Selective lesions of the dentate gyrus produce disruptions in place learning for adjacent spatial locations

The hippocampus (HPP) plays a known role in learning novel spatial information. More specifically, the dentate gyrus (DG) hippocampal subregion is thought to support pattern separation, a mechanism for encoding and separating spatially similar events into distinct representations. Several studies have shown that lesions of the dorsal DG (dDG) in rodents result in inefficient spatial pattern separation for working memory; however, it is unclear whether selective dDG lesions disrupt spatial pattern separation for reference memory. Therefore, the current study investigated the role of the dDG in pattern separation using a spatial reference memory paradigm to determine whether the dDG is necessary for acquiring spatial discriminations for adjacent locations. Male Long-Evans rats were randomly assigned to receive bilateral intracranial infusions of colchicine or saline (control) into the dDG. Following recovery from surgery, each rat was pseudo-randomly assigned to an adjacent arm or separate arm condition and subsequently tested on a place-learning task using an eight-arm radial maze. Rats were trained to discriminate between a rewarded arm and a nonrewarded arm that were either adjacent to one another or separated by a distance of two arm positions. Each rat received 10 trials per day and was tested until the animal reached a criterion of nine correct choices out of 10 consecutive trials across 2 consecutive days of testing. Both groups acquired spatial discriminations for the separate condition at similar rates. However, in the adjacent condition, dDG lesioned animals required significantly more trials to reach the learning criterion than controls. The results suggest that dDG lesions decrease efficiency in pattern separation resulting in impairments in the adjacent condition involving greater overlap among the distal cues. Conversely, in the separate condition, there was less overlap among distal cues during encoding and less need for pattern separation. These findings provide further support for a critical role for the dDG in spatial pattern separation by demonstrating the importance of a processing mechanism that is capable of reducing interference among overlapping spatial inputs across a variety of memory demands.     

Cortisol and Children’s Adjustment: The Moderating Role of Sympathetic Nervous System Activity

We examined relations among cortisol, markers of sympathetic nervous system (SNS) activity (including salivary alpha-amylase and skin conductance level), and children's adjustment. We also tested the Bauer et al. (Journal of Developmental and Behavioral Pediatrics, 23(2), 102-113, 2002) hypothesis that interactions between the SNS and cortisol would be associated with internalizing and externalizing problems. Saliva samples were obtained from 8- to 9-year-olds before and after a laboratory assessment battery, and were assayed for cortisol and alpha-amylase (sAA). Basal skin conductance level (SCL) was measured during resting conditions. Parents reported on child adjustment. Interactions between basal SNS and cortisol levels explained moderate amounts of unique variance in children's externalizing and internalizing problems. More specifically, higher basal cortisol levels were positively associated with higher internalizing and externalizing problems among children with higher SNS activity, as compared to children with lower SNS activity. Findings underscore the utility of including information about the coordination between hypothalamic-pituitary-adrenal (HPA) and SNS activity in biosocial models of atypical child development.     

Cholinergic afferents to the locus coeruleus and noradrenergic afferents to the medial septum mediate LTP-reinforcement in the dentate gyrus by stimulation of the amygdala

Transient long-term potentiation (E-LTP) can be transformed into a long-lasting LTP (L-LTP) in the dentate gyrus (DG) by behavioral stimuli with high motivational content. Previous research from our group has identified several brain structures, such as the basolateral amygdala (BLA), the locus coeruleus (LC), the medial septum (MS) and transmitters as noradrenaline (NA) and acetylcholine (ACh) that are involved in these processes. Here we have investigated the functional interplay among brain structures and systems which result in the conversion of a E-LTP into a L-LTP (reinforcement) by stimulation of the BLA (BLA-R). We used topical application of specific drugs into DG, and other targets, while following the time course of LTP induced by stimulation of the perforant pathway (PP) to study their specific contribution to BLA-R. One injection cannula, a recording electrode in the DG and stimulating electrodes in the PP and the BLA were stereotactically implanted one week before electrophysiological experiments. Topical application of atropine or propranolol into the DG blocked BLA-R in both cases, but the effect of propranolol occurred earlier, suggesting a role of NA within the DG during an intermediate stage of LTP maintenance. The injection of lidocaine into the LC abolished BLA-R indicating that the LC is part of the functional neural reinforcing system. The effect on the LC is mediated by cholinergic afferents because application of atropine into the LC produced the same effect. Injection of lidocaine inactivating the MS also abolished BLA-R. This effect was mediated by noradrenergic afferents (probably from the LC) because the application of propranolol into the MS prevented BLA-R. These findings suggest a functional loop for BLA-R involving cholinergic afferents to the LC, a noradrenergic projection from the LC to the DG and the MS, and finally, the cholinergic projection from the MS to the DG.     

