Unidirectional Movement Fibres from A Proprioceptive Organ of the Crab, Carcinus Maenas

1. The proprioceptive organ of the shore crab Carcinus maenas, which signals all proprioceptive sensation from the joint between propodite and dactylopodite, has been shown to contain sense cells receptive to position as well as to movement. 2. Certain cells of the organ increase their discharge frequency in response to greater degrees of flexion, while other endings respond to greater degrees of extension. Movement has little effect on the frequency of the position fibres. 3. Cells responding to movement in one direction only are present, certain ones signalling fiexion and others extension. The most sensitive undirectional movement fibres are almost completely independent of position and velocity. They provide the crab with an extremely sensitive movement sense not as yet reported in other proprioceptive mechanisms. 4. Both position-sensitive and movement-sensitive cells show a wide range of thresholds. 5. Cells which cannot be strictly classified as either position or movement sensitive have also been found. 6. By tracing the origin of the signals to the cell bodies, it appears that movement fibres have on the whole larger cell bodies than position fibres and are more proximally located. 7. Flexor and extensor movement cells appear to lie on different sides of elastic strand. 8. The question of how unidirectional sensitivity may be achieved is discussed

Addiction History Associates with the Propensity to Form Habits

Learned habitual responses to environmental stimuli allow efficient interaction with the environment, freeing cognitive resources for more demanding tasks. However, when the outcome of such actions is no longer a desired goal, established stimulus-response (S-R) associations, or habits, must be overcome. Among people with substance use disorders (SUDs), difficulty in overcoming habitual responses to stimuli associated with their addiction in favor of new, goal-directed behaviors, contributes to relapse. Animal models of habit learning demonstrate that chronic self-administration of drugs of abuse promotes habitual responding beyond the domain of compulsive drug seeking. However, whether a similar propensity toward domain-general habitual responding occurs in humans with SUDs has remained unclear. To address this question, we used a visuomotor S-R learning and re-learning task, the Hidden Association Between Images Task (HABIT), which employs abstract visual stimuli and manual responses. This task allows us to measure new S-R association learning, well-learned S-R association execution, and includes a response contingency change manipulation to quantify the degree to which responding is habit-based, rather than goal-directed. We find that people with SUDs learn new S-R associations as well as healthy control subjects do. Moreover, people with an SUD history slightly outperform controls in S-R execution. In contrast, people with SUDs are specifically impaired in overcoming well-learned S-R associations; those with SUDs make a significantly greater proportion of perseverative errors during well-learned S-R replacement, indicating the more habitual nature of their responses. Thus, with equivalent training and practice, people with SUDs appear to show enhanced domain-general habit formation

COMT Val158Met Polymorphism Exerts Sex-Dependent Effects on fMRI Measures of Brain Function

Evidence suggests that dopamine levels in the prefrontal cortex (PFC) modulate executive functions. A key regulator of PFC dopamine is catechol-O-methyltransferase (COMT). The activity level of the COMT enzyme are influenced by sex and the Val158Met polymorphism (rs4680) of the COMT gene, with male sex and Val alleles both being associated with higher bulk enzyme activity, and presumably lower PFC dopamine. COMT genotype has not only been associated with individual differences in frontal dopamine-mediated behaviors, but also with variations in neuroimaging measures of brain activity and functional connectivity. In this study, we investigated whether COMT genotype predicts individual differences in neural activity and connectivity, and whether such effects are sex-dependent. We tested 93 healthy adults (48 females), genotyped for the Val158Met polymorphism, in a delay discounting task and at rest during fMRI. Delay discounting behavior was predicted by an interaction of COMT genotype and sex, consistent with a U-shaped relationship with enzyme activity. COMT genotype and sex similarly exhibited U-shaped relationships with individual differences in neural activation, particularly among networks that were most engaged by the task, including the default-mode network. Effects of COMT genotype and sex on functional connectivity during rest were also U-shaped. In contrast, flexible reorganization of network connections across task conditions varied linearly with COMT among both sexes. These data provide insight into the potential influences of COMT-regulated variations in catecholamine levels on brain function, which may represent endophenotypes for disorders of impulsivity

Neural Systems Underlying Individual Differences in Intertemporal Decision-making

