Xie, Kun; Kuang, Hui; Tsien, Joe Z
There is a general interest in understanding of whether and how exposure to emotionally traumatizing events can alter memory function and anxiety behaviors. Here we have developed a novel laboratory-version of mild blast exposure comprised of high decibel bomb explosion sound coupled with strong air blast to mice. This model allows us to isolate the effects of emotionally fearful components from those of traumatic brain injury or bodily injury typical associated with bomb blasts. We demonstrate that this mild blast exposure is capable of impairing object recognition memory, increasing anxiety in elevated O-maze test, and resulting contextual generalization. Our in vivo neural ensemble recording reveal that such mild blast exposures produced diverse firing changes in the anterior cingulate cortex, a region processing emotional memory and inhibitory control. Moreover, we show that these real-time neural ensemble patterns underwent post-event reverberations, indicating rapid consolidation of those fearful experiences. Identification of blast-induced neural activity changes in the frontal brain may allow us to better understand how mild blast experiences result in abnormal changes in memory functions and excessive fear generalization related to post-traumatic stress disorder.
Moon, Chung-Man; Jeong, Gwang-Woo
Background Generalized anxiety disorder (GAD) has been related to functional brain activities and structural brain abnormalities. Purpose To investigate the neural mechanism on working memory dysfunction in patients with GAD in terms of the combined functional and morphological brain abnormalities. Material and Methods Patients with GAD and healthy controls matched for age, sex, and education level underwent high-resolution T1-weighted (T1W) magnetic resonance imaging (MRI) and functional MRI (fMRI). In this study, fMRI and voxel-based morphometry (VBM) were used for assessing the differential brain activation patterns, as well as for comparing the morphological alterations between the two groups. Results In response to the neutral distractors, the patients showed significantly lower activities in the regions of the fusiform gyrus (FuG), superior parietal gyrus (SPG), precuneus (PCu), superior occipital gyrus (SOG), lingual gyrus (LiG), cuneus (Cun), calcarine cortex (CaC), parahippocampal gyrus (PHG) and cerebellar cortex (Cb) compared to the controls. In response to the anxiety-inducing distractors, the patients showed significantly higher activity in the hippocampus and lower activities in the regions of the dorsolateral prefrontal cortex (DLPFC), FuG, SPG, PCu, SOG, and Cb. Also, the patients showed a significant reduction of the white matter volumes in the DLPFC, anterior limb of the internal capsule (ALIC) and midbrain. Conclusion This study provides the first evidence for the association between the morphometric alterations and functional deficit in the working memory processing with the neutral and anxiety-inducing distractors in GAD patients. These findings would be helpful to understand the neural mechanisms on working memory impairment in connection with GAD symptoms.
Charpentier, Caroline J.; Hindocha, Chandni; Roiser, Jonathan P.; Robinson, Oliver J.
Pathological anxiety is associated with disrupted cognitive processing, including working memory and decision-making. In healthy individuals, experimentally-induced state anxiety or high trait anxiety often results in the deployment of adaptive harm-avoidant behaviours. However, how these processes affect cognition is largely unknown. To investigate this question, we implemented a translational within-subjects anxiety induction, threat of shock, in healthy participants reporting a wide range of trait anxiety scores. Participants completed a gambling task, embedded within an emotional working memory task, with some blocks under unpredictable threat and others safe from shock. Relative to the safe condition, threat of shock improved recall of threat-congruent (fearful) face location, especially in highly trait anxious participants. This suggests that threat boosts working memory for mood-congruent stimuli in vulnerable individuals, mirroring memory biases in clinical anxiety. By contrast, Bayesian analysis indicated that gambling decisions were better explained by models that did not include threat or treat anxiety, suggesting that: (i) higher-level executive functions are robust to these anxiety manipulations; and (ii) decreased risk-taking may be specific to pathological anxiety. These findings provide insight into the complex interactions between trait anxiety, acute state anxiety and cognition, and may help understand the cognitive mechanisms underlying adaptive anxiety. PMID:27098489
Charpentier, Caroline J; Hindocha, Chandni; Roiser, Jonathan P; Robinson, Oliver J
Pathological anxiety is associated with disrupted cognitive processing, including working memory and decision-making. In healthy individuals, experimentally-induced state anxiety or high trait anxiety often results in the deployment of adaptive harm-avoidant behaviours. However, how these processes affect cognition is largely unknown. To investigate this question, we implemented a translational within-subjects anxiety induction, threat of shock, in healthy participants reporting a wide range of trait anxiety scores. Participants completed a gambling task, embedded within an emotional working memory task, with some blocks under unpredictable threat and others safe from shock. Relative to the safe condition, threat of shock improved recall of threat-congruent (fearful) face location, especially in highly trait anxious participants. This suggests that threat boosts working memory for mood-congruent stimuli in vulnerable individuals, mirroring memory biases in clinical anxiety. By contrast, Bayesian analysis indicated that gambling decisions were better explained by models that did not include threat or treat anxiety, suggesting that: (i) higher-level executive functions are robust to these anxiety manipulations; and (ii) decreased risk-taking may be specific to pathological anxiety. These findings provide insight into the complex interactions between trait anxiety, acute state anxiety and cognition, and may help understand the cognitive mechanisms underlying adaptive anxiety.
