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Background: Most electroencephalographic (EEG) investigations on alcohol have focused on adults, and scarce data is available about the potential of EEG measurements to detect young people at high-risk, as well as, to understand possible sex differences in alcohol impact on the brain., Objective: This systematic review aimed to explore sex-related differences in EEG among young people with alcohol misuse, alcohol use disorder (AUD), and offspring of families with AUD., Methods: A systematic review of the literature was conducted following PRISMA guidelines. Review protocol was registered in Prospero (ID: CRD42024511471). After article selection process and quality assessment, 25 studies were included in our review. The search included participants between 12 and 30 years old with problematic alcohol consumption, as defined by DSM, AUDIT, or specific alcohol misuse questionnaires., Results: It seems that beta was generally higher in young males with AUD, and they usually exhibited greater interhemispheric connectivity (interHC), whereas young females with AUD tended towards enhanced intraHC. P3 appears to be particularly sensitive to alcohol misuse, with males typically exhibiting a lower amplitude than young females. Other event related potentials (ERPs) such as N415, P640, and the error-related negativity (ERN) lacked sufficient methodological support to draw conclusions regarding sex differences, N340 and P540 suggested avenues for expanding research on memory processing, indicating differences in amplitude between males and females., Conclusion: Considering sex variables in clinical research will enhance our understanding of alterations in brain function and structure with the goal of tailoring treatment strategies for AUD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The college years represent a crucial developmental period in which unhealthy behaviors, including smoking, alcohol consumption, inadequate physical activity (PA), poor sleep quality, and unhealthy nutrition habits are often acquired, influencing the onset or exacerbation of pre-existing mental disturbances such as anxiety, depression, or difficulties in emotion regulation. Our aim was to analyze the effect of the intensity of physical activity (PA) on the emotional, behavioral, and cognitive variables in a sample of young people. We recruited 103 participants (19.85 ± 0.25) who completed several online questionnaires (IPAQ-SF, STAI-t, DERS, UPPS-P, ISP-20, and Mini-IPIP). Subsequently, face-to-face sessions were conducted to assess the cognitive variables and to collect more details about their lifestyle habits, including drug use, sleep quality, and leisure activities. Based on the IPAQ-SF results, we categorized the sample into three groups: light PA (n = 47), moderate PA (n = 29), and vigorous PA (n = 27). Vigorous PA group showed better emotional regulation, lower impulsivity, fewer prefrontal symptoms and unhealthy behaviors, better sleep quality, and more leisure activities. No significant cognitive differences were found. It seems that young people are a vulnerable group with emotional and impulsivity traits and engaging in intense PA appears to be a promising avenue for managing these symptoms. In conclusion, our study suggests that young people are a vulnerable group with emotional and impulsivity traits that may precipitate in future mental disorders. Nevertheless, engaging in PA, particularly at high intensity, appears to be a promising avenue for reducing and managing these symptoms during this critical period of life.

Background: Stress is one of the main environmental factors involved in the onset of different psychopathologies. In youth, stressful life events can trigger inappropriate and health-damaging behaviors, such as binge drinking. This behavior, in turn, can lead to long-lasting changes in the neurophysiological response to stress and the development of psychological disorders late in life, e.g., alcohol use disorder. Our aim was to analyze the pattern of neurophysiological responses triggered with the exposition to a stressful virtual environment in young binge drinkers., Methods: AUDIT-3 (third question from the full AUDIT) was used to detect binge drinking (BD) in our young sample (age 18-25 years). According to the score, participants were divided into control (CO) and BD group. Next, a standardized virtual reality (VR) scenario (Richie's Plank) was used for triggering the stress response while measuring the following neurophysiological variables: brain electrical activity by electroencephalogram (EEG) and cortisol levels through saliva samples both measurements registered before and after the stressful situation. Besides, heart rate (HR) with a pulsometer and electrodermal response (EDA) through electrodes placed on fingers were analyzed before, during and after the VR task., Results: Regarding the behavior assessed during the VR task, BD group spent significantly less amount of time walking forward the table and a tendency toward more time walking backwards. There was no statistically significant difference between the BD and the CO group regarding time looking down, but when we controlled the variable sex, the BD women group displayed higher amount of time looking down than the rest of the groups. Neurophysiological measurements revealed that there was not any statistically significant difference between groups in any of the EEG registered measures, EDA response and cortisol levels. Sex-related differences were found in HR response to VR scenario, in which BD women displayed the highest peak of response to the stressor. Also, the change in heartbeat was higher in BD women than men., Conclusion: Unveiling the neurophysiological alterations associated with BD can help us to prevent and detect early onset of alcohol use disorder. Also, from our data we conclude that participants' sex can modulate some stress responses, especially when unhealthy behaviors such as BD are present. Nevertheless, the moment of registration of the neurophysiological variables respect to the stressor seems to be a crucial variable., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Moreno-Fernández, Bernabéu-Brotons, Carbonell-Colomer, Buades-Sitjar and Sampedro-Piquero.)

