The role of δ-opioid receptors in learning and memory underlying the development of addiction

Opioids are important endogenous ligands that exist in both invertebrates and vertebrates and signal by activation of opioid receptors to produce analgesia and reward or pleasure. The μ-opioid receptor is the best known of the opioid receptors and mediates the acute analgesic effects of opiates, while the δ-opioid receptor (DOR) has been less well studied and has been linked to effects that follow from chronic use of opiates such as stress, inflammation and anxiety. Recently, DORs have been shown to play an essential role in emotions and increasing evidence points to a role in learning actions and outcomes. The process of learning and memory in addiction has been proposed to involve strengthening of specific brain circuits when a drug is paired with a context or environment. The DOR is highly expressed in the hippocampus, amygdala, striatum and other basal ganglia structures known to participate in learning and memory. In this review, we will focus on the role of the DOR and its potential role in learning and memory underlying the development of addiction.

Memory and Epileptogenesis in Complex Biological and Simulated Systems

Oscillations of neural activity may bind widespread cortical areas into a neural representation that encodes disparate aspects of an event. In order to test this theory we have turned to data collected from complex partial epilepsy (CPE) patients with chronically implanted depth electrodes. Data from regions critical to word and face information processing was analyzed using spectral coherence measurements. Similar analyses of intracranial EEG (iEEG) during seizure episodes display HippoCampal Formation (HCF)—NeoCortical (NC) spectral coherence patterns that are characteristic of specific seizure stages (Klopp et al. 1996). We are now building a computational memory model to examine whether spatio-temporal patterns of human iEEG spectral coherence emerge in a computer simulation of HCF cellular distribution, membrane physiology and synaptic connectivity. Once the model is reasonably scaled it will be used as a tool to explore neural parameters that are critical to memory formation and epileptogenesis.

Mice behaviorally selected for high Pavlovian fear memory exhibit fear generalization, HPA-axis alterations and increased basal activity in cortico-limbic circuits

Biological factors underlying individual variability in fearfulness and anxiety have important implications for stress-related psychiatric illness including PTSD and major depression. Using an advanced intercross line (AIL) derived from C57BL/6 and DBA/2J mouse strains and behavioral selection over 3 generations, we established two lines exhibiting High or Low fear behavior after fear conditioning. Across the selection generations, the two lines showed clear differences in training and tests for contextual and conditioned fear. Before fear conditioning training, there were no differences between lines in baseline freezing to a novel context. However, after fear conditioning High line mice demonstrated pronounced freezing in a new context suggestive of poor context discrimination. Fear generalization was not restricted to contextual fear. High fear mice froze to a novel acoustic stimulus while freezing in the Low line did not increase over baseline. Enhanced fear learning and generalization are consistent with transgenic and pharmacological disruption of the hypothalamic-pituitary-adrenal axis (HPA-axis) (Brinks, 2009, Thompson, 2004, Kaouane, 2012). To determine whether there were differences in HPA-axis regulation between the lines, morning urine samples were collected to measure basal corticosterone. Levels of secreted corticosterone in the circadian trough were analyzed by corticosterone ELISA. High fear mice were found to have higher basal corticosterone levels than low line animals. Examination of hormonal stress response components by qPCR revealed increased expression of CRH mRNA and decreased mRNA for MR and CRHR1 in hypothalamus of high fear mice. These alterations may contribute to both the behavioral phenotype and higher basal corticosterone in High fear mice. To determine basal brain activity in vivo in High and Low fear mice we used manganese-enhanced magnetic resonance imaging (MEMRI). Analysis revealed a pattern of basal brain activity made up of amygdala, cortical and hippocampal circuits that was elevated in the High line. Ongoing studies also seek to determine the relative balance of excitatory and inhibitory tone in the amygdala and hippocampus and the neuronal structure of its neurons. While these heterogeneous lines are selected on fear memory expression, HPA-axis alterations and differences in hippocampal activity segregate with the behavioral phenotypes. These differences are detectable in a basal state strongly suggesting these are biological traits underlying the behavioral phenotype (Johnson et al, 2011).

