Differential Effects of Forebrain 5-Hydroxytryptamine Depletions on Pavlovian Aversive Conditioning to Discrete and Contextual Stimuli in the Rat

The experiments examined the effects of depleting forebrain 5-hydroxytryptamine (5HT) on Pavlovian aversive conditioning to discrete and contextual stimuli. Rats were lesioned with intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine and then conditioned in a distinctive environment (termed the context) to a 30 s auditory stimulus. In 50% of animals the interval between the offset of the discrete auditory stimulus and the reinforcer, a mild foot-shock (0.5 mA, 0.5 s), was 5 s (the short-trace group) and in the other 50%, 30 s (the long-trace group). Theory predicts that animals in the short-trace condition will learn more about the discrete stimulus as a predictor of shock and become strongly conditioned, while those in the long-trace condition learn relatively more about the context. The extent of conditioning to the discrete and contextual stimuli was assessed separately, in extinction, using lick-suppression and place-preference measures respectively. Under these conditions sham subjects exhibited the expected dissociation with respect to trace interval. However, lesioned animals exhibited a specific impairment in contextual conditioning. The results are discussed in terms of the behavioural, neurochemical and neuroanatomical specificity of 5HT function in aversive conditioning and the implications for general theories of the role of 5HT in aversive processes.     

Dissociations in Hippocampal 5-Hydroxytryptamine Release in the Rat Following Pavlovian Aversive Conditioning to Discrete and Contextual Stimuli

The experiments examined the release of 5-hydroxytryptamine using in vivo microdialysis methods in the hippocampus of freely moving rats following Pavlovian aversive conditioning to discrete and contextual stimuli. Differential conditioning was achieved by manipulating the interval between the offset of a discrete auditory ‘clicker’stimulus and the onset of a mild foot-shock reinforcer (0.5 mA, 0.5 s). Foot-shock occurred either simultaneously with the last second of the discrete auditory stimulus (in short-trace subjects) or 60 s later (long-trace subjects). In this way, subjects were preferentially conditioned to the discrete stimulus and background ‘contextual’stimuli respectively. During conditioning subjects also received two identical unpaired visual stimuli. At test, dialysates were collected and behavioural measures taken as all animals experienced (i) the aversive and two other ‘neutral’environments, and (ii) the discrete unconditioned and conditioned stimuli presented in both aversive and neutral environments. Exposure to the aversive environment, but not to either of the two neutral environments, was associated with significantly increased hippocampal 5-hydroxytryptamine release in long-trace subjects. There was also a small but non-significant increase in 5-hydroxytryptamine release in short-trace animals. In contrast, hippocampal 5-hydroxytryptamine release was unaffected by presentation of either of the discrete stimuli under all conditions. The last result was obtained despite robust behavioural responses (freezing) to the discrete conditioned stimulus. These data do not agree with the hypothesis that aversive cues generally activate 5-hydroxytryptamine function in the hippocampus. Rather, they suggest a degree of specificity whereby 5-hydroxytryptamine release in the hippocampus was determined primarily by other qualitative properties of the conditioned aversive stimulus, namely whether the aversive cue was discrete or contextual, as well as by the magnitude of conditioning.     

Dorsal Anterior Cingulate Cortex Encodes the Integrated Incentive Motivational Value of Cognitive Task Performance