The identification of the risk factors of alcohol consumption in youths is crucial for early interventions focused on reducing harmful alcohol use. In our study, 82 college students (40 healthy control (CO group) and 42 with risky alcohol use (RAU group) determined by AUDIT questionnaire) between the ages of 18 and 25 years underwent a comprehensive neuropsychological assessment covering emotional and cognitive functioning. Their resting-state activity was also recorded with an EEG for 10 min with their eyes open (EO) and 10 min with their eyes closed (EC) and analyzed using the Fitting Oscillations & One-Over-F (FOOOF) paradigm. After adjusting for sex, those in the RAU group had higher emotional dysregulation and impulsivity traits. The RAU girls presented more emotional regulation problems, such as dysregulation and negative urgency compared with the RAU boys. The RAU youths had significantly worse functioning in several cognitive domains, such as sustained attention, verbal memory, and executive functions. Cognitive network analysis revealed a different pattern of connections in each group showing that in the RAU group, the verbal memory domain had the highest connection with other cognitive functions. The EEG analyses did not reveal any significant differences between the CO and the RAU groups. However, we observed only in the EO condition that boys the from the RAU group displayed a higher theta/beta ratio than the RAU girls, whereas these differences were not observed within the CO group. Our findings highlight the need to explore more deeply the emotional, cognitive and brain changes underlying the RAU in young people., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: When addressing antisocial behaviour among adolescents, programs based on the paradigm of positive psychology through enhancing self-efficacy have demonstrated their effectiveness in furthering the positive development of young people with a history of antisocial behaviour. Nevertheless, there has been little research into the effectiveness of these type of programs in mitigating substance abuse among juvenile offenders. The aim of this paper is to analyse the effectiveness of a contingency management program in reducing the prevalence of relapses into drug consumption among adolescents who have committed serious crimes., Methods: The study consisted of a sample of 91 male adolescents, between 15 and 19 years, in juvenile detention, who were divided into two treatment groups. For both groups, biological testing was used to detect drug consumption upon their re-turn from leave permits from the Centre., Results: The quasi-experimental group had significantly lower rates of relapse than the quasi-control group. Furthermore, being part of the quasi-experimental group was a significant predictor of reduced rates of relapses., Conclusion: The results suggest that the incorporation of treatment strategies which reinforce feelings of self-efficacy and adequate orientation towards the future, as a complement to disciplinary sanctions, are effective in reducing relapses in drug use among adolescent offenders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fernández-Moreno, Roncero and Moreno-Fernández.)

Anxious depression is a prevalent disease with devastating consequences. Despite the lack of knowledge about the neurobiological basis of this subtype of depression, recently our group has identified a relationship between the LPA 1 receptor, one of the six characterized G protein-coupled receptors (LPA 1-6 ) for lysophosphatidic acid, with a mixed depressive-anxiety phenotype. Dysfunctional social behaviors, which have been related to increased activation of the hypothalamus-pituitary-adrenal (HPA) axis, are key symptoms of depression and are even more prominent in patients with comorbid anxiety and depressive disorders. Social behavior and HPA functioning were assessed in animals lacking the LPA 1 receptor. For these purposes, we first examined social behaviors in wild-type and LPA 1 receptor-null mice. In addition, a dexamethasone (DEX) suppression test was carried out. maLPA 1 -null mice exhibited social avoidance, a blunted response to DEX administration and an impaired circadian rhythm of corticosterone levels, which are features that are consistently dysregulated in many mental illnesses including anxious depression. Here, we have strengthened the previous experimental evidence for maLPA 1 -null mice to represent a good animal model of anxious depression, providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, particularly this subtype of depression., Competing Interests: Declaration of Competing Interest Authors declare no conflicts of interest. All authors have agreed with the submission in its present form, (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Stressful events appear to be risky situations that can precipitate the consumption of drugs. One way to recreate stressful contexts, in an ecological and controlled method, is through immersive virtual reality (VR). In our study, we designed the scenario of an elevated plus-maze (EPM) using VR, which is widely used in animal models to assess unconditioned anxiety. This task allowed us to analyze the behavioral, psychophysiological (heart rate and electrodermal activity), and hormonal response (salivary cortisol and Alpha-amylase) to this stressful situation in different moments (before VR task (anticipation), at the end of the task and 10 minutes later) in young people with problematic alcohol use (AU, n = 27), alcohol combined with cannabis consumption (AU + C, n = 10), as well as in a control group (CO, n = 33). Behavioral analysis revealed that the AU group displayed fewer entries into open arms than the CO group, whereas both experimental groups spent less time at the end of the open arms, as well as lower time by look down index compared to the CO group. Moreover, our VR EPM induced different psychophysiological responses in the different moments measured. In general, electrodermal activity seemed to be a good biomarker of recovery from a stressful situation, as once the exposure to the stressful situation ended, the AU + C group took longer to recover compared to the CO group. Regarding hormonal analyses, we observed a similar response pattern in all groups suggesting that our VR task was able to activate both stress systems. The alpha-amylase to cortisol ratio, proposed as a biomarker of stress systems dysregulation, was higher in the group of young participants with alcohol abuse. Interestingly, our VR EPM was able to induce a slight alcohol craving in both experimental groups. In conclusion, our results suggest certain subtle behavioral and physiological differences that could be used to detect young individuals at risk of future severe addictions or other stress-related comorbidities. Moreover, it could help us to develop prevention strategies focused on emotional, cognitive, and psychophysiological aspects., Competing Interests: Authors declare no conflicts of interest., (© 2023 The Authors.)