Virtual business role-play : leveraging familiar environments to prime stakeholder memory during process elicitation

Business process models have traditionally been an effective way of examining business practices to identify areas for improvement. While common information gathering approaches are generally efficacious, they can be quite time consuming and have the risk of developing inaccuracies when information is forgotten or incorrectly interpreted by analysts. In this study, the potential of a role-playing approach for process elicitation and specification has been examined. This method allows stakeholders to enter a virtual world and role-play actions as they would in reality. As actions are completed, a model is automatically developed, removing the need for stakeholders to learn and understand a modelling grammar. Empirical data obtained in this study suggests that this approach may not only improve both the number of individual process task steps remembered and the correctness of task ordering, but also provide a reduction in the time required for stakeholders to model a process view.

In loving memory of Corfu

A travel story about a return journey to the Greek island of Corfu. "THEY say it doesn’t pay to go back. The more a place meant to you in the past, the more likely it is that you’ll be disappointed when you return. Recently I tested the theory, and endangered my memories of the Greek island of Corfu with a second visit..."--publisher website

The Ex/centric fixations project # 2 - Memory, language and polyvocal performative writing

In this paper, Bree Hadley discusses The Ex/centric Fixations Project, a practice-led research project which explores the inadequacy of language as a technology for expressing human experiences of difference, discrimination or marginalisation within mainstream cultures. The project asks questions about the way experience, memory and the public discourses available to express them are bound together, about the silences, failures and falsehoods embedded in any effort to convey human experience via public discourses, and about how these failures might form the basis of a performative writing method. It has, to date, focused on developing a method that expresses experience through improvised, intertextual and discontinous collages of language drawn from a variety of public discourses. Aesthetically, this method works with what Hans Theis Lehmann (Postdramatic Theatre p. 17) calls a “textual variant” of the postdramatic “in which language appears not as the speech of characters – if there are still definable characters at all – but as an autonomous theatricality” (Ibid. 18). It is defined by what Lehmann, following Julia Kristeva, calls a “polylogue”, which presents experience as a conflicted, discontinuous and circular phenomenon, akin to a musical fugue, to break away from “an order centred on one logos” (Ibid. 32). The texts function simultaneously as a series of parts, and as wholes, interwoven voices seeming almost to connect, almost to respond to each other, and almost to tell – or challenging each other’s telling – of a story. In this paper, Hadley offers a performative demonstration, together with descriptions of the way spectators respond, including the way their playful, polyvocal texture impacts on engagement, and the way the presence or non-presence of performing bodies to which the experiences depicted can be attached impacts on engagement. She suggests that the improvised, intertextual and experimental enactments of self embodied in the texts encourage spectators to engage at an emotional level, and make-meaning based primarily on memories they recall in the moment, and thus has the potential to counter the risk that people may read depictions of experiences radically different from their own in reductive, essentialised ways.

Quantifying the heritability of task-related brain activation and performance during the N-back working memory task: A twin fMRI study

Working memory-related brain activation has been widely studied, and impaired activation patterns have been reported for several psychiatric disorders. We investigated whether variation in N-back working memory brain activation is genetically influenced in 60 pairs of twins, (29 monozygotic (MZ), 31 dizygotic (DZ); mean age 24.4 ± 1.7S.D.). Task-related brain response (BOLD percent signal difference of 2 minus 0-back) was measured in three regions of interest. Although statistical power was low due to the small sample size, for middle frontal gyrus, angular gyrus, and supramarginal gyrus, the MZ correlations were, in general, approximately twice those of the DZ pairs, with non-significant heritability estimates (14-30%) in the low-moderate range. Task performance was strongly influenced by genes (57-73%) and highly correlated with cognitive ability (0.44-0.55). This study, which will be expanded over the next 3 years, provides the first support that individual variation in working memory-related brain activation is to some extent influenced by genes.

Genetic effects on the cerebellar role in working memory: Same brain, different genes?

Over the past several years, evidence has accumulated showing that the cerebellum plays a significant role in cognitive function. Here we show, in a large genetically informative twin sample (n= 430; aged 16-30. years), that the cerebellum is strongly, and reliably (n=30 rescans), activated during an n-back working memory task, particularly lobules I-IV, VIIa Crus I and II, IX and the vermis. Monozygotic twin correlations for cerebellar activation were generally much larger than dizygotic twin correlations, consistent with genetic influences. Structural equation models showed that up to 65% of the variance in cerebellar activation during working memory is genetic (averaging 34% across significant voxels), most prominently in the lobules VI, and VIIa Crus I, with the remaining variance explained by unique/unshared environmental factors. Heritability estimates for brain activation in the cerebellum agree with those found for working memory activation in the cerebral cortex, even though cerebellar cyto-architecture differs substantially. Phenotypic correlations between BOLD percent signal change in cerebrum and cerebellum were low, and bivariate modeling indicated that genetic influences on the cerebellum are at least partly specific to the cerebellum. Activation on the voxel-level correlated very weakly with cerebellar gray matter volume, suggesting specific genetic influences on the BOLD signal. Heritable signals identified here should facilitate discovery of genetic polymorphisms influencing cerebellar function through genome-wide association studies, to elucidate the genetic liability to brain disorders affecting the cerebellum.