Gender differences in salivary alpha-amylase and attentional bias towards negative facial expressions following acute stress induction

This study investigated gender differences in two key processes involved in anxiety, arousal and attentional bias towards threat. Arousal was assessed using salivary alpha-amylase (sAA), a biomarker of noradrenergic arousal and attention bias using a dot-probe task. Twenty-nine women and 27 men completed the dot-probe task and provided saliva samples before and after a stress induction [cold pressor stress (CPS) test]. Women displayed a significant increase in arousal (sAA) following the stressor compared to men, who displayed a significant reduction in arousal. Reaction time data revealed a significant avoidance of threat in women at baseline, but a significant change to an attention bias towards threat following the stressor. Men did not significantly respond to the stressor in terms of attentional bias. These findings suggest that women are more reactive to a stressor than men, and display an initial avoidance response to threat, but an attentional bias towards threat following stress.     

Inducing a Rule in Wason's 2-4-6 Task: A Test of the Information-Quantity and Goal-Complementarity Hypotheses

In the standard 2-4-6 induction task, subjects are instructed to discover the rule generating sequences of three numbers by inventing number triples for which they receive immediate feedback. The rule is “ascending numbers”. Performance is greatly aided with Dual Goal (DG) instructions that ask subjects to discover two rules, one that generates “Dax” triples (equivalent to “yes” instances with Single Goal [SG] instructions) and another that generates “Med” triples (equivalent to “no” instances). The present study eliminates two explanations for this effect suggested by Wharton, Cheng, and Wickens (1993). Experiment 1 tested their Information-Quantity hypothesis that the effect results simply from the DG subjects testing more triples prior to proposing a rule. Our DG subjects were more likely to solve the problem and produced more “negative” triples than SG subjects when both groups generated exactly 15 triples. Two further groups received feedback only after generating all 15 triples, and again DG subjects were more likely to solve the problem and to generate more “negative” triples. Experiment 2 tested Wharton et al.'s Goal-Complementarity hypothesis that success under DG instructions hinges on preserving the complementary representation of the two rules. We compared SG instructions with three types of DG instructions that suggested different types of triples (Dax, Med, both Dax and Med, neither Dax nor Med). DG instructions were more effective in promoting successful rule discovery regardless of differences in rule complementarity. Our analysis of the heterogeneity of the examplars generated with DG instructions in both experiments suggest that success on the 2-4-6 task is as much a consequence of the breadth of hypotheses that subjects entertain as it is a consequence of the testing strategy.     

Effect of a kickboxing match on salivary cortisol and immunoglobulin A

The hypothesis that salivary cortisol would increase and salivary immunoglobulin A (IgA) decrease after a kickboxing match was tested among 20 male athletes. Saliva samples collected before and after the match were analyzed. Salivary cortisol and salivary IgA concentrations (absolute concentration, salivary IgAabs) and the secretion rate of IgA (salivary IgArate) were measured by enzyme-linked immunosorbent assay. A Wilcoxon test for paired samples showed significant increases in salivary cortisol from pre- to postmatch. No significant changes were observed in salivary IgAabs or secretory IgArate and saliva flow rate. This study indicates that a kickboxing match might increase salivary concentration and thereafter it could be considered a significant source of exercise-related stress. On the other hand, the effect of a kickboxing match on mucosal immunity seems not to be relevant.     