Humans can seamlessly combine value signals from diverse motivational incentives, yet it is not well understood how these signals are “bundled” in the brain to modulate cognitive control. The dorsal ACC (dACC) is theorized to integrate motivational value dimensions in the service of goal-directed action, although this hypothesis has yet to receive rigorous confirmation. In the present study, we examined the role of human dACC in motivational incentive integration. Healthy young adult men and women were scanned with fMRI while engaged in an experimental paradigm that quantifies the combined effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. Monetary incentives modulated trial-by-trial dACC activation, whereas block-related effects of liquid incentives on dACC activity were observed. When bundled together, incentive-related dACC modulation predicted fluctuations in both cognitive performance and self-report motivation ratings. Statistical mediation analyses suggest that dACC encoded the incentives in terms of their integrated subjective motivational value, and that this value signal was most proximally associated with task performance. Finally, we confirmed that these incentive integration effects were selectively present in dACC. Together, the results support an account in which dACC integrates motivational signals to compute the expected value of goal-directed cognitive control.SIGNIFICANCE STATEMENT How are primary and secondary incentives integrated in the brain to influence goal-directed behavior? Using an innovative experimental fMRI paradigm that combines motivational incentives that have historically been studied independently between species (e.g., monetary rewards for humans, food rewards for animals), we examine the relationship between incentive motivational value and cognitive control allocation. We find evidence that the integrated incentive motivational value of combined incentives is encoded in human dorsal ACC. Further, self-reported motivational shifts mediated the effects of incentive-modulated dorsal ACC activity on task performance, revealing convergence in how self-reported and experimentally induced motivation are encoded in the human brain. Our findings may inform future translational studies examining affective/motivational and cognitive impairments in psychopathology (e.g., anxiety, depression, addiction).     

Direct and Passive Prenatal Nicotine Exposure and the Development of Externalizing Psychopathology

The association between maternal smoking during pregnancy and childhood antisocial outcomes has been demonstrated repeatedly across a variety of outcomes. Yet debate continues as to whether this association reflects a direct programming effect of nicotine on fetal brain development, or a phenotypic indicator of heritable liability passed from mother to child. In the current study, we examine relations between maternal smoking and child behavior among 133 women and their 7–15-year-olds, who were recruited for clinical levels of psychopathology. In order to disentangle correlates of maternal smoking, women who smoked during pregnancy were compared with (a) those who did not smoke, and (b) those who did not smoke but experienced significant second-hand exposure. Second-hand exposure was associated with increased externalizing psychopathology in participant mothers’ offspring. Moreover, regression analyses indicated that smoke exposure during pregnancy predicted conduct disorder symptoms, over and above the effects of income, parental antisocial tendencies, prematurity, birth weight, and poor parenting practices. This is the first study to extend the findings of externalizing vulnerability to second hand smoke exposure. Funding for this study comes from Grant R01 MH63699 awarded to Theodore P. Beauchaine by the National Institute of Mental Health.     

Ontogenetic Exposure of Rats to Pre- and Post-Natal Manganese Enhances Behavioral Impairments Produced by Perinatal 6-Hydroxydopamine

Rats lesioned shortly after birth with 6-hydroxydopamine (6-OHDA; 134 μg icv) represent a near-ideal model of severe Parkinson’s disease because of the near-total destruction of nigrostriatal dopaminergic fibers. The element manganese, an essential cofactor for many enzymatic reactions, itself in toxic amount, replicates some clinical features similar to those of Parkinson’s disease. The aim of this study was to examine the effect of neonatal manganese exposure on 6-OHDA modeling of Parkinson’s disease in rats. Manganese (MnCl₂·4H₂O) 10,000 ppm was included in the drinking water of pregnant Wistar rats from the time of conception until the 21st day after delivery, the age when neonatal rats were weaned. Control rats consumed tap water. Other groups of neonatal rat pups, on the 3rd day after birth, were pretreated with desipramine (20 mg/kg ip 1 h) prior to bilateral icv administration of 6-OHDA (30, 60, or 137 μg) or its vehicle saline-ascorbic (0.1%) (control). At 2 months after birth, in rats lesioned with 30, 60, or 134 μg 6-OHDA, endogenous striatal dopamine (DA) content was reduced, respectively, by 66, 92, and 98% (HPLC/ED), while co-exposure of these groups to perinatal manganese did not magnify the DA depletion. However, there was prominent enhancement of DA D₁ agonist (i.e., SKF 38393)-induced oral activity in the group of rats exposed perinatally to manganese and also treated neonatally with the 30 mg/kg dose of 6-OHDA. The 30 mg/kg 6-OHDA group, demonstrating cataleptogenic responses to SCH 23390 (0.5 mg/kg) and haloperidol (0.5 mg/kg ip), developed resistance if co-exposed to perinatal manganese. In the group exposed to manganese and lesioned with the 60 mg/kg dose of 6-OHDA, there was a reduction in D₂ agonist (i.e., quinpirole, 0.1 mg/kg)-induced yawning. The series of findings demonstrate that ontogenetic exposure to manganese results in an enhancement of behavioral toxicity to a moderate dose of 6-OHDA, despite the fact that there is no enhanced depletion of striatal DA depletion by the manganese treatment.     

