Luis Miguel García-Moreno

Evaluation of two experimental models of hepatic encephalopathy in rats

The serious neuropsychological repercussions of hepatic encephalopathy have led to the creation of several experimental models in order to better understand the pathogenesis of the disease. In the present investigation, two possible causes of hepatic encephalopathy, cholestasis and portal hypertension, were chosen to study the behavioral impairments caused by the disease using an object recognition task. This working memory test is based on a paradigm of spontaneous delayed non-matching to sample and was performed 60 days after surgery. Male Wistar rats (225-250 g) were divided into three groups: two experimental groups, microsurgical cholestasis (N = 20) and extrahepatic portal hypertension (N = 20), and a control group (N = 20). A mild alteration of the recognition memory occurred in rats with cholestasis compared to control rats and portal hypertensive rats. The latter group showed the poorest performance on the basis of the behavioral indexes tested. In particular, only the control group spent significantly more time exploring novel objects compared to familiar ones (P < 0.001). In addition, the portal hypertension group spent the shortest time exploring both the novel and familiar objects (P < 0.001). These results suggest that the existence of portosystemic collateral circulation per se may be responsible for subclinical encephalopathy.

Hippocampal AgNOR activity after chronic alcohol consumption and alcohol deprivation in rats

Chronic alcohol consumption induces morphological changes in the central nervous system and withdrawal does not reverse these changes. It is well known that the hippocampal formation is one of the brain regions most sensitive to prolonged alcohol ingestion. The aim of our study was to evaluate the transcriptional neuronal activity by measuring the argyrophilic nucleolar organizer regions (AgNORs) in the dentate gyrus, CA3, and CA1 hippocampal areas from adult male rats receiving chronic administration of ethanol (ALC) and after withdrawal (WDL). The parameters evaluated were the number and area of AgNORs, together with the area of nucleus and the proportion between AgNOR and nuclear areas (ratio). The animals from ALC and WDL groups showed a reduction in the number of AgNOR per cell as compared to the control group. CA3 was the hippocampal area most affected by chronic alcohol intake. No improvement was observed in animals after withdrawal. Our data support the idea that the chronic intake of alcohol decreases protein synthesis in hippocampal neurons at an early age. This decrease may explain the memory impairment showed by rats receiving chronic treatment with alcohol because, both in humans and rats, it is associated with a reduction in the number of cholinergic neurons in the basal forebrain that would in turn affect the hippocampal function.

Brain ag-NOR activity in cholestatic rats with hepatic encephalopathy

The serious repercussions of cholestasis in the liver and other organic systems have led to the creation of many experimental models in efforts to understand better its pathogenesis, prophylaxis and treatment. The extrahepatic cholestasis produces an encephalopathy by the deposition of neurotoxins in the brain similar to alcoholic and other hepatic encephalopathies. This work was designed to assess the effects of cholestasis and hepatic encephalopathy on argyrophilic nucleolar organiser region (Ag-NOR) activity in the hippocampus and inferotemporal cortex (INF). Twenty-eight male Wistar rats were used and the parameters evaluated were the area of nucleus, the area of Ag-NORs, the number of Ag-NORs per cell and the ratio of the area of Ag-NORs to that of the nucleus. The results show that cholestasis decreased neuronal synthetic activity significantly and affected the nuclear cytoarchitecture in the hippocampus and the INF.

Exploratory Analysis of Power Spectrum and Functional Connectivity During Resting State in Young Binge Drinkers: A MEG Study

Binge Drinking (BD) is a pattern of intermittent intensive alcohol intake which has spread among young adults over the last decades. Adolescence constitutes a critical neuromaturation period in which the brain is particularly sensitive to the effects of alcohol. However, little is known about how BD affects the brain activity. This study aimed to characterize the brains functional organization in BD and non-BD young population by means of analyzing functional connectivity (FC) and relative power spectra (PS) profiles measured with magnetoencephalography (MEG) during eyes-closed resting state. Our sample composed 73 first-year university students (35 BDs and 38 controls). Results showed that the BD subjects displayed a decreased alpha FC in frontal-parietal regions, and conversely, an enhanced FC in the delta, theta and beta bands in fronto-temporal networks. Besides the FC differences, the BD group showed a decreased PS within alpha range and an increased PS within theta range in the brains occipital region. These differences in FC and PS measurements provide new evidence of the neurophysiological alterations related to the alcohol neurotoxicity and could represent an initial sign of an anomalous neural activity caused by a BD pattern of alcohol consumption during youth.