Caceres, L G; Cid, M P; Uran, S L; Zorrilla Zubilete, M A; Salvatierra, N A; Guelman, L R
It is widely known that ionizing radiation is a physical agent broadly used to kill tumor cells during human cancer therapy. Unfortunately, adjacent normal tissues can concurrently undergo undesirable cell injury. Previous data of our laboratory demonstrated that exposure of developing rats to ionizing radiations induced a variety of behavioral differences respect to controls, including changes in associative memory and in anxiety state. However, there is a lack of data concerning modifications in different related pharmacological intermediaries. Therefore, the aim of the present study was to investigate whether the behavioral differences observed in young animals irradiated at birth might be underlain by early changes in PKCß1 levels which, in turn, could lead to changes in hippocampal GABAergic neurotransmission. Male Wistar rats were irradiated with 5Gy of X rays between 24 and 48 h after birth. Different pharmacological markers related to the affected behavioral tasks were assessed in control and irradiated hippocampus at 15 and 30 days, namely GABAA receptor, GAD65-67, ROS and PKCß1. Results showed that all measured parameters were increased in the hippocampus of 30-days-old irradiated animals. In contrast, in the hippocampus of 15-days-old irradiated animals only the levels of PKCß1 were decreased. These data suggest that PKCß1 might constitute a primary target for neonatal radiation damage on the hippocampus. Therefore, it could be hypothesized that an initial decrease in the levels of this protein can trigger a subsequent compensatory increase that, in turn, could be responsible for the plethora of biochemical changes that might underlie the previously observed behavioral alterations.
Gastambide, Francois; Taylor, Amy M; Palmer, Clare; Svard, Heta; Karjalainen, Maija; Janhunen, Sanna K; Tricklebank, Mark; Bannerman, David M
Adult rats exposed to methylazoxymethanol acetate (MAM) at embryonic day 17 (E17) display robust pathological alterations in the hippocampus. However, discrepancies exist in the literature regarding the behavioural effects of this pre-natal manipulation. Therefore, a systematic assessment of MAM E17-induced behavioural alterations was conducted using a battery of dorsal and ventral hippocampus-dependent tests. Compared to saline controls, MAM E17-treated rats displayed deficits in spatial reference memory in both the aversive hidden platform watermaze task and an appetitive Y-maze task. Deficits in the spatial reference memory watermaze task were replicated across three different cohorts and two laboratories. In contrast, there was little, or no, effect on the non-spatial, visible platform watermaze task or an appetitive, non-spatial, visual discrimination task, respectively. MAM rats were also impaired in the spatial novelty preference task which assesses short-term memory, and displayed reduced anxiety levels in the elevated plus maze task. Thus, MAM E17 administration resulted in abnormal spatial information processing and reduced anxiety in a number of hippocampus-dependent behavioural tests, paralleling the effects of dorsal and ventral hippocampal lesions, respectively. These findings corroborate recent pathological and physiological studies, further highlighting the usefulness of MAM E17 as a model of hippocampal dysfunction in at least some aspects of schizophrenia.
Zlomuzica, Armin; Dere, Dorothea; Machulska, Alla; Adolph, Dirk; Dere, Ekrem; Margraf, Jürgen
The aim of this review is to summarize research on the emerging role of episodic memories in the context of anxiety disorders (AD). The available literature on explicit, autobiographical, and episodic memory function in AD including neuroimaging studies is critically discussed. We describe the methodological diversity of episodic memory research in AD and discuss the need for novel tests to measure episodic memory in a clinical setting. We argue that alterations in episodic memory functions might contribute to the etiology of AD. We further explain why future research on the interplay between episodic memory function and emotional disorders as well as its neuroanatomical foundations offers the promise to increase the effectiveness of modern psychological treatments. We conclude that one major task is to develop methods and training programs that might help patients suffering from AD to better understand, interpret, and possibly actively use their episodic memories in a way that would support therapeutic interventions and counteract the occurrence of symptoms. PMID:24795583
Tryon, Warren W; McKay, Dean
Learning and memory are interdependent processes. Memories are learned, and cumulative learning requires memory. It is generally accepted that learning contributes to psychopathology and consequently to pertinent memory formation. Neuroscience and psychological research have established that memory is an active reconstructive process that is influenced by thoughts, feelings, and behaviors including post-event information. Recent research on the treatment of anxiety disorders using medications (i.e., d-cyclcloserine) to alter neurological systems associated with memory used in conjunction with behavior therapy suggests that memory is part of a central mechanism in the etiology and maintenance of these conditions. The main thesis of this article is that learning-based interventions create new memories that may modify existing ones. This raises the possibility of using such memory modifications to measure intervention outcome. A connectionist context for understanding this phenomenon and informing intervention is provided, with specific reference to post-traumatic stress disorder, obsessive-compulsive disorder, and generalized anxiety disorder. Recommendations for future research examining the role of memory change in treatment outcome are suggested.
