of schizophrenic patients (Chumakov et al. 2002; Hashimoto et al. 2003, 2005; Schumacher et al. 2004; Morita et al. 2007). These observations prompted clinical trials with direct and indirect activators of the NMDAR glycine site, including D-serine, and improvements were revealed when these compounds were added to conventional antipsychotic regimes, particularly with the negative and cognitive symptoms of schizophrenia (Tsai et al. 1998; Coyle and Tsai 2004; Heresco-Levy et al. 2005). Furthermore, altered NMDAR activation has also been shown to affect extinction, a learning process that may be of benefit in anxiety illnesses, such as post-traumatic stress syndrome and obsessive-compulsive disorder (Davis et al. 2006). In rodents, extinction was shown to be impaired following inhibition of NMDARs in contextual fear conditioning, inhibitory avoidance, and eyeblink conditioning tasks (Kehoe et al. 1996; Lee and Kim 1998; Szapiro et al. 2003). In contrast, the partial NMDAR agonist D-cycloserine facilitated the extinction of fear memories in rodents and individuals with phobias and other anxiety disorders (Ressler et al. 2004; Ledgerwood et al. 2005; Norberg et al. 2008). Thus, the NMDAR glycine site and its related modulatory proteins may be important targets for the amelioration of psychopathologies involving cognitive dysfunction and maladaptive behaviors.Endogenous levels of D-serine in the brain are regulated by its catabolic enzyme, D-amino acid oxidase (DAO); by the D-serine synthesis enzyme, serine racemase (Srr); and by neuronal and glial transporters (Foltyn et al. 2005; Martineau et al. 2006). Agents targeting such proteins may prove to be an effective method of increasing cerebral D-serine and occupancy of the NMDAR glycine site, which could overcome the difficulties D-serine and similar compounds have with penetrating the blood-brain barrier (Coyle and Tsai 2004; Bauer et al. 2005). Inhibiting DAO function in the brain is of particular interest as it would circumvent any nephrotoxicity associated with high levels of systemic D-serine (Maekawa et al. 2005a). DAO is a peroxisomal flavoprotein that at physiological pH is highly selective for D-serine, and in the brain, DAO is located predominantly in astrocytes (Mothet et al. 2000). An inverse correlation between the brain distribution of DAO and D-serine evinces the efficacy of this enzyme, with the most abundant DAO expression located in the D-serine-sparse hindbrain and cerebellum (Schell et al. 1995; Moreno et al. 1999). To study the effects of limiting DAO function, we tested a line of mice carrying a single point mutation (G181R) that results in a complete lack of DAO activity and consequently augmented D-serine in serum and brain (Sasaki et al. 1992; Hashimoto et al. 1993). These mice have previously been shown to exhibit an in vitro increase in NMDAR-mediated excitatory postsynaptic currents in dorsal horn neurons of the spinal cord and an in vivo elevation of cGMP that is indicative of augmented NMDAR activity (Wake et al. 2001; Almond et al. 2006). This demonstrates that reduced DAO function is capable of augmenting NMDAR activation, and it may follow that cognitive and extinction processes influenced by NMDARs are enhanced in Dao1^G181R mutant mice. To investigate this possibility, we assessed the effects of the Dao1^G181R mutation on learning, memory, and extinction in Morris water maze (MWM) and in contextual and cued fear conditioning paradigms.     

Interactions between spatial and kinetic dimensions in movement aftereffect

In some conditions, the surface of the test figure on which one sees an aftereffect of movement does not fit with that part of the visual field previously adapted to a movement. Such an effect, called kinetic-figural effect, may be conceived of as resulting from an interaction between two perceptual systems, each one giving specific information: one for the kinetic aspects which are spatially defined, the other for the spatial relationship inside the visual field. Experiments are presented which indicated the validity of a “law of location” for a movement aftereffect, together with some effects of the spatial relationships between adapting and test fields upon the movement aftereffect.     

Age-related changes in duration reproduction: involvement of working memory processes

The aim of the present research was to study age-related changes in duration reproduction by differentiating the working memory processes underlying this time estimation task. We compared performances of young and elderly adults in a duration reproduction task performed in simple and concurrent task conditions. Participants were also administered working memory tests to measure storage and central executive functions. Findings indicated a differential involvement of working memory storage and central executive functions in age-related differences in temporal tasks. The limited storage capacities explained age-related changes in the simple task of duration reproduction, and the dysfunctioning of central executive functions accounted for age-related changes in duration reproduction performed in a concurrent task condition, which involves greater attentional resources.     

Auditory/visual duration bisection in patients with left or right medial-temporal lobe resection

Patients with unilateral (left or right) medial temporal lobe lesions and normal control (NC) volunteers participated in two experiments, both using a duration bisection procedure. Experiment 1 assessed discrimination of auditory and visual signal durations ranging from 2 to 8 s, in the same test session. Patients and NC participants judged auditory signals as longer than equivalent duration visual signals. The difference between auditory and visual time discrimination was equivalent for the three groups, suggesting that a unilateral temporal lobe resection does not modulate the modality effect. To document interval-timing abilities after temporal lobe resection for different duration ranges, Experiment 2 investigated the discrimination of brief, 50-200 ms, auditory durations in the same patients. Overall, patients with right temporal lobe resection were found to have more variable duration judgments across both signal modality and duration range. These findings suggest the involvement of the right temporal lobe at the level of the decision process in temporal discriminations.     

Time-dependent effects of treadmill exercise on aversive memory and cyclooxygenase pathway function

Exercise induces brain function adaptations and improves learning and memory; however the time window of exercise effects has been poorly investigated. Studies demonstrate an important role for cyclooxygenase-2 (COX-2) pathway function in the mechanisms underlying memory formation. The aim of present work was to investigate the effects of treadmill exercise on aversive memory and COX-2, PGE(2) and E-prostanoid receptors contents in the rat hippocampus at different time points after exercise has ended. Adult male Wistar rats were assigned to non-exercised (sedentary) and exercised (running daily for 20min, for 2weeks) groups. The inhibitory avoidance task was used to assess aversive memory and the COX-2, PGE(2) and E-prostanoid receptors (EP1, EP2, EP3 and EP4) levels were determined 1h, 18h, 3days or 7days after the last training session of treadmill exercise. The step down latency in the inhibitory avoidance, COX-2 and EP4 receptors levels were acutely increased by exercise, with a significant positive correlation between aversive memory performance and COX-2 levels. Increased EP2 content decreased PGE(2) levels were observed 7days after the last running session. The treadmill exercise protocol facilitates inhibitory avoidance memory and induces time-dependent changes on COX-2 pathways function (COX-2, PGE(2) and EP receptors).     

The role of stability in the dynamics of learning, memorizing, and forgetting new coordination patterns

According to a dynamic theory of learning, how a new memory is formed depends on the stability of the nearest preexisting memories. To predict retention after practice, the authors analyzed how 15 participants memorized 2 bimanual coordination patterns (45 degrees or 135 degrees relative phase). The authors assessed (a) how participants memorized the required patterns with learning and (b) how the associated memory layout evolved. Results showed that a practiced 45 degrees pattern near a very stable memory (0 degrees ) persisted, whereas a 135 degrees pattern near a less stable memory (180 degrees ) was forgotten. Those findings corroborate the proposition that retention of coordination patterns depends on the stability of the extant motor memories. The authors discuss that proposal in terms of the coevolution of accuracy and stability with learning to predict persistence of required or false memories.