Heritability of working memory brain activation

Although key to understanding individual variation in task-related brain activation, the genetic contribution to these individual differences remains largely unknown. Here we report voxel-by-voxel genetic model fitting in a large sample of 319 healthy, young adult, human identical and fraternal twins (mean ± SD age, 23.6 ±1.8 years) who performed an n-back working memory task during functional magnetic resonance imaging (fMRI) at a high magnetic field (4 tesla). Patterns of task-related brain response (BOLD signal difference of 2-back minus 0-back) were significantly heritable, with the highest estimates (40 - 65%) in the inferior, middle, and superior frontal gyri, left supplementary motor area, precentral and postcentral gyri, middle cingulate cortex, superior medial gyrus, angular gyrus, superior parietal lobule, including precuneus, and superior occipital gyri. Furthermore, high test-retest reliability for a subsample of 40 twins indicates that nongenetic variance in the fMRI brain response is largely due to unique environmental influences rather than measurement error. Individual variations in activation of the working memory network are therefore significantly influenced by genetic factors. By establishing the heritability of cognitive brain function in a large sample that affords good statistical power, and using voxel-by-voxel analyses, this study provides the necessary evidence for task-related brain activation to be considered as an endophenotype for psychiatric or neurological disorders, and represents a substantial new contribution to the field of neuroimaging genetics. These genetic brain maps should facilitate discovery of gene variants influencing cognitive brain function through genome-wide association studies, potentially opening up new avenues in the treatment of brain disorders.

Memory strength effects in fMRI studies: A matter of confidence

To investigate potentially dissociable recognition memory responses in the hippocampus and perirhinal cortex, fMRI studies have often used confidence ratings as an index of memory strength. Confidence ratings, although correlated with memory strength, also reflect sources of variability, including task-irrelevant item effects and differences both within and across individuals in terms of applying decision criteria to separate weak from strong memories. We presented words one, two, or four times at study in each of two different conditions, focused and divided attention, and then conducted separate fMRI analyses of correct old responses on the basis of subjective confidence ratings or estimates from single- versus dual-process recognition memory models. Overall, the effect of focussing attention on spaced repetitions at study manifested as enhanced recognition memory performance. Confidence- versus model-based analyses revealed disparate patterns of hippocampal and perirhinal cortex activity at both study and test and both within and across hemispheres. The failure to observe equivalent patterns of activity indicates that fMRI signals associated with subjective confidence ratings reflect additional sources of variability. The results are consistent with predictions of single-process models of recognition memory.

fMRI evidence of word frequency and strength effects in recognition memory

We used event-related fMRI to investigate the neural correlates of encoding strength and word frequency effects in recognition memory. At test, participants made Old/New decisions to intermixed low (LF) and high frequency (HF) words that had been presented once or twice at study and to new, unstudied words. The Old/New effect for all hits vs. correctly rejected unstudied words was associated with differential activity in multiple cortical regions, including the anterior medial temporal lobe (MTL), hippocampus, left lateral parietal cortex and anterior left inferior prefrontal cortex (LIPC). Items repeated at study had superior hit rates (HR) compared to items presented once and were associated with reduced activity in the right anterior MTL. By contrast, other regions that had shown conventional Old/New effects did not demonstrate modulation according to memory strength. A mirror effect for word frequency was demonstrated, with the LF word HR advantage associated with increased activity in the left lateral temporal cortex. However, none of the regions that had demonstrated Old/New item retrieval effects showed modulation according to word frequency. These findings are interpreted as supporting single-process memory models proposing a unitary strength-like memory signal and models attributing the LF word HR advantage to the greater lexico-semantic context-noise associated with HF words due to their being experienced in many pre-experimental contexts.