The unpredictable chronic mild stress (UCMS) model has been used to induce depressive-like symptoms in animal models, showing adequate predictive validity. Our work aims to evaluate the effects of environmental enrichment (EE) on resilience in this experimental model of depression. We also aim to assess changes in brain connectivity using cytochrome c oxidase histochemistry in cerebral regions related to cognitive-affective processes associated with depressive disorder: dorsal hippocampus, prefrontal cortex, amygdala, accumbens, and habenula nuclei. Five groups of rats were used: UCMS, EE, EE + UCMS (enrichment + stress), BG (basal level of brain activity), and CONT (behavioral tests only). We assessed the hedonic responses elicited by sucrose solution using a consumption test; the anxiety level was evaluated using the elevated zero maze test, and the unconditioned fear responses were assessed by the cat odor test. The behavioral results showed that the UCMS protocol induces elevated anhedonia and anxiety. But these responses are attenuated previous exposure to EE. Regarding brain activity, the UCMS group showed greater activity in the habenula compared to the EE + UCMS group. EE induced a functional reorganization of brain activity. The EE + UCMS and UCMS groups showed different patterns of connections between brain regions. Our results showed that EE favors greater resilience and could reduce vulnerability to disorders such as depression and anxiety, modifying metabolic brain activity., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Adolescence and youth are critical periods in which alcohol consumption is usually initiated, especially in the form of binge drinking. In recent years, it is increasingly common to find adolescents and young people who also present binge behaviors towards unhealthy food with the aim of alleviating their anxiety (emotional eating) and/or because of impulsive personality. Despite the social and health relevance of this issue, it remains scarcely studied and more preventive research needs to be developed. Our meta-analysis study aimed to evaluate the relationship and co-occurrence of both binge behaviors during adolescence and young adulthood to clarify the link between binge drinking and eating. Selective literature search on different online databases was performed. We identified discrete but significant results regarding the direct association between binge drinking and binge eating in correlation coefficients and odds ratio. Future research should focus on the common psychological background and motives behind these problematic behaviors owing to their clinical implications for effective prevention and treatment.

Our aim was to assess the cognitive and emotional state, as well as related-changes in the glucocorticoid receptor (GR), the corticotropin-releasing factor (CRF) and the brain-derived neurotrophic factor (BDNF) expression of adolescent C57BL/6J male mice after a 5-week two-bottle choice protocol (postnatal day [pd]21 to pd52). Additionally, we wanted to analyse whether the behavioural and neurobiological effects observed in late adolescence (pd62) lasted until adulthood (pd84). Behavioural testing revealed that alcohol during early adolescence increased anxiety-like and compulsive-related behaviours, which was maintained in adulthood. Concerning cognition, working memory was only altered in late adolescent mice, whereas object location test performance was impaired in both ages. In contrast, novel object recognition remained unaltered. Immunohistochemical analysis showed that alcohol during adolescence diminished BDNF+ cells in the cingulate cortex, the hippocampal CA1 layer and the central amygdala. Regarding hypothalamic-pituitary-adrenal axis (HPA) functioning, alcohol abuse increased the GR and CRF expression in the hypothalamic paraventricular nucleus and the central amygdala. Besides this, GR density was also higher in the prelimbic cortex and the basolateral amygdala, regardless of the animals' age. Our findings suggest that adolescent alcohol exposure led to long-term behavioural alterations, along with changes in BDNF, GR and CRF expression in limbic brain areas involved in stress response, emotional regulation and cognition., (© 2022 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

