Adrián Marcelo Bueno

Memory destabilization is critical for the success of the reactivation-extinction procedure.

It has been suggested that, unlike pure extinction which typically results in the return of the fear response under a variety of circumstances, memory reactivation followed by extinction can attenuate the reemergence of conditioned fear. The reactivation-extinction procedure has attracted the attention of basic and clinical researchers due to its potential clinical value for the treatment of psychiatric conditions, such as anxiety and drug abuse disorders. However, mixed results have been achieved so far in replicating and understanding this paradigm. It has been proposed that memory destabilization could be critical in this sense. Using contextual fear conditioning in rats and midazolam as an amnesic agent, we first determined what reactivation conditions are necessary to destabilize the mnemonic trace. After establishing the conditions for memory destabilization, a series of experiments was conducted to determine if destabilization is critical for the success of the reactivation-extinction procedure. Data confirmed the importance of memory destabilization prior to extinction inside the reconsolidation window to attenuate spontaneous recovery and retard reacquisition of conditioned fear. The present report offers a candidate explanation of the discrepancy in results obtained with the reactivation-extinction procedure by different laboratories.

Prediction Error and Trace Dominance Determine the Fate of Fear Memories after Post-Training Manipulations.

Different mnemonic outcomes have been observed when associative memories are reactivated by CS exposure and followed by amnestics. These outcomes include mere retrieval, destabilization-reconsolidation, a transitional period (which is insensitive to amnestics), and extinction learning. However, little is known about the interaction between initial learning conditions and these outcomes during a reinforced or nonreinforced reactivation. Here we systematically combined temporally specific memories with different reactivation parameters to observe whether these four outcomes are determined by the conditions established during training. First, we validated two training regimens with different temporal expectations about US arrival. Then, using Midazolam (MDZ) as an amnestic agent, fear memories in both learning conditions were submitted to retraining either under identical or different parameters to the original training. Destabilization (i.e., susceptibly to MDZ) occurred when reactivation was reinforced, provided the occurrence of a temporal prediction error about US arrival. In subsequent experiments, both treatments were systematically reactivated by nonreinforced context exposure of different lengths, which allowed to explore the interaction between training and reactivation lengths. These results suggest that temporal prediction error and trace dominance determine the extent to which reactivation produces the different outcomes.

Comparative analyses of the neurodegeneration induced by the non-competitive NMDA-receptor-antagonist drug MK801 in mice and rats

Non-competitive NMDA-receptor-antagonist drugs such as dizocilpine (MK801) induce behavioral changes and neurotoxicity that have made an impact in different fields of neuroscience. New approaches in research use transgenic mice to elucidate cellular mechanisms and circuits involved in the effects of these drugs. However, the neurodegeneration induced by these drugs has been extensively studied in rats, but the data in mice is limited. Therefore it is important to characterize if the neurotoxic pattern in mice corresponds to that of rats. A comparative analysis of the neurodegeneration induced by MK801 (10mg/kg) between Wistar rats, and CD-1, CF-1, and C57BL/6-129/Sv mice of both sexes, at different survival times (15, 24, 32, 48, 56 and 72 h) was analysed with the amino-cupric-silver and fluoro-jade B techniques. To compare different administration patterns, groups of mice received subchronic treatments with different doses (final doses of 20 and 40 mg/kg). Results showed that mice treated with MK801 presented different neurotoxic profiles, such as excitotoxic-like cell death in the retrosplenial cortex, terminal degeneration in CA1 and apoptotic-like degeneration in the olfactory bulb. Unlike rats, mice subjected to the same treatment failed to show neurodegeneration in corticolimbic areas such as piriform cortex and dentate gyrus. The amount of degeneration was lower in mice, and the subchronic administration of MK801 did not change the neurotoxic pattern. Additionally, mice lacked the sexually dimorphic response to MK801 toxicity observed in rats. Altogether these results indicate important species dissimilarities. Neurotoxicological studies aimed to explore pathways and mechanisms of MK801 toxicity should consider these differences when using mice as rodent models.

