The roles of carbon monoxide and nitric oxide in the control of the neuroendocrine stress response: complementary or redundant

There is widespread evidence in favour of nitric oxide (NO) acting as a gaseous neurotransmitter in the central nervous system, diffusing from its cells of origin and affecting surrounding neuronal tissue in evanescent three-dimensional waves. This is also true of the hypothalamus, where amongst other activities NO inhibits stimulation of corticotrophin-releasing hormone (CRH) and vasopressin release by inflammatory stressors, effects thought to be mediated by binding with soluble guanylate cyclase (sGC). Carbon monoxide is being increasingly recognised as another gaseous neuromodulator, but with principal effects on other hemoproteins such as cyclo-oxygenase, and a distinctly different profile of localisation.NO is predominantly a pro-inflammatory agent in the periphery while CO is often anti-inflammatory. In the hypothalamus, the actions of CO are also distinct from those of NO,with marked antagonistic effects on the inflammatory release of vasopressin, both in vitro and in vivo, but with little involvement in the regulation of CRH. Thus, it would appear that these apparently similar gases exert quite distinct and separate effects, although they cause broadly similar overall changes in the secretion of neuroendocrine stress hormones. We conclude that these two gases may play significant but different roles in the control of the neuroendocrine stress response, but one common feature may be attenuation of inflammation-induced release of stress hormones.     

Relationship between neuropsychological data and response to behavioral treatment in a case of carbon monoxide toxicity and dementia

The ability of learning measures to predict a behavioral treatment response was of interest in this study. A severely impaired and behaviorally disturbed female neuropsychiatric patient was unable to demonstrate any learning on "direct" tests involving multiple free recall trials or cued paired associate recall. However, she performed normally on an "indirect" test involving implicit learning of new associations. To assess whether direct or indirect measures tapped the kind of learning required by a positive reinforcement-based treatment approach, a token program was carried out. There was a 72.5% reduction in maladaptive behavior relative to baseline, indicating a positive treatment response. The results are discussed in terms of the potential treatment utility and predictive validity of indirect measures of learning and memory and the relation of neuropsychological data to intervention issues in general.     

Inhibition of nitric oxide synthesis and gene knockout of neuronal nitric oxide synthase impaired adaptation of mouse optokinetic response eye movements

Nitric oxide (NO) plays a key role in synaptic transmission efficiency in the central nervous system. To gain an insight on the role of NO in cerebellar functions, we, here, measured the dynamics of the horizontal optokinetic response (HOKR) and vestibulo-ocular reflex (HVOR), and the adaptation of HOKR in mice locally injected with N(G)-monomethyl-L-arginine (L-NMMA) that inhibits NO synthesis and in mice devoid of neuronal nitric oxide synthase (nNOS). Local application of L-NMMA into the cerebellar flocculi induced no change in the dynamics of the HOKR but markedly depressed the adaptation of the HOKR induced by 1 hr of sustained screen oscillation. A slight difference was seen in the HOKR but not in the HVOR dynamics between nNOS(-/-) mutant and wild-type mice. One hour of sustained screen oscillation induced adaptation of the HOKR gains in wild-type mice but not in mutants. These observations suggest that NO is essential for the adaptation of the HOKR and that nNOS is the major enzyme for NO synthesis in the process.     

Reactivated memory of an inhibitory avoidance response in mice is sensitive to a nitric oxide synthase inhibitor

It is accepted that once consolidation is completed memory becomes permanent. However, it has also been suggested that reactivation (retrieval) of the original memory, again, makes it sensitive to the same treatments that affect memory consolidation when given after training. Previous results demonstrated that the immediate post-training intraperitoneal administration of N^ω-nitro-l-arginine methyl ester (L-NAME), a non-specific inhibitor of nitric oxide synthase (NOS), impairs retention test performance of a one-trial step-through inhibitory avoidance response in adult mice. The effect of L-NAME on retention was attributed to an action on memory consolidation of the original learning. For the first time, we report that the administration of L-NAME after the first retention test (memory reactivation) of the inhibitory avoidance response impairs retention performance over six consecutive days. This impairment effect is dose-and-time dependent and could not be attributed to a retrieval deficit since a mild footshock did not reinstate the original avoidance response and no spontaneous recovery was observed at least 21 days after training. Further support for a storage deficit interpretation as opposed to a retrieval deficit was obtained from the fact that L-NAME’s effects after retrieval were not due to state-dependency. The impairment effect of L-NAME was dependent on the age of the original memory. That is, there was an inverse correlation between the susceptibility of the memory trace when reactivated and the time elapsed between training and the first retrieval session. We suggest an action of L-NAME on memory reactivation-induced processes that are different from memory extinction of the original learning extending the biological significance of nitric oxide on memory.     