The amount of carbon stored in deadwood is equivalent to about 8 per cent of the global forest carbon stocks 1 . The decomposition of deadwood is largely governed by climate 2-5 with decomposer groups-such as microorganisms and insects-contributing to variations in the decomposition rates 2,6,7 . At the global scale, the contribution of insects to the decomposition of deadwood and carbon release remains poorly understood 7 . Here we present a field experiment of wood decomposition across 55 forest sites and 6 continents. We find that the deadwood decomposition rates increase with temperature, and the strongest temperature effect is found at high precipitation levels. Precipitation affects the decomposition rates negatively at low temperatures and positively at high temperatures. As a net effect-including the direct consumption by insects and indirect effects through interactions with microorganisms-insects accelerate the decomposition in tropical forests (3.9% median mass loss per year). In temperate and boreal forests, we find weak positive and negative effects with a median mass loss of 0.9 per cent and -0.1 per cent per year, respectively. Furthermore, we apply the experimentally derived decomposition function to a global map of deadwood carbon synthesized from empirical and remote-sensing data, obtaining an estimate of 10.9 ± 3.2 petagram of carbon per year released from deadwood globally, with 93 per cent originating from tropical forests. Globally, the net effect of insects may account for 29 per cent of the carbon flux from deadwood, which suggests a functional importance of insects in the decomposition of deadwood and the carbon cycle., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Both preclinical and clinical studies have pointed that aerobic exercise, at moderate doses, is beneficial at all stages of life by promoting a range of physiological and neuroplastic adaptations that reduce the anxiety response. Previous research about this topic has repeatedly described how the regular practice of aerobic exercise induces a positive regulation of neuroplasticity and neurogenesis-related genes, as well as a better control of the HPA axis function. However, limited progress has been carried out in the integration of neuroendocrine and neuroplastic changes, as well as in introducing new factors to understand how aerobic exercise can promote resilience to future stressful conditions. Resilience is defined as the ability to adapt to stress while maintaining healthy mental and physical performance. Consistent findings point to an important role of FKBP5, the gene expressing FK506-binding protein 51 (FKBP51), as a strong inhibitor of the glucocorticoid receptor (GR), and thus, an important regulator of the stress response. We propose that aerobic exercise could contribute to modulate FKBP5 activity acting as a potential therapeutic approach for mood disorders. In this sense, aerobic exercise is well known for increasing the growth factor BDNF, which by downstream pathways could affect the FKBP5 activity. Therefore, our manuscript has the aim of analyzing how FKBP5 could constitute a promising target of aerobic exercise promoting resilient-related phenotypes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net)

The binge-drinking pattern of EtOH consumption, which is frequently observed in adolescents, is known to induce several neurobehavioral alterations, but protection strategies against these impairments remain scarcely explored. We aimed to study the protective role of treadmill physical exercise on the deficits caused after repeated cycles of binge-like EtOH exposure in the cognition, motivation, exploration, and emotion of C57BL/6J mice from adolescence to adulthood. Animals were divided into four groups: control group, exercised group, EtOH group, and exercised + EtOH group (20% in tap water). The exercise was performed for 20 min, 5 days/week at 20 cm/s. Then, animals were submitted to several behavioral tasks. Compared to binge-drinking mice, the exercised + EtOH group exhibited diminished anxiolytic-related behaviors in the elevated plus-maze, enhanced exploratory activity in the open field, reduced preference for alcohol odor when another rewarding stimulus was present (social stimulus) and lower latency to start self-cleaning behaviors in the sucrose splash test. In contrast, other measurements such as habituation learning and working memory were not improved by exercise. Besides, exercise was not able to reduce alcohol consumption across the weeks. In conclusion, physical activity during adolescence and early adulthood could buffer certain neurobehavioral alterations associated with binge-drinking, despite not reducing the quantity of consumed alcohol.

The LPA 1 receptor, one of the six characterized G protein-coupled receptors (LPA 1-6 ) through which lysophosphatidic acid acts, is likely involved in promoting normal emotional behaviours. Current data suggest that the LPA-LPA 1- receptor pathway may be involved in mediating the negative consequences of stress on hippocampal function. However, to date, there is no available information regarding the mechanisms whereby the LPA 1 receptor mediates this adaptation. To gain further insight into how the LPA-LPA 1 pathway may prevent the negative consequences of chronic stress, we assessed the effects of the continuous delivery of LPA on depressive-like behaviours induced by a chronic restraint stress protocol. Because a proper excitatory/inhibitory balance seems to be key for controlling the stress response system, the gene expression of molecular markers of excitatory and inhibitory neurotransmission was also determined. In addition, the hippocampal expression of mineralocorticoid receptor genes and glucocorticoid receptor genes and proteins as well as plasma corticosterone levels were determined. Contrary to our expectations, the continuous delivery of LPA in chronically stressed animals potentiated rather than inhibited some (e.g., anhedonia, reduced latency to the first immobility period), though not all, behavioural effects of stress. Furthermore, this treatment led to an alteration in the genes coding for proteins involved in the excitatory/inhibitory balance in the ventral hippocampus and to changes in corticosterone levels. In conclusion, the results of this study reinforce the assumption that LPA is involved in emotional regulation, mainly through the LPA 1 receptor, and regulates the effects of stress on hippocampal gene expression and hippocampus-dependent behaviour., (Copyright © 2019. Published by Elsevier Ltd.)

N-acetylated α-synuclein (αSyn) has long been established as an intrinsically disordered protein associated with a dysfunctional role in Parkinson's disease. In recent years, a physiologically relevant, higher order conformation has been identified as a helical tetramer that is tailored by buried hydrophobic interactions and is distinctively aggregation resistant. The canonical mechanism by which the tetramer assembles remains elusive. As novel biochemical approaches, computational methods, pioneering purification platforms, and powerful imaging techniques continue to develop, puzzling information that once sparked debate as to the veracity of the tetramer has now shed light upon this new counterpart in αSyn neurobiology. Nuclear magnetic resonance and computational studies on multimeric αSyn structure have revealed that the protein folding propensity is controlled by small energy barriers that enable large scale reconfiguration. Alternatively, familial mutations ablate tetramerization and reconfigure polymorphic fibrillization. In this review, we will discuss the dynamic landscape of αSyn quaternary structure with a focus on the tetrameric conformation., Competing Interests: None