Developing physiologic stress profiles for school-age children who stutter

Purpose

Physiologic reactivity profiles were generated for 9 school-age children with a history of stuttering. Utilizing salivary sampling, stress biomarkers cortisol and alpha-amylase were measured in response to normal daily stressors. Children with a history of stuttering were characterized as high or low autonomic reactors when compared to age-normed references established for cortisol and alpha-amylase levels.

Method

Salivary samples were collected four times daily over three consecutive days from children (6 boys and 3 girls) aged 6–11 years. Samples were measured for two important stress biomarkers, cortisol and alpha-amylase. Following laboratory training on appropriate sampling technique using the Salivette, families collected all samples in their homes.

Results

Compared to published references established for normal children, children with a history of stuttering exhibited mean cortisol and alpha-amylase levels that were significantly lower, though within normal limits.

Conclusions

Results reflect an initial investigation into the use of salivary sampling to measure reactivity in children who stutter. As children who stutter have historically been excluded from physiologic stress studies, salivary sampling appears to provide an innovative and minimally invasive option for investigators. Though interpreted with caution secondary to the small sample size, initial findings suggest that in response to normal daily stressors, school-age children with a history of stuttering do not exhibit significantly elevated stress biomarkers.Educational objectives: The reader will be able to: (1) identify two biomarkers that reflect activation of the body's stress response; (2) discuss possible implications the generation of individualized stress profiles may have on the treatment of stuttering; and (3) discuss and evaluate the research needs associated with the inclusion of children in physiological studies of fluency.     

A Psychogenic Study of Dark-Adaptation

Skin conductance responses (SCRs), heart rate (HR), and respiration were recorded in various rest, cold pressor (CP), and CP recovery phases in 20 former drug users (DG) and 20 control Ss (CG), matched on sex and age in a repeated measures design. With regard to the abused drugs (barbiturates and narcotic analgesics), the hypothesis was tested that autonomic responses are decreased after long-term use of barbiturates and narcotic analgesics. The results partially supported that hypothesis: (a) SCRs, HR change, and HR deceleration were significantly lower in DG compared to control Ss; (b) HR baseline, respiration rate, and amplitude, however, tended to be increased in DG in the rest and CP phases. A second hypothesis, addressed to different habituation rates of SCRs and HR in both groups, was confirmed for SCRs and partly for HR, indicating that the habituation rates of SCRs, HR change, and HR deceleration were greater in DG than in CG. A third question concerned the consistency of SCR and HR results in both sessions. A trend for consistent results was found as the direction of the group differences was the same in sessions 1 and 2. The CP results were compared with similar findings in the same Ss during visual and auditory stimulation.     

Temporal constraints on apparent motion in auditory space

The hypothesis that the extent of spatial separation between successive sound events directly affects the perception of time intervals between these events was tested using an apparent motion paradigm. Subjects listened to four-tone pitch patterns whose individual tones were sounded alternately at one of two loudspeaker positions, and they adjusted the alternation rate until they could no longer distinguish the four-tone ordering of the pattern. Four horizontal and two vertical loudspeaker separations were tested. Results indicate a direct relation between horizontal separation and the critical stimulus onset asynchrony (SOA) between successive tones within a pattern. At the critical SOA, subjects reported hearing not a four-tone pattern, but two pairs of two-note groups overlapping in time. The findings are discussed in the context .of auditory spatial processing mechanisms and possible sensory-specific representational constraints.     

Cognitive performance and morning levels of salivary cortisol and alpha-amylase in children reporting high vs. low daily stress perception

The aim of the present study was to assess the effects of daily stress perception on cognitive performance and morning basal salivary cortisol and alpha-amylase levels in healthy children aged 9-12. Participants were classified by whether they had low daily perceived stress (LPS, n = 27) or a high daily perceived stress (HPS, n = 26) using the Children Daily Stress Inventory (CDSI). Salivary cortisol and alpha-amylase were measured at awakening and 30 minutes later. Cognitive performance was assessed using the Cognitive Drug Research assessment system. The HPS group exhibited significantly poorer scores on speed of memory (p < .05) and continuity of attention (p < .05) relative to the LPS group. The HPS group also showed significantly lower morning cortisol levels at awakening and at +30 minutes measures in comparison with the LPS group (p < .05), and mean morning cortisol levels were negatively correlated with speed of memory (p < .05) in the 53 participants. No significant differences were observed between both groups in alpha-amylase levels. These findings suggest that daily perceived stress in children may impoverish cognitive performance via its modulating effects on the HPA axis activity.     