Strain and colony differences in the neurotoxic sequelae of MK-801 visualized with the amino-cupric-silver method

The strain and sex of a species under investigation may influence the animals physiological response to a variety of stimuli. Strain and sex differences are important considerations when evaluating animal models. In the rodent MK-801 model of schizophrenia, degenerative changes occur widely in the main olfactory system and in a number of cortical brain regions. In the present report, we compare the effects of MK-801 neurotoxicity in two strains of female rats and also two lines within each strain. The magnitude and regional extent of the neurodegeneration detected with the amino-cupric-silver method varied markedly both between the Sprague-Dawley and Wistar rat strains and also between two lines derived from each strain. For example, terminal degeneration occurred in layer VI of somatosensory cortex and the central extended amygdala in Sprague-Dawley but not Wistar rats. Moreover, MK-801 treatment led to somatodendritic degeneration in the dentate gyrus of the dorsal hippocampus and basolateral amygdala in Wistar rats from Charles River Laboratories but not those from Ferreyra Institute. There are thus both strain and intrastrain differences in the magnitude of the neurodegenerative response to MK-801 treatment. The differing neurotoxicity of MK-801 between rat strains and between lines within a strain may reflect genetic variation and/or differences in hepatic biotransformation and thus the bioavailability of the drug between strains and lines within a strain.

An appetitive experience after fear memory destabilization attenuates fear retention: involvement GluN2B-NMDA receptors in the Basolateral Amygdala Complex.

It is known that a consolidated memory can return to a labile state and become transiently malleable following reactivation. This instability is followed by a restabilization phase termed reconsolidation. In this work, we explored whether an unrelated appetitive experience (voluntary consumption of diluted sucrose) can affect a contextual fear memory in rats during the reactivation-induced destabilization phase. Our findings show that exposure to an appetitive experience following reactivation can diminish fear retention. This effect persisted after 1 wk. Importantly, it was achieved only under conditions that induced fear memory destabilization. This result could not be explained as a potentiated extinction, because sucrose was unable to promote extinction. Since GluN2B-containing NMDA receptors in the basolateral amygdala complex (BLA) have been implicated in triggering fear memory destabilization, we decided to block pharmacologically these receptors to explore the neurobiological bases of the observed effect. Intra-BLA infusion with ifenprodil, a GluN2B-NMDA antagonist, prevented the fear reduction caused by the appetitive experience. In sum, these results suggest that the expression of a fear memory can be dampened by an unrelated appetitive experience, as long as memory destabilization is achieved during reactivation. Possible mechanisms behind this effect and its clinical implications are discussed.

Attention in patients with chronic schizophrenia: Deficit in inhibitory control and positive symptoms

Background and Objectives: Attention is a central mechanism controlling information processing, activating and inhibiting processes, and forming a complex sys- tem including diferent networks in specific areas of the brain1. To correctly assess the role of attention in schizophrenia it is necessary to discriminate its different attentional com- ponents, which may by selectively altered. Attention span, focused attention, selective at- tention, sustained attention and inhibitory response, were assessed in patients with chron- ic schizophrenia and healthy matched controls. Methods: The study included 32 patients diagnosed with chronic schizophrenia and 32 healthy subjects. The groups were matched in age, sex, and level of education. Symptom severity (positive symptoms, negative symptoms, and general psychopathology) was as- sessed with the Scale for the Assessment of Positive and Negative Symptoms (SAPS and SANS). Attentional components were measured by Forward Digit Span, Symbol Search, Digit Symbol Coding, Stroop Test and Picture Completion. Results: Schizophrenic patients exhibited lower attentional scores in all tests compared to the control group. Inhibitory control and sustained attention were the most affected traits in schizophrenic patients. An inverse correlation was observed between inhibitory control and delusions and disorganized thinking. No significant correlations were ob- served between negative symptoms and attentional performance. Conclusions: The pattern of results obtained in this paper evidences the role of an in- hibitory control deficit in patients with chronic schizophrenia that could also be involved in other attentional and cognitive failures, and also be connected to positive symptoms.