Ileal inducible nitric oxide synthase mRNA expression in response to stress is modified in Sprague-Dawley rats exposed to a previous intestinal inflammation

The ability of stress to initiate or reactivate an inflammatory process seems to depend on an individual's susceptibility to stressful stimuli. The aim of this study was to establish whether previous inflammation alters the response to stress in Sprague-Dawley rats, a strain not especially susceptible to stressful stimuli. Stress exposure was performed in rats treated with indomethacin, to induce cyclic intestinal inflammation, during the inactive phase of inflammation. Both control and indomethacin-treated rats submitted to stress showed a decrease in body weight gain and blood leukocyte levels, as well as an increase in fecal pellet output. The increase in intestinal mucosal mast cell count induced by stress was similar in both groups of animals. Moreover, no differences were observed between control and indomethacin-treated rats in the degree of bacterial translocation and myeloperoxidase levels after stress exposure. Despite these similarities, differences between groups were observed in inducible nitric oxide synthase (iNOS) mRNA expression. Although ileal iNOS mRNA expression was inhibited in healthy rats submitted to stress, stress failed to modify this parameter in indomethacin-treated rats. As iNOS is another inflammatory marker, our results may allow the possibility that a previous intestinal inflammation could change the intestinal susceptibility to stress. Whether these differences in ileal iNOS expression can be indicative of a possible change in the predisposition to develop an intestinal inflammatory reaction in response to stress in Sprague-Dawley rats remains to be elucidated.     

Relative importance of perceptual and mnemonic variance in human temporal bisection

We investigated the relative contributions of perception and reference memory to behavioural variability in a temporal discrimination with human subjects. We used two temporal bisection tasks. In both tasks each trial consisted of a sequential presentation of three intervals, two standards, and a probe, and subjects were asked to judge the similarity of each probe against the two standards. In a "single bisection", the standards' duration was constant across trials. In a "roving bisection", the two standards were trial unique. We compared our results with the predictions from a model related to Scalar Expectancy Theory, with the added assumption that the decision process minimizes the expected number of errors given the information available. The model shows that if errors in reference memory were dominant the psychometric function should be identical for single and roving tasks, and if perceptual errors were dominant the psychometric function should be steeper for the single than for the roving bisection. As we found that psychometric functions were steeper for the single than for the roving tasks, we concluded that perceptual errors are dominant.     

Relationship of type A behavior pattern in smokers to carbon monoxide exposure and smoking topography

Stress-related physiological factors have been proposed to mediate the Type A behavior pattern (TABP) and coronary heart disease (CHD). However, collateral behavioral factors, such as the exaggerated consummatory response patterns of Type As, may also be involved. Study 1 examined this hypothesis by comparing exposure to cigarette smoke in 42 graduate and undergraduate student smokers assessed for the TABP. After controlling for smoking rate and Federal Trade Commission cigarette carbon monoxide yield, Type As' alveolar carbon monoxide (COa) levels were higher than Type Bs', and Jenkins Activity Survey scores were correlated with COa. To determine the source of this difference, we measured smoking topography in 10 Type As and 10 Type Bs in Study 2. Type As and Type Bs did not differ in number of puffs taken or puff volume, but Type As' inhalation duration was 70% longer than Type Bs'. These results suggest that consummatory behaviors of Type As may help account for the Type A-CHD relationship for smokers. Due to increased smoke exposure, Type A smokers may also be at greater risk for cancer and lung disease than Type B smokers.     