Deepened extinction following compound stimulus presentation: noradrenergic modulation

Behavioral extinction is an active form of new learning involving the prediction of nonreward where reward has previously been present. The expression of extinction learning can be disrupted by the presentation of reward itself or reward-predictive stimuli (reinstatement) as well as the passage of time (spontaneous recovery) or contextual changes (renewal). The following experiments replicated the demonstration that presenting multiple previously rewarded stimuli in compound during extinction enhances extinction learning. To explore the pharmacological basis for this we next examined the effects of pharmacological treatments that either facilitated or blocked noradrenergic activity to test the hypothesis that increased noradrenergic activity at the time of extinction training would improve, whereas blockade of noradrenergic activity would impair the extinction of appetitive stimulus-reward memories. Different groups of rats were trained in a discriminative stimulus paradigm to lever-press for food reward. Once stable responding was achieved, responding was extinguished for 2 d. Prior to a third extinction session, rats received systemic administration of either saline, yohimbine (α2 antagonist), atomoxetine (norepinephrine reuptake inhibitor), or propranolol (β-receptor antagonist). Spontaneous recovery of responding to the stimuli was tested 4 wk later. Our results indicate that increasing noradrenergic activity during extinction augments extinction learning resulting in less recovery of responding at test. These results have important implications for models of relapse to drug seeking and the development of extinction-based therapies.     

Effects of reversible inactivation of locus coeruleus on long-term potentiation in perforant path-DG synapses in rats

The locus coeruleus (LC) is the main source of noradrenergic innervations to the forebrain and the hippocampal formation but does not receive noradrenergic projections itself. Previous studies have suggested that hippocampal neural response is modulated by the noradrenergic pathway and that the experimental activation of the LC can potentiate hippocampal responses. Most studies have suggested that the noradrenergic system has controversial effects on long-term potentiation (LTP) in hippocampal neurons, because its influence on synaptic plasticity in perforant path-DG synapses is ambiguous. The aim of this article was to study the LC's role in baseline activity and LTP in perforant path-DG cells of hippocampus by in vivo LC inactivation. Rats were anesthetized with urethane, and LC was temporarily suppressed by intra-LC injection of lidocaine. Population spike (PS) amplitude and excitatory postsynaptic potential (EPSP) slope in DG were recorded 10 min before and 5, 10, 20, 40, 60, and 120 min after tetanization (400 Hz). Saline or lidocaine was injected during the baseline recording (experiment 1), 5 min before tetanus (experiment 2), and 5 min after tetanus (experiment 3). The results from this study indicated that the LC inactivation has no effect on baseline activity of granular cells or maintenance of LTP after tetanization. Moreover, LC inactivation before tetanus had no effect on LTP induction but decreased PS-LTP amplitude 60 and 120 min after tetanization. Taken together, the LC noradrenergic system likely influences LTP induction in later time periods while it has no effect on LTP in earlier time periods.     

Effects of repetitive hypoglycemia on neuroendocrine response and brain tyrosine hydroxylase activity in the rat

Hypoglycemia-associated autonomic failure (HAAF) is a syndrome of acute adaptation to a metabolic stressor, in which neuroendocrine responses to repetitive hypoglycemic bouts are blunted. The CNS mechanisms that contribute to HAAF are unknown. In the present study, we modeled HAAF in the rat and measured the activity of tyrosine hydroxylase (TH) as an index of acute noradrenergic activation, to test the hypothesis that noradrenergic activation of the hypothalamus might be impaired. In association with a significant counter-regulatory response to a single bout of hypoglycemia (elevated corticosterone, catecholamines, and glucagon), TH activity was elevated overall in brainstem NE cell body areas and hypothalamus. With multiple hypoglycemic episodes in a 24 h period, the counter-regulatory response was blunted, and hypothalamic TH activity was comparable to that of saline-infused controls. In a similar paradigm, multiple bouts of CNS neuroglucopenia did not blunt the hyperglycemic or corticosterone responses, and were required for elevation of TH activity. This alternate response pattern suggests that insulin-induced hypoglycemia and cerebral neuroglucopenia represent somewhat different metabolic stressors at the CNS.     