A comparison of behavioral and pharmacological interventions to attenuate reactivated fear memories

Two experiments using rats in a contextual fear memory preparation compared two approaches to reduce conditioned fear: (1) pharmacological reconsolidation blockade and (2) reactivation-plus-extinction training. In Experiment 1, we explored different combinations of reactivation-plus-extinction parameters to reduce conditioned fear and attenuate reacquisition. In Experiment 2, memory reactivation was followed by extinction training or administration of midazolam (MDZ) (vs. vehicle) to reduce conditioned fear and attenuate spontaneous recovery. We found both treatments to be equally effective in both experiments. This study suggests that parameters leading to memory destabilization during reactivation are critical to observe long-lasting effects of MDZ or reactivation plus extinction.

Verbal fluency in chronic schizophrenia and severity of psychotic symptoms. Consideration of their relationship with errors in the tasks

There are many associations between psychotic symptoms and performance in Verbal Fluency (VF) tasks. However, most of these are found are with negative symptoms. In this study we examined the relationship between the performance in four VF tasks and the severity of both positive and negative symptoms. Methods: To compare performance in different VF tasks, two groups of participants were matched for age, sex and educational level, a Healthy Control Group (N = 83) and a Chronic Schizophrenia Group (N = 83). We examined the correlation between cognitive performance in these verbal tests and the severity of psychotic symptoms in the group of patients. Results: The results show that the performance of patients with chronic schizophrenia in VF tests is significantly lower than for healthy individuals. The analysis of correlations between tasks showed a significant correlation between the severity of negative symptoms and poor performance in VF tasks. Another interesting result was the association between the severity of formal thought disorder and poor performance in semantic VF. A particularly striking result was the correlation between the severity of positive symptoms and the number of errors in VF tasks in the patient group. Conclusions: These results have provided evidence for some of the proposed hypotheses and are in accordance with previous investigations. The correlations between the positive symptoms and the number of errors in the different VF tasks have not been previously reported. It is important to note that most of these correlations are between the severity of positive symptoms and intrusion errors.

Severity of negative symptoms significantly affects cognitive functioning in patients with chronic schizophrenia: The slowing in cognitive processing

Studies in patients with schizophrenia have shown a decreased overall cognitive performance, and it was found that processing speed and working memory functions are affected. The aim of this study was to describe the general cognitive performance of patients with chronic schizophrenia and analyze its relationship with the severity of psychotic symptoms. Methods: Forty-eight patients diagnosed with DSM IV-TR schizophrenia disorder were examined for symptom improvement, measured by scales SAPS and SANS. Participants also completed the full scale WAIS-III. Results: The results show a generalized cognitive deficit, reflected in the low level of general intelligence, as well as the different index that comprise the scale. The most compromised index was the processing speed. The correlations showed that the overall severity of negative symptoms significantly affects cognitive functioning of chronic patients. The formal thought disorder and alogia significantly correlated with almost all the WAIS-III measures. Conclusions: Multiple studies of specific cognitive domains in schizophrenia have shown that deficits in processing speed are the core element of cognitive impairment in schizophrenia. We support the hypothesis about the slowing in cognitive processing affect both the performance of the basic and more complex cognitive task

Positive Emotional Induction Interferes with the Reconsolidation of Negative Autobiographical Memories, in women only

&NA; After reactivation, a previously consolidated memory can enter into a labile state followed by a re‐stabilization process defined as reconsolidation. The aim of this study was to explore whether an existing negative autobiographical memory can be modified by using a non‐invasive interference (audiovisual positive preparation) after reactivation and to determine if this effect could be dependent on the reconsolidation process. We found that the presentation of a positive inductor after a negative autobiographical memory reactivation may lead to a change in the emotional information of the original trace and that such effect can be mediated by the reconsolidation process. The modification of the memory has been shown in women only. These results suggest that a positive audiovisual induction may play a potential role in psychotherapeutic techniques for the modification of dysfunctional autobiographical memories.