Functional and structural brain connectivity of young binge drinkers: a follow-up study

Adolescence is a period of ongoing brain maturation characterized by hierarchical changes in the functional and structural networks. For this reason, the young brain is particularly vulnerable to the toxic effects of alcohol. Nowadays, binge drinking is a pattern of alcohol consumption increasingly prevalent among adolescents. The aim of the present study is to evaluate the evolution of the functional and anatomical connectivity of the Default Mode Network (DMN) in young binge drinkers along two years. Magnetoencephalography signal during eyes closed resting state as well as Diffusion Tensor Imaging (DTI) were acquired twice within a 2-year interval from 39 undergraduate students (22 controls, 17 binge drinkers) with neither personal nor family history of alcoholism. The group comparison showed that, after maintaining a binge drinking pattern along at least two years, binge drinkers displayed an increased brain connectivity of the DMN in comparison with the control group. On the other hand, the structural connectivity did not show significant differences neither between groups nor over the time. These findings point out that a continued pattern of binge drinking leads to functional alterations in the normal brain maturation process, even before anatomical changes can be detected.

Young alcohol binge drinkers have elevated blood endotoxin, peripheral inflammation and low cortisol levels: neuropsychological correlations in women

Alcohol binge drinking is a pattern of heavy alcohol consumption that is increasingly practiced by adolescents and young adults. Evidence indicates that alcohol binges induce peripheral inflammation and an exacerbated neuroimmune response that may participate in alcohol‐induced cognitive/behavioral dysfunctions. Here, we recruited 20‐year‐old male and female university students who were identified as binge drinkers for at least 2 years. Compared with controls, young alcohol binge drinkers had elevated levels of blood endotoxin and upregulated markers of the toll‐like receptor 4/NF‐κB inflammatory pathway in peripheral blood mononuclear cells, together with pro‐inflammatory cytokine/chemokine release, oxidative stress and lipid peroxidation. These changes positively correlate with the estimated blood alcohol levels achieved during alcohol binge intoxication and negatively correlate with the time elapsed from the last alcohol consumption. The immune/inflammatory changes were more prominent in female drinkers, who showed elevated levels of alcohol danger‐associated molecules, such as high mobility group box 1, indicating that there are sex‐related differences in the peripheral inflammatory response to alcohol. In contrast, cortisol levels were decreased in alcohol binge drinkers. Finally, higher levels of inflammatory markers, mainly monocyte chemoattractant protein‐1, as well as LPS, high mobility group box 1, toll‐like receptor 4, IL‐6 and ciclooxygenase‐2, correlated with worse scores on episodic memory and executive functioning tasks in female binge drinkers but not in male binge drinkers. These results emphasize possible risky consequences of alcohol use in binge episodes during young adulthood and call attention to sex‐related differences in the alcohol‐induced immune/inflammatory and neurocognitive responses.

Almeria spatial memory recognition test (ASMRT): Gender differences emerged in a new passive spatial task

Many different human spatial memory tasks were developed in the last two decades. Virtual reality based tasks make possible developing different scenarios and situations to assess spatial orientation but sometimes these tasks are complex for specific populations like children and older-adults. A new spatial task with a very limited technological requirement was developed in this study. It demanded the use of spatial memory for an accurate solution. It also proved to be sensitive to gender differences, with men outperforming women under high specific difficulty levels. Thanks to its simplicity it could be applied as a screening test and is easy to combine with EEG and fMRI studies.

Alcohol Binge Drinking and Executive Functioning during Adolescent Brain Development

Alcohol consumption in adolescents causes negative effects on familiar, social, academic life, as well as neurocognitive alterations. The binge drinking (BD) pattern of alcohol is characterized by the alternation of episodes of heavy drinking in a short interval of time, and periods of abstinence, a practice that can result in important brain alterations; even more than regular alcohol consumption. The prefrontal cortex, which acts as neural support for the executive processes, is particularly affected by alcohol; however, not all studies are in agreement about how BD alcohol consumption affects executive functioning. Some research has found that alcohol consumption in adolescence does not significantly affect executive functioning while others found it does. It is possible that these discrepancies could be due to the history of alcohol consumption, that is, at what age the subjects started drinking. The aim of our study is to assess the performance on executive functioning tasks of 13–19-year-old adolescents according to their pattern of alcohol consumption. We hypothesize that BD adolescents will perform worse than non-BD subjects in tasks that evaluate executive functions, and these differences will increase depending on how long they have been consuming alcohol. Three hundred and twenty-two students (48.14% females; age range 13–22 years; mean aged 16.7 ± 2.59) participated in the study; all of them had begun drinking at the age of 13 years. Participant were divided into three groups, according to their age range (13–15, 16–18, and 19–22 years) and divided according to their pattern of alcohol consumption (BD and control groups). Then, the subjects were evaluated with neuropsychological tasks that assess executive functions like working memory, inhibition, cognitive flexibility, or self-control among others. The entire sample showed a normal improvement in their executive performance, but this improvement was more stable and robust in the control group. Regarding the executive performance among age groups, control subjects only obtained better results than BDs in the 19–22-year-old range, whereas the performance was quite similar at younger ages. Considering that all the BD subjects started drinking at the same age (13 years old), it is possible that a kind of compensation mechanism exists in the adolescent brain which allows them to reach a normal performance in executive tasks. This theoretical mechanism would depend upon neuronal labor, which could lose efficacy over time with further alcohol ingestion. This process would account for the differences in neuropsychological performance, which were only observed in older students with a longer history of alcohol consumption.