Chronic cocaine abuse induces long-term neural adaptations as a consequence of alterations in gene expression. This study was undertaken to identify those transcripts differentially regulated in the nucleus accumbens of human cocaine abusers. Affymetrix microarrays were used to measure transcript abundance in 10 cocaine abusers and 10 control subjects matched for age, race, sex, and brain pH. As expected, gene expression of cocaine-and amphetamine-regulated transcript (CART) was increased in the nucleus accumbens of cocaine abusers. The most robust and consistent finding, however, was a decrease in the expression of a number of myelin-related genes, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin-associated oligodendrocyte basic protein (MOBP). The differential expression seen by microarray for CART as well as MBP, MOBP, and PLP was verified by RT-PCR. In addition, immunohistochemical experiments revealed a decrease in the number of MBP-immunoreactive oligodendrocytes present in the nucleus accumbens and surrounding white matter of cocaine abusers. These findings suggest a dysregulation of myelin in human cocaine abusers. Keywords: cocaine, human, microarray, myelin basic protein, nucleus accumbens, post-mortem. Drug addiction, which constitutes a serious threat to public health, is a multifaceted disorder involving tolerance, dependence, craving, and relapse (Nestler 2002). A better understanding of the molecular mechanisms underlying drug addiction would presumably facilitate the development of more successful treatment strategies. Although the molecular basis of drug abuse is not fully understood, more is known about the neural systems subserving this disorder. In particular, animal studies have identified the nucleus accumbens as a brain region that plays a critical role in addiction (Dackis and O'Brien 2001;Everitt and Wolf 2002). Furthermore, in animal models, chronic exposure to cocaine induces structural and functional changes in the nucleus accumbens that are presumably mediated by altered gene expression (Toda et al. 2002;Norrholm et al. 2003).Although animal models continue to advance our understanding of the neurobiological underpinnings of drug abuse, it is difficult to model some uniquely human aspects of cocaine abuse, namely the spontaneous self-administration of cocaine, most often in a binging pattern of abuse, over a period of years or decades. Analysis of post-mortem brain provides a unique opportunity to examine changes in gene expression in the human drug abuser (Hurd and Herkenham 1993;Segal et al. 1997;Bannon et al. 2002). Recently, microarray technology has been employed to analyze gene expression in complex brain disorders (Mirnics et al. 2001). In the present study, we used DNA microarrays to investigate changes in gene expression in the nucleus accumbens of chronic cocaine abusers relative to carefully matched control subjects. Received September 8, 2003; revised manuscript received October 30, 2003; accepted October 31, 2003. Address corresponde...
Gene expression profiles from the anterior cingulate cortex (ACC) of human, chimpanzee, gorilla, and macaque samples provide clues about genetic regulatory changes in human and other catarrhine primate brains. The ACC, a cerebral neocortical region, has humanspecific histological features. Physiologically, an individual's ACC displays increased activity during that individual's performance of cognitive tasks. Of Ϸ45,000 probe sets on microarray chips representing transcripts of all or most human genes, Ϸ16,000 were commonly detected in human ACC samples and comparable numbers, 14,000 -15,000, in gorilla and chimpanzee ACC samples. Phylogenetic results obtained from gene expression profiles contradict the traditional expectation that the non-human African apes (i.e., chimpanzee and gorilla) should be more like each other than either should be like humans. Instead, the chimpanzee ACC profiles are more like the human than like the gorilla; these profiles demonstrate that chimpanzees are the sister group of humans. Moreover, for those unambiguous expression changes mapping to important biological processes and molecular functions that statistically are significantly represented in the data, the chimpanzee clade shows at least as much apparent regulatory evolution as does the human clade. Among important changes in the ancestry of both humans and chimpanzees, but to a greater extent in humans, are the up-regulated expression profiles of aerobic energy metabolism genes and neuronal functionrelated genes, suggesting that increased neuronal activity required increased supplies of energy. T raditionally, humans are presumed to have superior cognitive abilities and, thereby, to be very different from other animals. This presumed superiority lies in the supposed uniqueness of such human abilities as producing cultural artifacts and engaging in language and symbolic thought. Recent work, however, shows that chimpanzees, who are the sister group of humans (1-6), engage in culture (7), use tools (8-10), and display rudimentary forms of language (11-13). Moreover, with regard to DNA changes that alter proteins and are favored by natural selection, chimpanzees diverge about as much from the most recent common human-chimpanzee ancestor as do humans (1,14). Here, by estimating the relative abundance of transcribed messages of different expressed genes, we examine in humans and several other catarrhine primates gene expression profiles in an important cerebral region involved in cognition, the anterior cingulate cortex (ACC).The ACC is typically viewed as a bridge between paleocortex and neocortex but is actually part of the neocortex (15). Histologically, the ACC shows human-specific features. For example, clusters of spindle cell pyramidal neurons occur in the ACC of humans, lesser numbers in bonobo and common chimpanzees, lesser yet in gorillas, least in orangutans, and not at all in other primates and other mammals. Moreover, the spindle cells in humans are more than twice as large as in common and bonobo chimpanzees and three...
Epilepsy is a disorder of recurrent seizures that affects 1% of the population. To understand why some areas of cerebral cortex produce seizures and others do not, we identified differentially expressed genes in human epileptic neocortex compared to nearby regions that did not produce seizures. The transcriptome that emerged strongly implicates MAP kinase signaling and CREB-dependent transcription, with 74% of differentially expressed genes containing a cyclic AMP response element (CRE) in their proximal promoter, more than half of which are conserved. Despite the absence of recent seizures in these patients, epileptic brain regions prone to seizures showed persistent activation of ERK and CREB. Persistent CREB activation was directly linked to CREB-dependent gene transcription by chromatin immunoprecipitation that showed phosphorylated CREB constitutively associated with the proximal promoters of many of the induced target genes involved in neuronal signaling, excitability and synaptic plasticity. A distinct spatial pattern of ERK activation was seen in superficial axodendritic processes of epileptic neocortex that co-localized with both CREB phosphorylation and CREB target gene induction in well-demarcated populations of layer 2/3 neurons. These same neuronal lamina showed a marked increase in synaptic density. The findings generated in this study generate a robust and spatially-restricted pattern of epileptic biomarkers and associated synaptic changes that could lead to new mechanistic insights and potential therapeutic targets for human epilepsy.
Drug abuse is thought to induce long-term cellular and behavioral adaptations as a result of alterations in gene expression. Understanding the molecular consequences of addiction may contribute to the development of better treatment strategies. This study utilized highthroughput Affymetrix microarrays to identify gene expression changes in the post-mortem nucleus accumbens of chronic heroin abusers. These data were analyzed independently and in relation to our previously reported data involving human cocaine abusers, in order to determine which expression changes were drug specific and which may be common to the phenomenon of addiction. A significant decrease in the expression of numerous genes encoding proteins involved in presynaptic release of neurotransmitter was seen in heroin abusers, a finding not seen in the cocaine-abusing cohort. Conversely, the striking decrease in myelin-related genes observed in cocaine abusers was not evident in our cohort of heroin subjects. Overall, little overlap in gene expression profiles was seen between the two drug-abusing cohorts: out of the approximately 39 000 transcripts investigated, the abundance of only 25 was significantly changed in both cocaine and heroin abusers, with nearly one-half of these being altered in opposite directions. These data suggest that the profiles of nucleus accumbens gene expression associated with chronic heroin or cocaine abuse are largely unique, despite what are thought to be common effects of these drugs on dopamine neurotransmission in this brain region. A re-examination of our current assumptions about the commonality of molecular mechanisms associated with substance abuse seems warranted.
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