The sensory basis of avoidance responding in the rat : Relative dominance of auditory or visual warning signals and safety signals

Three experiments determined the relative degree of stimulus control exerted by the elements of a compound auditory-visual stimulus when this stimulus was presented in various temporal relationships to a barpress avoidance response. When the compound discriminative stimulus for barpress avoidance responding consisted of onset of white noise and onset of either light or darkness, the white noise always exerted dominant control. When the compound discriminative stimulus consisted of offset of white noise and onset of light, neither element controlled avoidance responding. On the other hand, when a barpress avoidance response produced a compound feedback stimulus consisting of onset of white noise and onset of either light or darkness, the visual element always exerted dominant control. When the compound feedback stimulus consisted of offset of white noise and onset of light, both elements exerted stimulus control.     

Involvement of hippocampal nitric oxide in spatial learning in the rat

Nitric oxide (NO) is thought to be involved in synaptic plasticity contributing to learning and memory in several brain areas including the hippocampus. The hippocampus is believed to have a critical role in the processing of spatial information. But, data on the role of hippocampal NO in spatial learning are not consistent. So the effect of NO synthase (NOS) inhibition in the CA1 region of rat hippocampus on spatial localization was investigated in the Morris water maze (MWM). Male albino Wistar rats cannulated in their CA1 region received bilateral injections of vehicle (saline) or N(omega)-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor (50, 100 and 200 microg/0.5 microl) through the cannulae 30 min before training each day. Animals were subjected to 5 days of training in the MWM; 4 days with the invisible platform to test spatial learning and the 5th day with the visible platform to test motivation and sensorimotor coordination. The results showed dose-dependent increases (p<0.001) in escape latency, traveled distance, heading angle, and dose-dependent decreases (p<0.01) in target quadrant entries in L-NAME-received groups as compared to the control group. This impairment was reversed by co-administration of mole-equivalent doses of L-arginine (L-Arg), the NO precursor. L-Arg alone at the dose of 129.2 microg, increased heading angle (p<0.01) with no effect on other parameters. On the basis of the present data, it is concluded that processes mediated by NO synthesis in the hippocampus are essentially involved in spatial learning.     

The importance of response type to the relationship between temporal order and numerical magnitude

Time, number, and space may be represented in the brain by a common set of cognitive/neural mechanisms. In support of this conjecture, Schwarz and Eiselt (Journal of Experimental Psychology: Human Perception and Performance, 35, 989-1004, 2009) found that numerically smaller digits were perceived to occur earlier than larger digits, and they concluded that this difference reflected faster processing of smaller numbers. This difference, however, could have been related to a response bias, whereby participants map responses of "which first" onto the "first" number along the mental number line. In Experiment 1, participants made temporal order judgements between digits presented to the left or to the right. The point of subjective simultaneity was shifted so that the 9 had to be presented before the 2 in order for simultaneity to be perceived. This difference could reflect either faster processing of the 2 or a response bias. Experiments 2a and 2b eliminated response biases by using simultaneity judgements, which have no logical stimulus mapping. Both of the latter experiments established that the 2 was not processed faster than the 9. Although the present results relate specifically to numerical magnitude and temporal order associations, they also have broader implications. Other studies have reported associations between dimensions such as size, duration, and number and have attributed these to parietal mechanisms. Such associations, however, may also be an artefact of response biases.     

Use of carbon monoxide breath validation in assessing exposure to cigarette smoke in a worksite population

Assessed the usefulness of carbon monoxide (CO) breath validation of self-reported smoking status in a large worksite population (N = 4,647). CO assessment was performed as part of a baseline survey procedure. CO levels differed substantially in relation to self-reported smoking status and amount smoked. Correcting for ambient exposure (estimated by mean CO levels among never smokers) produced more satisfactory results than uncorrected CO levels. Striking company differences were observed in mean CO exposures among self-reported never smokers. An unexpected finding was that 17.1% of current smokers reported smoking less than daily. Although the CO measure was excellent in detecting moderate and heavy smokers, it was inadequate in detecting occasional and light smokers. If detection of occasional or lighter smoking is critical to the purposes of the study, the more expensive (but more accurate) cotinine measure is preferred.     