Exploring the determinants of dual goal facilitation in a rule discovery task

Wason's standard 2-4-6 task requires discovery of a single rule and leads to around 20% solutions, whereas the dual goal (DG) version requires discovery of two rules and elevates solutions to over 60%. We report an experiment that aimed to discriminate between competing accounts of DG facilitation by manipulating the degree of complementarity between the to-be-discovered rules. Results indicated that perfect rule complementarity is not essential for task success, thereby undermining a key tenet of the goal complementarity account of DG facilitation. The triple heterogeneity account received a good degree of support since more varied triple exploration was associated with facilitatory DG conditions, in line with this account's prediction that task success is associated with the creative search of the problem space. The contrast class account (an extension of Oaksford & Chater's, 1994, iterative counterfactual model) was also corroborated in that the generation of descending triples was demonstrated to be the dominant predictor of DG success. We focus our discussion on conceptual ideas relating to the way in which iterative counterfactual testing and contrast class identification may work together to provide a powerful basis for effective hypothesis testing.     

Patterns of neuronal activation in the rat brain and spinal cord in response to increasing durations of restraint stress

By most accounts the psychological stressor restraint produces a distinct pattern of neuronal activation in the brain. However, some evidence is incongruous with this pattern, leading us to propose that the restraint-induced pattern in the central nervous system might depend on the duration of restraint used. We therefore determined the pattern of neuronal activation (as indicated by the presence of Fos protein) seen in the paraventricular nucleus (PVN), bed nucleus of the stria terminalis, amygdala, locus coeruleus, nucleus tractus solitarius (NTS), ventrolateral medulla (VLM) and thoracic spinal cord of the rat in response to 0, 15, 30 or 60 min periods of restraint. We found that although a number of cell groups displayed a linear increase in activity with increasing durations of restraint (e.g. hypothalamic corticotrophin-releasing factor (CRF) cells, medial amygdala neurons and sympathetic preganglionic neurons of the thoracic spinal cord), a number of cell groups did not. For example, in the central amygdala restraint produced both a decrease in CRF cell activity and an increase in non-CRF cell activity. In the locus coeruleus, noradrenergic neurons did not display Fos in response to 15 min of restraint, but were significantly activated by 30 or 60 min restraint. After 30 or 60 min restraint a greater degree of activation of more rostral A1 noradrenergic neurons was observed compared with the pattern of A1 noradrenergic neurons in response to 15 min restraint. The results of this study demonstrate that restraint stress duration determines the amount and the pattern of neuronal activation seen in response to this psychological stressor.     

The father-daughter dance: the relationship between father-daughter relationship quality and daughters' stress response

The goal of the study was to determine whether father-daughter relationship quality is related to activity of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol) and autonomic nervous system (salivary alpha-amylase, sAA) in late adolescence-emerging adulthood during peer interactions. In the 1st study, reported father-daughter relationships characterized by rejection, chaos, and coercion had lower morning cortisol levels and were temperamentally more sensitive to emotional changes. In the 2nd study, young women who reported father-daughter relationships characterized by warmth, autonomy, support, and structure had lower pretask cortisol levels, and they had attenuated cortisol responses to problem discussion with a friend. In contrast, those who reported father-daughter relationships characterized by rejection, chaos, and coercion had higher pretask cortisol levels, had elevated cortisol in response to problem discussion with a friend, and were more likely to self-disclose about psychosocial stressors. No differences were observed between reported father-daughter relationship quality and sAA levels or task-related reactivity. The findings suggest that father-daughter interactions potentially influence both social cognition and HPA reactivity to developmentally salient stressors in young women.     