A Meta-Analysis of the Neuropsychological Effects of Occupational Exposure to Manganese

Even though the veracity of children's claim of psychiatric symptoms has received increased attention in recent years, identification of noncredible neuropsychological symptoms in children has been virtually overlooked in clinical practice and research. A case is presented of a 9-year-old child involved in litigation regarding a head injury sustained when he was struck by a car. Neuropsychological evaluation revealed evidence of feigned cognitive symptoms; the child displayed noncredible performance on several specialized tests designed to discreetly assess effort and an atypical pattern of responses on standard cognitive measures, as well as discrepancies between neuropsychological scores and tests administered in school and the rehab setting. Results demonstrate that children as young as 9 years of age are capable of feigning cognitive impairment, which highlights the need for routine evaluation of effort, irrespective of the age of the patient.     

Effects of Attention and Background Verbal Stimuli on Event-Related Potentials to Tone Pips in Humans

Abstract: The effects of attention and background verbal stimuli on event-related potentials (ERPs) following tone pips were assessed under four conditions: tone pips presented alone when attending and ignoring the tones and tone pips plus verbal stimuli when attending the tones and attending the verbal stimuli. The data were quantified in terms of the N1-P2 amplitude and the similarity (correlation) between ERPs in corresponding placements over the two hemispheres. The main results were that attention influenced the ERP amplitude only with the verbal stimuli, that interhemispheric similarity was greatest with the tones only, and that similarity was greater under the tone plus verbal stimuli condition during tone-attention instructions.     

Differential Effects of Pre-Weaning Stress on Adrenocorticotrophin and Prolactin Response to Novel Stimuli in Adult Rats

Emotional responsiveness is reduced in adult animals which have been exposed to stress during their first few weeks of life (1, 2). The stress of 'handling', daily removal of pups from their mother during the pre-weaning period, also leads to a reduced corticosterone response to novel stimuli in adult life (3). In rats, exposure to novel stimuli results in the concomitant release of prolactin (PRL) and corticosterone (4–6). Here we show that, in male rats handled daily during the pre-weaning period of life and tested in adult life for their hormonal responses to exposure to novel audio-visual stimuli, the consequent secretion of adrenocorticotrophin (ACTH) is attenuated, but that of PRL is not. Thus, pre-weaning handling results in permanent changes in a neural system specific to the control of ACTH secretion rather than affecting pathways common to neuroendocrine responses to emotional stimuli (7).     

Nicotine reduces the binding of [H]MK-801 to brain membranes, but not via the stimulation of high-affinity nicotinic receptors

Nicotine (10 and 100 μM) inhibited [³H]MK-801 binding to rat cerebral cortical membranes and this effect was not blocked by dihydro-β-erythroidine, (+)-tubocurarine or mecamylamine. Cytisine, muscarine, mecamylamine and (+)-tubocurarine also inhibited [³H]MK-801 binding. Neither raising the MK-801 concentration, nor the addition ofn-methyl-D-aspartate (NMDA) receptor agonists altered the effects of nicotine. Hence this response is not mediated via high-affinity nicotinic receptor stimulation, competition for MK-801 binding sites or require NMDA receptor activation.     

Methodological Problems in the Neuropsychological Assessment of Effects of Exposure to Welding Fumes and Manganese

Recently, Kaiser (2003) Kaiser, J. 2003. Manganese: A high-octane dispute. Science, 300: 926–928.  [Google Scholar] raised concerns over the increase in brain damage claims reportedly due to exposure to welding fumes. In the present article, we discuss methodological problems in conducting neuropsychological research on the effects of welding exposure, using a recent paper by Bowler et al. (2003) Bowler, R. M., Gysens, S., Diamond, E., Booty, A., Hartney, C. and Roels, H. A. 2003. Neuropsychological sequelae of exposure to welding fumes in a group of occupationally exposed men. International Journal of Hygiene & Environmental Health, 206: 517–529. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar] as an example to illustrate problems common in the neurotoxicity literature. Our analysis highlights difficulties in conducting such quasi-experimental investigations, including subject selection bias, litigation effects on symptom report and neuropsychological test performance, response bias, and scientifically inadequate casual reasoning.     

Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism

To determine whether exposure to fox odor alters granule neuron production, we examined proliferating cells and their progeny in the dentate gyrus of adult male rats exposed to trimethyl thiazoline, a component of fox feces. Additionally, to determine whether this effect is adrenal hormone-mediated, we examined animals exposed to fox odor after bilateral adrenalectomy and replacement with low levels of the endogenous glucocorticoid corticosterone. Stereologic analyses of the number of 5-bromo-2'deoxyuridine (BrdU) -labeled cells revealed that exposure to fox odor but not other, nonthreatening, odors (mint or orange) rapidly decreased the number of proliferating cells in the dentate gyrus. This effect is dependent on a stress-induced rise in adrenal hormones; exposure to fox odor resulted in an increase in circulating corticosterone levels and prevention of this increase (by means of adrenalectomy plus low-dose corticosterone replacement) eliminated the suppression of cell proliferation. Examination at longer survival times revealed that the decrease in the number of new granule cells in fox odor-exposed animals was transient; a difference was still detectable at 1 week after BrdU labeling but not at 3 weeks. In both fox and sham odor-exposed animals, many new cells acquired morphologic and biochemical characteristics of mature granule neurons. The majority of these cells expressed a marker of immature granule neurons (TuJ1) by 1 week after BrdU labeling and markers of mature granule neurons (calbindin, NeuN) by 3 weeks after labeling. These findings suggest that stressful experiences rapidly diminish cell proliferation by increasing adrenal hormone levels, resulting in a transient decrease in the number of adult-generated immature granule neurons.     

Neonatal Exposure to Fenoterol and Betamethasone: Effects on the Behavioral Development in the Rat

We investigated longitudinally the behavioral development in the rat following exposure to β-agonists and glucocorticoids (GC). Neonatal rats received either 1 mg/kg fenoterol (FEN), 0.3 mg/kg betamethasone (BET), or saline (SAL). Weanling and young adult rats were tested in the open field, the elevated-plus maze, and the water maze. FEN-treated as well as BET-treated animals displayed increased anxiety-like behavior. Furthermore, BET-treated adult animals showed a reduced locomotor activity. An enhanced 24-h memory in the water maze in both treatment groups may be facilitated by emotional arousal due to the increased anxiety levels. The possible neurobiological underpinnings are discussed in detail.     

Exposure to Kainic Acid Mimics the Effects of Axotomy in Cerebellar Purkinje Cells of the Adult Rat

We have investigated the long-term structural changes which affect Purkinje cells exposed to a single dose of kainic acid. Following intraparenchymal injection of the excitotoxin in the cerebellar cortex (1 μ1 of a 1 mg/ml solution), Purkinje cells which survived within the lesioned area or close to its edges showed remarkable axonal abnormalities, involving the formation of torpedoes, hypertrophy of recurrent collaterals and atrophy of the corticofugal portion of the axon. In addition, their dendritic trees were often affected by conspicuous regressive alterations. The climbing fibres contacting these Purkinje cells were characterized by thick perisomatic plexuses, whereas their peridendritic branches were atrophic. The dendrites innervated by such atrophic olivary arbours were studded with huge numbers of newly formed spines. These alterations were already present a few days after kainic acid administration and persisted for the total period of observation of 6 months after the lesion. The remarkable similarity between the abnormalities of Purkinje cells exposed to kainic acid and those observed after axotomy indicates that in these two conditions common mechanisms determine analogous long-lasting modifications in the affected neurons. It is proposed that kainic acid-induced intracellular calcium overload disrupts cytoskeletal components and impairs axonal transport, thus depriving the affected Purkinje cells of retrograde trophic influences from their target neurons. As a consequence the affected neurons undergo long-lasting regressive modifications and compensatory remodelling phenomena.