Transcriptional and epigenetic mechanisms of addiction

Chapter 6 - Drug Addiction and Reward

Genome-wide Analysis of Chromatin Regulation by Cocaine Reveals a Role for Sirtuins

Chromatin Remodeling Is a Key Mechanism Underlying Cocaine-Induced Plasticity in Striatum

Analyzing structural and functional brain changes related to an integrative cognitive remediation program for schizophrenia: A randomized controlled trial.

The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first 8 days of gestation (GD 0.5-8.5). Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P) 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60): we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in different tissue types later in life.

P 44. Structural and functional brain alterations in patients with myasthenia gravis

Neurobiology of Addiction

Genes and early-life adversity (ELA) interactively increase the risk of developing major depressive disorder (MDD). A recent genome-wide association study suggests that the minor T-allele of single-nucleotide polymorphisms in the bicaudal C homolog 1 gene (BICC1) has a protective role against MDD. The aims of the study were to investigate whether the minor T-allele of BICC1 is protective against hippocampal structural brain changes, whether it is associated with increased functional brain activity in the emotion regulation system, and how ELA would modify this association. Forty-four patients with MDD and 44 healthy controls were investigated using structural magnetic resonance imaging (MRI) and functional MRI with an emotion inhibition task. Analysis of a single-nucleotide polymorphism in the BICC1-1 (rs999845) gene was performed. Right hippocampal bodies of patients and controls without a history of ELA and who carry the protective T-allele of BICC1 were significantly larger compared with those participants homozygous for the major C-allele of BICC1. However, MDD patients with ELA, who carry the T-allele, had smaller hippocampal head volumes compared with MDD patients without ELA. FMRI showed that patients and controls carrying the protective T-allele of BICC1 activate the emotion regulation system significantly more compared with those participants homozygous for the major C-allele (p<0.05, family wise error corrected). These results are suggestive that the minor T-allele of BICC1 has a protective role against MDD and its known structural and functional brain changes. However, this protective effect seems to be lost in the case of co-occurrence of ELA.

During the past decades brain structure and function have been studied intensively in schizophrenic patients. Schizophrenic patients have been reported to have smaller total brain volume and sulcal and ventricular enlargement compared with healthy controls. Functionally, lower metabolism or rCBF in prefrontal cortex, especially during frontal activation tests, has been the most reproducible finding. These structural and functional brain changes have been studied relative to specific schizophrenic symptoms. There seems to be a tendency that structural brain changes are related to more negative or less positive symptoms. The findings concerning functional brain changes are more complex, pointing to a lower total metabolism in autistic patients, while patients with many positive symptoms and/or thought disorder may have a relatively higher rCBF/metabolism in some cortical brain areas.

Phenocopy frontotemporal dementia (phFTD) shares core characteristics with behavioral variant frontotemporal dementia (bvFTD), yet without associated cognitive deficits and brain abnormalities on conventional magnetic resonance imaging (MRI), and without progression. Using advanced MRI techniques, we previously observed subtle structural and functional brain changes in phFTD similar to bvFTD. The aim of the current study was to follow these as well as cognition in phFTD over time, by means of a descriptive case series. Cognition, gray matter (GM) volume and white matter (WM) microstructure, and perfusion of 6 phFTD patients were qualitatively compared longitudinally (3-years follow-up), and cross-sectionally with baseline data from 9 bvFTD patients and 17 controls. For functional brain changes, arterial spin labeling (ASL) was performed to assess GM perfusion. For structural brain changes, diffusion tensor imaging was performed to assess WM microstructure and T1w imaging to assess GM volume. MRI acquisition was performed at 3T (General Electric, US). Clinical profiles of phFTD cases at follow-up are described. At follow-up phFTD patients showed clinical symptomatology similar to bvFTD, but had a relatively stable clinical profile. Longitudinal qualitative comparisons in phFTD showed some deterioration of language and memory function, a stable pattern of structural brain abnormalities and increased perfusion over time. Additionally, both baseline and follow-up cognitive scores and structural values in phFTD were generally in between those of controls and bvFTD. Although a descriptive case series does not allow for strong conclusions, these observations in a unique longitudinal phFTD patient cohort are suggestive of the notion that phFTD and bvFTD may belong to the same disease spectrum. They may also provide a basis for further longitudinal studies in phFTD, specifically exploring the structural vs. functional brain changes. Such studies are essential for improved insight, accurate diagnosis, and appropriate treatment of phFTD.

Obesity is a major health issue. Obesity started from teenagers has become a major health concern in recent years. Intermittent fasting increases the life span. However, it is not known whether obesity and intermittent fasting affect brain functions and structures before brain aging. Here, we subjected 7-week old CD-1 wild type male mice to intermittent (alternate-day) fasting or high fat diet (45% caloric supplied by fat) for 11 months. Mice on intermittent fasting had better learning and memory assessed by the Barnes maze and fear conditioning, thicker CA1 pyramidal cell layer, higher expression of drebrin, a dendritic protein, and lower oxidative stress than mice that had free access to regular diet (control mice). Mice fed with high fat diet was obese and with hyperlipidemia. They also had poorer exercise tolerance. However, these obese mice did not present significant learning and memory impairment or changes in brain structures or oxidative stress compared with control mice. These results suggest that intermittent fasting improves brain functions and structures and that high fat diet feeding started early in life does not cause significant changes in brain functions and structures in obese middle-aged animals.