Background: One challenge in the treatment of substance use disorders is to re-engage the interest toward non-drug-related activities. Among these activities, social interaction has had a prominent role due to its positive influence on treatment outcome., Aims and Methods: Our aim was to study whether the presence of a social stimulus during the cocaine-induced conditioned place preference test was able to reduce the time spent in the drug-paired compartment. For that purpose, mice were trained for four days on a conditioned place preference task with one compartment paired with cocaine and the opposite with saline. On the test day, we introduced an unfamiliar juvenile male mouse into the saline-conditioned compartment (inside a pencil cup) to analyse the animal preference towards the two rewarding stimuli (cocaine vs mouse). Additionally, to discard the possible effect of novelty, as well as the housing condition (social isolation) on social preference, we decided to include a novel object during the test session, as well as perform the same conditioned place preference protocol with a group of animals in social housing conditions., Results: The social stimulus was able to reduce the preference for cocaine and enhance the active interaction with the juvenile mouse (sniffing) compared to the empty pencil cup paired with the drug. The introduction of a novel object during the test session did not reduce the preference for the cocaine-paired compartment, and interestingly, the preference for the social stimulus was independent of the housing condition. c-Fos immunohistochemistry revealed a different pattern of activation based on cocaine-paired conditioning or the presence of social stimulus., Conclusions: These results suggest that social interaction could constitute a valuable component in the treatment of substance use disorders by reducing the salience of the drug.

Here we present a new updated and unified Poissonian earthquake catalog for Mexico. The details about the catalog compilation, the removal of duplicate events, unifying the magnitude scales, removal of dependent events through the declustering process and its completeness analysis are presented. Earthquake and focal mechanism data have been compiled from various local, regional and international sources. Large earthquake events (M W  ≥ 6.5) have been carefully revised for their epicentral locations and magnitudes from trusted publications. Different magnitude-conversion relationships, compatible with available local and regional ones, has been established to obtain unified moment magnitude estimates for the whole catalog. Completeness periods for the declustered catalog were estimated for the definition of appropriate seismic source models for the whole territory. The final unified Poissonian earthquake catalog spans from 1787 to 2018, covering a spatial extent of 13° to 33°N and 91° to 117°W. This catalog is compatible with other published catalogs providing basis for new analysis related to seismicity, seismotectonics and seismic hazard assessment in Mexico.

Lysophosphatidic acid (LPA) is an important bioactive lipid species that functions in intracellular signaling through six characterized G protein-coupled receptors (LPA 1-6 ). Among these receptors, LPA 1 is a strong candidate to mediate the central effects of LPA on emotion and may be involved in promoting normal emotional behaviors. Alterations in this receptor may induce vulnerability to stress and predispose an individual to a psychopathological disease. In fact, mice lacking the LPA 1 receptor exhibit emotional dysregulation and cognitive alterations in hippocampus-dependent tasks. Moreover, the loss of this receptor results in a phenotype of low resilience with dysfunctional coping in response to stress and induces anxiety and several behavioral and neurobiological changes that are strongly correlated with mood disorders. In fact, our group proposes that maLPA1-null mice represent an animal model of anxious depression. However, despite the key role of the LPA-LPA 1 -pathway in emotion and stress coping behaviors, the available information describing the mechanisms by which the LPA-LPA 1 -pathway regulates emotion is currently insufficient. Because activation of LPA 1 requires LPA, here, we used a Matrix-Assisted Laser Desorption/ Ionization mass spectrometry-based approach to evaluate the effects of an LPA 1 receptor deficiency on the hippocampal levels of LPA species. Additionally, the impact of stress on the LPA profile was also examined in both wild-type (WT) and the Malaga variant of LPA1-null mice (maLPA 1 -null mice). Mice lacking LPA 1 did not exhibit gross perturbations in the hippocampal LPA species, but the LPA profile was modified, showing an altered relative abundance of 18:0 LPA. Regardless of the genotype, restraint stress produced profound changes in all LPA species examined, revealing that hippocampal LPA species are a key target of stress. Finally, the relationship between the hippocampal levels of LPA species and performance in the elevated plus maze was established. To our knowledge, this study is the first to detect, identify and profile LPA species in the hippocampus of both LPA 1 -receptor null mice and WT mice at baseline and after acute stress, as well as to link these LPA species with anxiety-like behaviors. In conclusion, the hippocampal LPA species are a key target of stress and may be involved in psychopathological conditions.

Erasing memories of cocaine-stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (an LPA 1/3 receptor antagonist) or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an approximately twofold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA 1 -receptor-deficient mice were acutely infused with LPA, which revealed that LPA 1 -mediated signaling was required for LPA-induced proliferative actions. These results suggest that the LPA/LPA 1 pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine., (© 2018 Society for the Study of Addiction.)

