Reorganization of Brain Networks as a Substrate of Resilience: An Analysis of Cytochrome c Oxidase Activity in Rats.

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.

Long-term consequences of alcohol use in early adolescent mice: Focus on neuroadaptations in GR, CRF and BDNF.

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.

The Relationship between Binge Drinking and Binge Eating in Adolescence and Youth: A Systematic Review and Meta-Analysis.

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.

Treadmill Exercise Buffers Behavioral Alterations Related to Ethanol Binge-Drinking in Adolescent Mice.

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 presence of a social stimulus reduces cocaine-seeking in a place preference conditioning paradigm.

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.

Training memory without aversion: Appetitive hole-board spatial learning increases adult hippocampal neurogenesis.

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.

Systemic blockade of LPA1/3 lysophosphatidic acid receptors by ki16425 modulates the effects of ethanol on the brain and behavior.

The systemic administration of lysophosphatidic acid (LPA) LPA1/3 receptor antagonists is a promising clinical tool for cancer, sclerosis and fibrosis-related diseases. Since LPA1 receptor-null mice engage in increased ethanol consumption, we evaluated the effects of systemic administration of an LPA1/3 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 LPA1/3 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.