Separation and Traumatic Distress in Prolonged Grief: The Role of Cause of Death and Relationship to the Deceased

A distinction has been drawn between symptoms of separation distress (e.g., yearning/longing for the lost relationship) and traumatic distress (e.g., numbness, anger/bitterness) in prolonged grief disorder (PGD), a chronic and severe form of grieving that has been shown to predict a range of negative mental and physical health outcomes. The present study relied upon information from 947 recently bereaved young adults and tested the hypothesis that levels of separation distress primarily would be influenced by aspects of the relationship with the deceased (i.e., primary attachment figures vs. more distant relationships), whereas levels of traumatic distress would be influenced more by situational factors surrounding the death itself (i.e., cause of death). Results generally supported this hypothesis with a few important qualifications. Implications for the assessment and treatment of bereaved individuals are discussed.     

Enhancing effects of acute psychosocial stress on priming of non-declarative memory in healthy young adults

Social stress affects cognitive processes in general, and memory performance in particular. However, the direction of these effects has not been clearly established, as it depends on several factors. Our aim was to determine the impact of the hypothalamus-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) reactivity to psychosocial stress on short-term non-declarative memory and declarative memory performance. Fifty-two young participants (18 men, 34 women) were subjected to the Trier Social Stress Task (TSST) and a control condition in a crossover design. Implicit memory was assessed by a priming test, and explicit memory was assessed by the Rey Auditory Verbal Learning Test (RAVLT). The TSST provoked greater salivary cortisol and salivary alpha-amylase (sAA) responses than the control task. Men had a higher cortisol response to stress than women, but no sex differences were found for sAA release. Stress was associated with an enhancement of priming but did not affect declarative memory. Additionally, the enhancement on the priming test was higher in those whose sAA levels increased more in response to stress (r(48)?=?0.339, p?=?0.018). Our results confirm an effect of acute stress on priming, and that this effect is related to SNS activity. In addition, they suggest a different relationship between stress biomarkers and the different memory systems.     

Neuroendocrine stress responses to an oral academic examination: No strong influence of sex, repeated participation and personality traits

Public speaking tasks have been widely used as laboratory stressors in human research. Fewer studies have investigated similar real life situations like oral examinations and results have been inconsistent. The present study investigated salivary cortisol (as a marker of hypothalamus-pituitary-adrenal (HPA) activity) and salivary alpha-amylase (sAA as a marker of sympathetic nervous system (SNS) activity) within the context of a university examination. Subjects were 40 undergraduate students who participated in an oral examination. Of these, 20 also participated in a second examination within a few weeks. Cortisol and sAA were measured immediately before and after the examination and on a control day. Additionally, subjects filled out personality questionnaires. A strong anticipatory increase in salivary cortisol and sAA as well as more modest further increases between the pre- and post-measurements were detected during the examination. Sex or oral contraceptive use had no influence on either measure. In addition, no significant differences between the first and second examination were observed. The findings indicate the neuroendocrine stress responses to laboratory stressors and to heralded real life stressors as well as the modulatory variables involved differ from each other.     

Subjective, Autonomic, and Endocrine Reactivity during Social Stress in Children with Social Phobia

Reports of exaggerated anxiety and physiological hyperreactivity to social-evaluative situations are characteristic of childhood social phobia (SP). However, laboratory research on subjective, autonomic and endocrine functioning in childhood SP is scarce, inconsistent and limited by small sample sizes, limited breadth of measurements, and the use of non-standardized stressor tasks. We exposed 8–12-year-old children with DSM-IV SP (n = 41) and matched healthy control children (HC; n = 40) to the Trier Social Stress Test for Children (TSST-C) while measuring subjective anxiety, heart rate (HR) and salivary alpha-amylase (sAA) as well as salivary cortisol. The SP children showed heightened reactivity to the TSST-C on subjective anxiety compared to the HC children but not a heightened reactivity in HR, sAA or cortisol. However, the SP children showed chronically elevated HR levels throughout the whole laboratory session. Whereas subjective anxiety seems to respond specifically to social-evaluative stress in childhood SP, HR levels may be chronically elevated suggesting a more generalized autonomic hyperreactivity.