Risky alcohol use during youth: Impact on emotion, cognitive networks, and resting-state EEG activity.

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.

Social avoidance and altered hypothalamic-pituitary-adrenal axis in a mouse model of anxious depression: The role of LPA1 receptor.

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 LPA1 receptor, one of the six characterized G protein-coupled receptors (LPA1-6) 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 LPA1 receptor. For these purposes, we first examined social behaviors in wild-type and LPA1 receptor-null mice. In addition, a dexamethasone (DEX) suppression test was carried out. maLPA1-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 maLPA1-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.

Immersive virtual plus-maze to examine behavior and psychophysiological-related variables in young people with problematic alcohol and cannabis consumption.

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.

Building Resilience with Aerobic Exercise: Role of FKBP5.

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.

LPA1 receptor and chronic stress: Effects on behaviour and the genes involved in the hippocampal excitatory/inhibitory balance.

The LPA1 receptor, one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts, is likely involved in promoting normal emotional behaviours. Current data suggest that the LPA-LPA1-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 LPA1 receptor mediates this adaptation. To gain further insight into how the LPA-LPA1 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 LPA1 receptor, and regulates the effects of stress on hippocampal gene expression and hippocampus-dependent behaviour.

Environmental Enrichment Results in Both Brain Connectivity Efficiency and Selective Improvement in Different Behavioral Tasks.

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.

maLPA1-null mice as an endophenotype of anxious depression.

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.