The structurally dynamic amyloidogenic protein α-synuclein (αS) is universally recognized as a key player in Parkinson's disease (PD). Copper, which acts as a neuronal signaling agent, is also an effector of αS structure, aggregation, and localization in vivo. In humans, αS is known to carry an acetyl group on the starting methionine residue, capping the N-terminal free amine which was a known high-affinity Cu II binding site. We now report the first detailed characterization data using electron paramagnetic resonance (EPR) spectroscopy to describe the Cu II coordination modes of N-terminally acetylated αS ( NAc αS). Through use of EPR hyperfine structure analyses and the Peisach-Blumberg correlation, an N3O1 binding mode was established that involves the single histidine residue at position 50 and a lower population of a second Cu II -binding mode that may involve a C-terminal contribution. We additionally generated an N-terminally acetylated disease-relevant variant, NAc H50Q, that promotes a shift in the Cu II binding site to the C-terminus of the protein. Moreover, fibrillar NAc H50Q-Cu II exhibits enhanced parallel β-sheet character and increased hydrophobic surface area compared to NAc αS-Cu II and to both protein variants that lack a coordinated cupric ion. The results presented herein demonstrate the differential impact of distinct Cu II binding sites within NAc αS, revealing that C-terminal Cu II binding exacerbates the structural consequences of the H50Q missense mutation. Likewise, the global structural modifications that result from N-terminal capping augment the properties of Cu II coordination. Hence, consideration of the effect of Cu II on NAc αS and NAc H50Q misfolding may shed light on the extrinsic or environmental factors that influence PD pathology.

Aggregation of the neuronal protein α-synuclein (αS) is a critical factor in the pathogenesis of Parkinson's disease. Analytical methods to detect post-translational modifications of αS are under development, yet the mechanistic underpinnings of biomarkers like dityrosine formation within αS have yet to be established. In our work, we demonstrate that Cu I -bound N-terminally acetylated αS ( NAc αS) activates O 2 resulting in both intermolecular dityrosine cross-linking within the fibrillar core as well as intramolecular cross-linking within the C-terminal region. Substitution of the H50 residue with a disease relevant Q mutation abolishes intermolecular dityrosine cross-linking and limits the Cu I /O 2 promoted cross-linking to the C-terminal region. Such a dramatic change in reaction behavior establishes a previously unidentified role for H50 in facilitating intermolecular cross-linking. Involvement of H50 in the reaction profile implies that long-range histidine coordination with the upstream Cu I coordination site is necessary to stabilize the transition of Cu I to Cu II as is a required mechanistic outcome of Cu I /O 2 reactivity. The aggregation propensity of NAc H50Q-Cu I is also enhanced in comparison to NAc αS-Cu I , suggesting a potential functional role for both copper and intermolecular cross-linking in attenuating NAc αS fibrillization.

Parkinson's disease (PD) is multifactorial, likely resulting from an intricate relationship of genetic and environmental factors affecting fundamental cellular processes. Histopathological hallmarks of PD include the development of granular inclusions known as Lewy bodies that are enriched with aggregates of the protein α-synuclein (αS). Historically, αS has been considered a natively unfolded protein prone to amyloidogenic behavior. However, recent studies have revealed a physiologically relevant folded αS tetramer that is both alpha-helical and aggregation-resistant. The two forms are thought to reside in a dynamic coexistence within cells, and it has been suggested that a shift from metastable tetramers to the monomeric form could serve as a mechanism for disease initiation. The underlying pathology causing this type of shift remains unknown, but the importance of understanding tetramer stability and disassembly has therapeutic potential that cannot be overemphasized. Isolation of tetrameric αS is complicated by its dynamic nature, so thorough and detailed biochemical and biophysical studies on this αS conformer have been hampered by accessibility issues. We now report a robust and reliable recombinant expression platform that enables purification of native tetrameric αS without any detergents or other structure-modifying additives., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Exposure to environmental enrichment (EE) has been a useful model for studying the effects of experience on brain plasticity, but to date, few is known about the impact of this condition on the brain functional networks that probably underlies the multiple behavioral improvements. Hence, we assessed the effect of an EE protocol in adult Wistar rats on the performance in several behavioral tasks testing different domains (Open field (OP): locomotor activity; Elevated-zero maze (EZM): anxiety-related behaviors; 5-choice serial reaction time task (5-CSRTT): attentional processes; 4-arm radial water maze (4-RAWM): spatial memory) in order to check its effectiveness in a wide range of functions. After this, we analyzed the functional brain connectivity underlying each experimental condition through cytochrome C oxidase (COx) histochemistry. Our EE protocol reduced both locomotor activity in the OP and anxiety-related behaviors in the EZM. On the other hand, enriched rats showed more accuracy in the 4-RAWM, whereas 5-CSRTT performance was not significantly ameliorated by EE condition. In relation to COx functional connectivity, we found that EE reduced the number of strong positive correlations both in basal and training conditions, suggesting a modulating effect on specific brain connections. Our results suggest that EE seems to have a selective effect on specific brain regions, such as prefrontal cortex and hippocampus, leading to a more efficient brain connectivity., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Tetrameric α-synuclein (αS) is an elusive multimer of the dynamic neuronal protein implicated in Parkinson׳s disease. Through the data reported herein, we demonstrate that this high molecular weight multimer is N-acetylated. Coexpression of tetrameric αS in Escherichia coli with the NatB acetylase derived from yeast enables access to N-terminally acetylated αS ( NAc αS), the native form in humans. Following purification and characterization as previously described by us in "Isolation of Recombinant Tetrameric N-acetylated α-synuclein" (Fernández and Lucas, 2018), the purified protein was excised from a native gel for confirmation of N-terminal acetylation. Through high-resolution mass spectrometry techniques, the identification of this helical tetramer as NAc αS has been clearly demonstrated.