Excessively choosing immediate over larger future rewards, or delay discounting (DD), associates with multiple clinical conditions. Individual differences in DD likely depend on variations in the activation of and functional interactions between networks, representing possible endophenotypes for associated disorders, including alcohol use disorders (AUDs). Numerous fMRI studies have probed the neural bases of DD, but investigations of large-scale networks remains scant. We addressed this gap by testing whether activation within large-scale networks during “Now/Later” decision-making predicts individual differences in DD. To do so, we scanned 95 social drinkers (18–40 years; 50 females) using fMRI during hypothetical choices between small monetary amounts available “today” or larger amounts available later. We identified neural networks engaged during Now/Later choice using independent component analysis (ICA) and tested the relationship between component activation and degree of DD. The activity of two components during Now/Later choice correlated with individual DD rates: a temporal lobe network positively correlated with DD, while a frontoparietal-striatal network negatively correlated with DD. Activation differences between these networks predicted individual differences in DD and their negative correlation during Now/Later choice suggests functional competition. A generalized psychophysiological interactions (gPPI) analysis confirmed a decrease in their functional connectivity during decision-making. The functional connectivity of these two networks negatively correlates with alcohol-related harm, potentially implicating these networks in AUDs. These findings provide novel insight into the neural underpinnings of individual differences in impulsive decision making with potential implications for addiction and related disorders in which impulsivity is a defining feature

Effects of Acute Dopamine Precusor Depletion on Immediate Reward Selection Bias and Working Memory Depend on Catechol- O -methyltransferase Genotype

Little agreement exists as to acute dopamine (DA) manipulation effects on intertemporal choice in humans. We previously found that catechol-O-methyltransferase (COMT) Val158Met genotype predicts individual differences in immediate reward selection bias among adults. Moreover, we and others have shown that the relationship between COMT genotype and immediate reward bias is inverted in adolescents. No previous pharmacology studies testing DA manipulation effects on intertemporal choice have accounted for COMT genotype, and many have included participants in the adolescent age range (18–21) as adults. Moreover, many studies have included female subjects without strict cycle phase control, although recent evidence demonstrates that cyclic estradiol elevations interact with COMT genotype to affect DA-dependent cognition. These factors may have interacted with DA manipulations in past studies, potentially occluding detection of effects. Therefore, we predicted that among healthy adult males (ages 22–40), frontal DA tone, as indexed by COMT genotype, would interact with acute changes in DA signaling to affect intertemporal choice. In a double-blind, placebo-controlled design, we decreased central DA via administration of an amino acid beverage deficient in the DA precursors, phenylalanine and tyrosine (P/T[−]), and tested effects on immediate reward bias in a delay-discounting (DD) task and working memory (WM) in an n-back task. We found no main effect of beverage on DD or WM performance, but did find significant beverage*genotype effects. These results suggest that the effect of DA manipulations on DD depends on individual differences in frontal DA tone, which may have impeded some past efforts to characterize DA’s role in immediate reward bias in humans

Age modulates the effect of COMT genotype on delay discounting behavior

A form of impulsivity, the tendency to choose immediate over delayed rewards (delay-discounting) has been associated with a single nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene (COMTval158met; rs4680). However, existing data regarding the nature of this association conflicts. We have previously reported that adults homozygous for valine (val) at the COMTval158met SNP demonstrate greater delay-discounting than do methionine (met) allele carriers (Boettiger et al. 2007). In contrast, a recent study of adolescent males found that those with the met/met genotype demonstrate greater delay-discounting than do val-allele carriers (Paloyelis et al. 2010). Based on reported age-related changes in frontal dopamine function and COMT expression, we hypothesized that the association of COMT genotype with delay-discounting behavior is modulated by age from late adolescence to young adulthood

Single-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes

Fluorescence in situ hybridization (FISH) is a powerful single-cell technique for studying nuclear structure and organization. Here we report two advances in FISH-based imaging. We first describe the in situ visualization of single-copy regions of the genome using two single-molecule super-resolution methodologies. We then introduce a robust and reliable system that harnesses single-nucleotide polymorphisms (SNPs) to visually distinguish the maternal and paternal homologous chromosomes in mammalian and insect systems. Both of these new technologies are enabled by renewable, bioinformatically designed, oligonucleotide-based Oligopaint probes, which we augment with a strategy that uses secondary oligonucleotides (oligos) to produce and enhance fluorescent signals. These advances should substantially expand the capability to query parent-of-origin-specific chromosome positioning and gene expression on a cell-by-cell basis

Targeting cognitive-affective risk mechanisms in stress-precipitated alcohol dependence: An integrated, biopsychosocial model of automaticity, allostasis, and addiction

This paper proposes a novel hypothetical model integrating formerly discrete theories of stress appraisal, neurobiological allostasis, automatic cognitive processing, and addictive behavior to elucidate how alcohol misuse and dependence are maintained and re-activated by stress. We outline a risk chain in which psychosocial stress initiates physiological arousal, perseverative cognition, and negative affect that, in turn, triggers automatized schema to compel alcohol consumption. This implicit cognitive process then leads to attentional biases toward alcohol, subjective experiences of craving, paradoxical increases in arousal and alcohol-related cognitions due to urge suppression, and palliative coping through drinking. When palliative coping relieves distress, it results in negative reinforcement conditioning that perpetuates the cycle by further sensitizing the system to future stressful encounters. This model has implications for development and implementation of innovative behavioral interventions (such as mindfulness training) that disrupt cognitive-affective mechanisms underpinning stress-precipitated dependence on alcohol