Threat Effects on Attention Networks in Individuals with a History of Externalizing Behaviors

Research identifying the biobehavioral processes that link threat exposure to cognitive alterations can inform treatments designed to reduce perpetration of stress-induced aggression. The present study attempted to specify the effects of relatively predictable (acute) vs unpredictable (diffuse) threat on two theoretically relevant attention networks, attentional alerting and executive control; and to examine the extent to which aggression proneness moderated those effects. In a sample with high rates of externalizing behaviors (n = 74), we measured event-related brain activity during an attention network test that manipulated cognitive systems activation under distinct contexts of threat (NPU manipulation). The first set of results confirmed that threat exposure alters alerting and executive control. The predictable threat condition, relative to unpredictable threat, increased visual alerting (alert cue N1) and decreased attention (P3) to subsequent task-relevant stimuli (flanker). In contrast, overall threat and unpredictable threat conditions were associated with alerting-related quicker responding and poorer conflict resolution (congruence-related flanker N2 reductions and RT interference). The second set of results indicated that different operationalizations of aggression proneness were inconsistently related to threat-related alterations in cognitive systems. While these results regarding threat-related cognitive alterations in aggression require more study, they nevertheless expand what is known about threat-related modulation of cognition in a sample of individuals with histories of externalizing behaviors.

RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples, and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction in inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease.

RTP801/REDD1 is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA-containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction of inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease.

Lifetime trauma history and cognitive functioning in major depression and their role for cognitive-behavioral therapy outcome

Background While cognitive-behavioral therapy (CBT) is the gold-standard psychological treatment for major depression (MD), non-response and lacking stability of treatment gains are persistent issues. Potential factors influencing treatment outcome might be lifetime trauma history and possibly associated primarily prefrontal-cortex- and hippocampus-dependent cognitive alterations. Method We investigated MD and healthy control participants with (MD+T+, n = 37; MD-T+, n = 39) and without lifetime trauma history (MD+T-, n = 26; MD-T-, n = 45) regarding working memory, interference susceptibility, conflict adaptation, and autobiographical memory specificity. Further, MD+T+ (n = 21) and MD+T- groups (n = 16) were re-examined after 25 CBT sessions, with MD-T- individuals (n = 34) invited in parallel in order to explore the stability of cognitive alterations and the predictive value of lifetime trauma history, cognitive functioning, and their interaction for treatment outcome. Results On a cross-sectional level, MD+T+ showed the highest conflict adaptation, but MD+T- the lowest autobiographical memory specificity, while no group differences emerged for working memory and interference susceptibility. Clinical improvement did not differ between groups and cognitive functioning remained stable over CBT. Further, only a singular predictive association of forward digit span, but no other facets of baseline cognitive functioning, lifetime trauma history, or their interaction with treatment outcome emerged. Discussion These results indicate differential roles of lifetime trauma history and psychopathology for cognitive functioning in MD, and add to the emerging literature on considering cognitive, next to clinical remission as a relevant treatment outcome.

Threat Effects on Cognitive Systems: Testing Links to Aggression Proneness

The biobehavioral study of aggression has implications for expanding our understanding of transdiagnostic processes that increase risk for disinhibited behaviors. Towards this end, our study tested the process model of aggression (Verona & Bresin, 2015), examining whether threat-related changes in cognitive functioning are associated with self- and informant-reports of aggressive actions. Using event-related potential (ERP) measures of cognitive-attentional processes, 143 community participants were administered well-validated and translational laboratory manipulations of threat (NPU task; Schmitz & Grillon, 2012) and cognitive systems activation (Posner et al., 1980). Results confirmed the differential effects of threat predictability on ERP and behavioral indices of attentional alerting and executive control. More unpredictable threat enhanced alerting-related quicker responding, whereas more predictable threat interfered with processing of and performance on the flanker task. The results, however, failed to support the process model of aggression regarding threat-related cognitive alterations in aggression. The findings fit with a broader literature on cognitive and behavioral outputs of threat activation and provide fruitful avenues for better understanding threat-related aggression.