Animal models of psychopathology are particularly useful for studying the neurobiology of depression and characterising the subtypes. Recently, our group was the first to identify a possible relationship between the LPA 1 receptor and a mixed anxiety-depression phenotype. Specifically, maLPA 1 -null mice exhibited a phenotype characterised by depressive and anxious features. However, the constitutive lack of the gene encoding the LPA 1 receptor ( Lpar1 ) can induce compensatory mechanisms that might have resulted in the observed deficits. Therefore, in the present study, we have compared the impact of permanent loss and acute pharmacological inhibition of the LPA 1 receptor on despair-like behaviours and on the functional brain map associated with these behaviours, as well as on the degree of functional connectivity among structures. Although the antagonist (intracerebroventricularly administered Ki16425) mimicked some, but not all, effects of genetic deletion of the LPA 1 receptor on the results of behavioural tests and engaged different brain circuits, both treatments induced depression-like behaviours with an agitation component that was linked to functional changes in key brain regions involved in the stress response and emotional regulation. In addition, both Ki16425 treatment and LPA 1 receptor deletion modified the functional brain maps in a way similar to the changes observed in depressed patients. In summary, the pharmacological and genetic approaches could ultimately assist in dissecting the function of the LPA 1 receptor in emotional regulation and brain responses, and a combination of those approaches might provide researchers with an opportunity to develop useful drugs that target the LPA 1 receptor as treatments for depression, mainly the anxious subtype.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

The systemic administration of lysophosphatidic acid (LPA) LPA 1/3 receptor antagonists is a promising clinical tool for cancer, sclerosis and fibrosis-related diseases. Since LPA 1 receptor-null mice engage in increased ethanol consumption, we evaluated the effects of systemic administration of an LPA 1/3 receptor antagonist (intraperitoneal ki16425, 20 mg/kg) on ethanol-related behaviors as well as on brain and plasma correlates. Acute administration of ki16425 reduced motivation for ethanol but not for saccharine in ethanol self-administering Wistar rats. Mouse experiments were conducted in two different strains. In Swiss mice, ki16425 treatment reduced both ethanol-induced sedation (loss of righting reflex, LORR) and ethanol reward (escalation in ethanol consumption and ethanol-induced conditioned place preference, CPP). Furthermore, in the CPP-trained Swiss mice, ki16425 prevented the effects of ethanol on basal c-Fos expression in the medial prefrontal cortex and on adult neurogenesis in the hippocampus. In the c57BL6/J mouse strain, however, no effects of ki16425 on LORR or voluntary drinking were observed. The c57BL6/J mouse strain was then evaluated for ethanol withdrawal symptoms, which were attenuated when ethanol was preceded by ki16425 administration. In these animals, ki16425 modulated the expression of glutamate-related genes in brain limbic regions after ethanol exposure; and peripheral LPA signaling was dysregulated by either ki16425 or ethanol. Overall, these results suggest that LPA 1/3 receptor antagonists might be a potential new class of drugs that are suitable for treating or preventing alcohol use disorders. A pharmacokinetic study revealed that systemic ki16425 showed poor brain penetration, suggesting the involvement of peripheral events to explain its effects., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Learning experiences are potent modulators of adult hippocampal neurogenesis (AHN). However, the vast majority of findings on the learning-induced regulation of AHN derive from aversively-motivated tasks, mainly the water maze paradigm, in which stress is a confounding factor that affects the AHN outcome. Currently, little is known regarding the effect of appetitively-motivated training on AHN. Hence we studied how spatial learning to find food rewards in a hole-board maze modulates AHN (cell proliferation and immature neurons) and AHN-related hippocampal neuroplasticity markers (BDNF, IGF-II and CREB phosphorylation) in mice. The 'Trained' mice were tested for both spatial reference and working memory and compared to 'Pseudotrained' mice (exposed to different baited holes in each session, thus avoiding the reference memory component of the task) and 'Control' mice (exposed to the maze without rewards). In contrast to Pseudotrained and Control mice, the number of proliferating hippocampal cells were reduced in Trained mice, but they notably increased their population of immature neurons assessed by immunohistochemistry. This evidence shows that hole-board spatial reference learning diminishes cell proliferation in favor of enhancing young neurons' survival. Interestingly, the enhanced AHN in the Trained mice (specifically in the suprapyramidal blade) positively correlated with their reference memory performance, but not with their working memory. Furthermore, the Trained animals increased the hippocampal protein expression of all the neuroplasticity markers analyzed by western blot. Results show that the appetitively-motivated hole-board task is a useful paradigm to potentiate and/or investigate AHN and hippocampal plasticity minimizing aversive variables such as fear or stress., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Brain metal dyshomeostasis and altered structural dynamics of the presynaptic protein α-synuclein (αS) are both implicated in the pathology of Parkinson's disease (PD), yet a mechanistic understanding of disease progression in the context of αS structure and metal interactions remains elusive. In this Communication, we detail the influence of iron, a prevalent redox-active brain biometal, on the aggregation propensity and secondary structure of N-terminally acetylated αS ( NAc αS), the physiologically relevant form in humans. We demonstrate that under aerobic conditions, Fe(II) commits NAc αS to a PD-relevant oligomeric assembly, verified by the oligomer-selective A11 antibody, that does not have any parallel β-sheet character but contains a substantial right-twisted antiparallel β-sheet component based on CD analyses and descriptive deconvolution of the secondary structure. This NAc αS-Fe II oligomer does not develop into the β-sheet fibrils that have become hallmarks of PD, even after extended incubation, as verified by TEM imaging and the fibril-specific OC antibody. Thioflavin T (ThT), a fluorescent probe for β-sheet fibril formation, also lacks coordination to this antiparallel conformer. We further show that this oligomeric state is not observed when O 2 is excluded, indicating a role for iron(II)-mediated O 2 chemistry in locking this dynamic protein into a conformation that may have physiological or pathological implications.