Relative and longitudinal evidence for the importance of the General Factor of Psychosocial Development in predicting well-being

The relationship between the General Factor of Psychosocial Development (GFPD) and well-being was examined. Support for three hypotheses was found. First, the GFPD accounted for more variance in well-being than the shared unique variance of the individual psychosocial stages. In fact, a number of the stages were negatively associated with well-being when controlling for the GFPD. Second, the GFPD accounted for a significant amount of variance in well-being when controlling for the General Factor of Personality. Third, the GFPD partially mediated the relationship between well-being at two points in time.     

Relative frequency of attribute relevance and response times in visual search

Two experiments, one using a between-Ss and one a within-Ss design, showed that response latencies to single attribute probe stimuli were longer when the target stimulus embodied two attributes (form and color) rather than a single attribute. The magnitude of this "mixed attribute effect" was influenced by the probability of attribute relevance, but the "probability effect" was mostly due to a "repetition effect," such that latencies on trials involving repetitions of the same attribute were shorter than when the relevant attribute was shifted. Implications of these results are drawn for the issues of holistic vs attributized representation of the target stimulus and serial vs parallel search of a set of attributes. Although no class of models can be ruled out on the basis of these experiments, constraints can be imposed on the versions of each that are compatible with the data presented.     

Effects of nitric oxide inhibition on avoidance learning in the chick are lateralized and localized

Bilateral administration of nitric oxide synthase inhibitors into the intermediate medial hyperstriatal (IMHV) region of the chick brain impairs memory formation for an avoidance task. The aim of the current study was to determine whether this effect was restricted to a particular location in the brain, and whether inhibition was equally effective in both hemispheres. White Leghorn x black Australorp chicks were administered 0.5 mM N(omega)-Nitro-L-arginine methyl ester bilaterally into the lobus parolfactorius (LPO), or unilaterally into the IMHV. Injections into the LPO between 5 min pre-training and 40 min post-training had no effect on retention. In contrast, unilateral injections into the IMHV impaired retention and memory loss occurred from 40 min post-training. The effective administration time was hemisphere-dependent, requiring left hemisphere administration around the time of training and right hemisphere administration between 15 and 25 min post-training. These data suggest that localized nitric oxide activity in each hemisphere of the chick brain is necessary for the consolidation of memory for this task.     

Relative rate of response and relative magnitude of reinforcement in multiple schedules

Pigeons were trained on a multiple schedule in which the duration of access to grain reinforcement was varied independently in the two components. The relative response rate in one component was an increasing function of the relative duration of reinforcement in that component. The similarity of this interaction to that found in multiple schedules of different reinforcement frequency is discussed. Extinction data were also similar to those obtained after training on multiple schedules of different reinforcement frequency.     

On the importance of critical thinking: A response to Wulf's (2015) commentary

In a recent paper (Toner & Moran, 2015), we argued that continued improvement among elite athletes requires alternation between external and internal foci of attention. In her commentary on this paper, Wulf (2015) claims that we have misunderstood the ‘attentional focus’ effect. Our rejoinder has three objectives. Firstly, we critically evaluate Wulf's arguments and counter her false allegations and spurious reasoning. Secondly, we explain our concerns about certain aspects of attentional focusing research. Finally, we propose that in order to explore the dynamic nature of attentional focusing, we need to go beyond restrictive theoretical dichotomies (e.g., “internal” versus “external” processes) using new approaches.     

Assertive training versus rehearsal and the importance of making an assertive response

This study dealt with whether mere practice would enhance assertion, and whether assertive training would reduce negative effect in simulated target situations, even when subjects (Ss) made no overt response. Males reporting difficulty with authority figures received either rehearsal alone or the complete assertive training package; in a subsequent behavioral test half in each group were told to make a response, with the remainder instructed to remain silent. Objective ratings revealed marked improvement following assertive training, while the effects of practice alone were negligible. For Ss receiving assertive training, reduction in selfreported negative affect in the target situations appeared to be independent of whether or not they engaged in overt verbalization, suggesting that assertive training, per se may enhance feelings of well-being.