Associations between a Polymorphism in the rat 5-HT1A Receptor Gene Promoter Region (rs198585630) and Cognitive Alterations Induced by Microwave Exposure

The nervous system is a sensitive target of electromagnetic radiation (EMR). Chronic microwave exposure can induce cognitive deficits, and the 5-HT system is involved in this effect. Genetic polymorphisms lead to individual differences. In this study, we evaluated whether the single-nucleotide polymorphism (SNP) rs198585630 of the 5-HT1A receptor is associated with cognitive alterations in rats after microwave exposure. The transcriptional activity of the 5-HT1A receptor promoter containing the rs198585630 C/T allele was determined in vitro. Electroencephalograms (EEGs), spatial learning and memory, and the mRNA and protein expression of 5-HT1A receptor were evaluated in vivo. We demonstrated that the transcriptional activity of 5-HT1A receptor promoter containing the rs198585630 C allele was higher than that of 5-HT1A receptor promoter containing the T allele. The transcriptional activity of the 5-HT1A receptor promoter was stimulated by 30 mW/cm2 microwave exposure, and the rs198585630 C allele was more sensitive to microwave exposure, as it showed stronger transcriptional activation. Rats carrying the rs198585630 C allele exhibited increased mRNA and protein expression of 5-HT1A receptor and were more susceptible to 30 mW/cm2 microwave exposure, showing cognitive deficits and inhibition of brain electrical activity.

Neuroprotector Effect Of Strength Training In An Neuroinflammation Animal Model

Background: The preventive role of muscular strength in the diminishing of a neuroinflammation is yet unknown. In this study, the role of the prophylactic muscular strength exercise was investigated, whether it would diminish cognitive alterations and modify the antioxidant intracellular scenery in an animal neuroinflammation model of the CA1 region of the hippocampus. Methods: The animals received muscular strength training for eight weeks, three times a week. Subsequently, the stereotaxic surgery, with intra-hippocampal infusion of either saline solution or l ipopolysaccharide (LPS) was performed. Next, behavioral tests were performed: objects and social recognition. At last, the animals were euthanized and the collect of the hippocampus and the prefrontal cortex were performed and, later, the dosage of the antioxidant activity was performed. Results: The results showed that the muscular strength exercises was capable of showing a beneficial prophylactic effect in the oxidative stress caused by an acute neuroinflammation. There was diminishing of the reduced glutathione concentration (GSH) and increase of the activity of the catalase enzyme (CAT) in the group (SE + LPS), regarding the control groups. In the prefrontal cortex, there was only an increase of the CAT activity in the group (SE + LPS), regarding the groups (CT) and (SE + SAL). As for the cognitive alterations there were found in the (SE + LPS) group, diminishing the mnemonic hazard of the discriminative and social memories, when compared to the control groups. Conclusion: We concluded, therefore, that the induction of a local inflammatory process in the hippocampus leads to mnemonic deficits in behavioral activities and increase of the GSH concentration, and that the muscular strength exercise performed prophylactically presents a protective effect capable of minimizing such mnemonic deficits and increasing the antioxidant defenses in mice that suffered a local neuroinflammatory process in the hippocampus.

Oxidative Stress and Cognitive Alterations Induced by Cancer Chemotherapy Drugs: A Scoping Review

Cognitive impairment is one of the most deleterious effects of chemotherapy treatment in cancer patients, and this problem sometimes remains even after chemotherapy ends. Common classes of chemotherapy-based regimens such as anthracyclines, taxanes, and platinum derivatives can induce both oxidative stress in the blood and in the brain, and these effects can be reproduced in neuronal and glia cell cultures. In rodent models, both the acute and repeated administration of doxorubicin or adriamycin (anthracyclines) or cisplatin impairs cognitive functions, as shown by their diminished performance in different learning and memory behavioural tasks. Administration of compounds with strong antioxidant effects such as N-acetylcysteine, gamma-glutamyl cysteine ethyl ester, polydatin, caffeic acid phenethyl ester, and 2-mercaptoethane sulfonate sodium (MESNA) counteract both oxidative stress and cognitive alterations induced by chemotherapeutic drugs. These antioxidant molecules provide the scientific basis to design clinical trials in patients with the aim of reducing the oxidative stress and cognitive alterations, among other probable central nervous system changes, elicited by chemotherapy in cancer patients. In particular, N-acetylcysteine and MESNA are currently used in clinical settings and are therefore attracting scientific attention.