This review describes our current understanding of the changes in brain function and structure that occur in response to an intensive form of motor rehabilitation, constraint-induced movement therapy (CIMT), that has been shown to be efficacious in promoting motor function of the paretic upper limb of stroke patients. Studies using transcranial magnetic stimulation have demonstrated consistently an increase in the size of the representation of paretic hand muscles in the ipsilesional motor cortex after CIMT. This motor map expansion occurs in response to CIMT delivered at all time periods after stroke, from within days to after several years. Functional neuroimaging studies have shown varying patterns of change in activation within the sensorimotor network after CIMT. This variability may depend on the extent of stroke-induced damage to the corticospinal tract, the major descending motor pathway in the brain. This variability may also stem from interacting plastic changes in brain structure occurring in response to CIMT. CIMT is the first well defined poststroke motor rehabilitation to have identified changes in brain function and structure that accompany gains in motor function of the paretic upper limb. However, a causal link between observed changes in brain function/structure and motor gains due to CIMT has not yet been established. There is still much work to be done to understand the relationship between changes in brain function/structure and gains in motor function. Such studies should employ rigorous experimental controls to enable strong conclusions to be drawn regarding the neural effects of CIMT and how those effects confer behavioral efficacy of the therapy.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis with a characteristic neuropsychiatric syndrome and severe and prolonged clinical courses. In contrast, standard clinical magnetic resonance imaging (MRI) remains normal in the majority of patients. Here, we investigated structural and functional brain changes in a cohort of patients with anti-NMDAR encephalitis. Twenty-four patients with established diagnosis of anti-NMDAR encephalitis and age- and gender-matched controls underwent neuropsychological testing and multimodal MRI, including T1w/T2w structural imaging, analysis of resting state functional connectivity, analysis of white matter using diffusion tensor imaging, and analysis of gray matter using voxel-based morphometry. Patients showed significantly reduced functional connectivity of the left and right hippocampus with the anterior default mode network. Connectivity of both hippocampi predicted memory performance in patients. Diffusion tensor imaging revealed extensive white matter changes, which were most prominent in the cingulum and which correlated with disease severity. In contrast, no differences in T1w/T2w structural imaging and gray matter morphology were observed between patients and controls. Anti-NMDAR encephalitis is associated with characteristic alterations of functional connectivity and widespread changes of white matter integrity despite normal findings in routine clinical MRI. These results may help to explain the clinicoradiological paradox in anti-NMDAR encephalitis and advance the pathophysiological understanding of the disease. Correlation of imaging abnormalities with disease symptoms and severity suggests that these changes play an important role in the symptomatology of anti-NMDAR encephalitis.

BackgroundDuring the aging process, physical capabilities (e.g., muscular strength) and cognitive functions (e.g., memory) gradually decrease. Regarding cognitive functions, substantial functional (e.g., compensatory brain activity) and structural changes (e.g., shrinking of the hippocampus) in the brain cause this decline. Notably, growing evidence points towards a relationship between cognition and measures of muscular strength and muscle mass. Based on this emerging evidence, resistance exercises and/or resistance training, which contributes to the preservation and augmentation of muscular strength and muscle mass, may trigger beneficial neurobiological processes and could be crucial for healthy aging that includes preservation of the brain and cognition. Compared with the multitude of studies that have investigated the influence of endurance exercises and/or endurance training on cognitive performance and brain structure, considerably less work has focused on the effects of resistance exercises and/or resistance training. While the available evidence regarding resistance exercise-induced changes in cognitive functions is pooled, the underlying neurobiological processes, such as functional and structural brain changes, have yet to be summarized. Hence, the purpose of this systematic review is to provide an overview of resistance exercise-induced functional and/or structural brain changes that are related to cognitive functions.Methods and resultsA systematic literature search was conducted by two independent researchers across six electronic databases; 5957 records were returned, of which 18 were considered relevant and were analyzed.Short conclusionBased on our analyses, resistance exercises and resistance training evoked substantial functional brain changes, especially in the frontal lobe, which were accompanied by improvements in executive functions. Furthermore, resistance training led to lower white matter atrophy and smaller white matter lesion volumes. However, based on the relatively small number of studies available, the findings should be interpreted cautiously. Hence, future studies are required to investigate the underlying neurobiological mechanisms and to verify whether the positive findings can be confirmed and transferred to other needy cohorts, such as older adults with dementia, sarcopenia and/or dynapenia.

The importance of understanding the biological mechanisms of trauma.