Anxious depression is a prevalent disease with devastating consequences and a poor prognosis. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intracellular signalling molecule. The loss of this receptor induces anxiety and several behavioural and neurobiological changes that have been strongly associated with depression. In this study, we sought to investigate the involvement of the LPA1 receptor in mood. We first examined hedonic and despair-like behaviours in wild-type and maLPA1 receptor null mice. Owing to the behavioural response exhibited by the maLPA1-null mice, the panic-like reaction was assessed. In addition, c-Fos expression was evaluated as a measure of the functional activity, followed by interregional correlation matrices to establish the brain map of functional activation. maLPA1-null mice exhibited anhedonia, agitation and increased stress reactivity, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxiety features. Furthermore, the functional brain maps differed between the genotypes. The maLPA1-null mice showed increased limbic-system activation, similar to that observed in depressive patients. Antidepressant treatment induced behavioural improvements and functional brain normalisation. Finally, based on validity criteria, maLPA1-null mice are proposed as an animal model of anxious depression. Here, for we believe the first time, we have identified a possible relationship between the LPA1 receptor and anxious depression, shedding light on the unknown neurobiological basis of this subtype of depression and providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, especially for the anxious subtype of depression.

Classifying is a way of organizing information, which can be defined as an activity where different objects, concepts or beings are assigned to categories according to a given criterion. The criteria for classification of living organisms have changed over the course of time. In this paper, based on a historical survey, the different ways that have existed for classifying living organisms are presented. Some current discussions regarding how organisms are grouped today are also presented, as well as the premises upon which such classifications are made, such as the notion of common ancestry, hierarchy and divergence, the notions of natural category and natural classifications within the biological sciences.

Although the use of personalized annuloplasty rings manufactured for each patient according to the size and morphology of their valve complex could be beneficial for the treatment of mitral insufficiency, this possibility has been limited for reasons of time-lines and costs as well as for design and manufacturing difficulties, as has been the case with other personalized implant and prosthetic developments. However, the present quality of medical image capture equipment together with the benefits to be had from computer-aided design and manufacturing technologies (CAD-CAM) and the capabilities furnished by rapid prototyping technologies, present new opportunities for a personalized response to the development of implants and prostheses, the social impact of which could turn out to be highly positive. This paper sets out a personalized development of an annuloplasty ring based on the combined use of information from medical imaging, from CAD-CAM design programs and prototype manufacture using rapid prototyping technologies.

Expansion of GAA triplet repeats in intron 1 of the FXN gene reduces frataxin expression and causes Friedreich's ataxia. (GAA)n repeats form non-B-DNA structures, including triple helix H-DNA and higher-order structures (sticky DNA). In the proposed mechanisms of frataxin gene silencing, central unanswered questions involve the characterization of non-B-DNA structure(s) that are strongly suggested to play a role in frataxin expression. Here we examined (GAA)n binding by triplex-stabilizing benzoquinoquinoxaline (BQQ) and the corresponding triplex-DNA-cleaving BQQ-1,10-phenanthroline (BQQ-OP) compounds. We also examined the ability of these compounds to act as structural probes for H-DNA formation within higher-order structures at pathological frataxin sequences in plasmids. DNA-complex-formation analyses with a gel-mobility-shift assay and sequence-specific probing of H-DNA-forming (GAA)n sequences by single-strand oligonucleotides and triplex-directed cleavage demonstrated that a parallel pyrimidine (rather than purine) triplex is the more stable motif formed at (GAA)n repeats under physiologically relevant conditions.

A new technique for cell counting, which allows to determine the concentration of leukocytes in the internal gingival sulcus, is presented. A method of extraction of fluid from the sulcus, with micropippetes, is used. Concentration of leukocytes is determined by the application of the technique of New Bauer chamber. This method has been already applied, successfully, in two investigative works.