Kanatsou, Sofia; Ter Horst, Judith P.; Harris, Anjanette P.; Seckl, Jonathan R.; Krugers, Harmen J.; Joëls, Marian
Early-life stress (ELS) is a risk factor for the development of psychopathology, particularly in women. Human studies have shown that certain haplotypes of NR3C2, encoding the mineralocorticoid receptor (MR), that result in gain of function, may protect against the consequences of stress exposure, including childhood trauma. Here, we tested the hypothesis that forebrain-specific overexpression of MR in female mice would ameliorate the effects of ELS on anxiety and memory in adulthood. We found that ELS increased anxiety, did not alter spatial discrimination and reduced contextual fear memory in adult female mice. Transgenic overexpression of MR did not alter anxiety but affected spatial memory performance and enhanced contextual fear memory formation. The effects of ELS on anxiety and contextual fear were not affected by transgenic overexpression of MR. Thus, MR overexpression in the forebrain does not represent a major resilience factor to early life adversity in female mice. PMID:26858618
Brown, Franklin C.; Westerveld, Michael; Langfitt, John T.; Hamberger, Marla; Hamid, Hamada; Shinnar, Shlomo; Sperling, Michael R.; Devinsky, Orrin; Barr, William; Tracy, Joseph; Masur, David; Bazil, Carl W.; Spencer, Susan S.
This study examined the degree to which anxiety contributed to inconsistent material-specific memory difficulties among 243 temporal lobe epilepsy patients from the Multisite Epilepsy Study. Visual memory performance on the Rey Complex Figure Test (RCFT) was lower for those with high versus low level of anxiety, but was not found to be related to side of TLE. Verbal memory on the California Verbal Learning Test (CVLT) was significantly lower for left than right TLE patients with low anxiety, but equally impaired for those with high anxiety. These results suggest that we can place more confidence in the ability of verbal memory tests like the CVLT to lateralize to left TLE for those with low anxiety, but that verbal memory will be less likely to produce lateralizing information for those with high anxiety. This suggests that more caution is needed when interpreting verbal memory tests for those with high anxiety. These results indicated that RCFT performance was significantly affected by anxiety and did not lateralize to either side, regardless of anxiety level. This study adds to the existing literature which suggests that drawing-based visual memory tests do not lateralize among TLE patients, regardless of anxiety level. PMID:24291525
Sawyer, Chris R.; Behnke, Ralph R.
Shows that recollections of state speaking anxiety decreased over time, and that the rate of attenuation was associated with the speaker's level of trait speaking anxiety. Finds also that recollections of state speaking anxiety (implicit memory) were attenuated over time, and that the magnitude of this decline was predicted by the speaker's level…
Social anxiety is associated with attentional bias and working memory for emotional stimuli; however, the ways in which social anxiety affects cognitive functions involving non-emotional stimuli remains unclear. The present study focused on the role of attentional networks (i.e. alerting, orienting, and executive control networks) and visuospatial working memory capacity (WMC) for non-emotional stimuli in the context of social anxiety. One hundred and seventeen undergraduates completed questionnaires on social anxiety. They then performed an attentional network test and a change detection task to measure visuospatial WMC. Orienting network and visuospatial WMC were positively correlated with social anxiety. A multiple regression analysis showed significant positive associations of alerting, orienting, and visuospatial WMC with social anxiety. Alerting, orienting networks, and high visuospatial WMC for non-emotional stimuli may predict degree of social anxiety.
Balderston, Nicholas L; Quispe-Escudero, David; Hale, Elizabeth; Davis, Andrew; O'Connell, Katherine; Ernst, Monique; Grillon, Christian
According to the attentional control theory (ACT) proposed by Eysenck and colleagues, anxiety interferes with cognitive processing by prioritizing bottom-up attentional processes over top-down attentional processes, leading to competition for access to limited resources in working memory, particularly the central executive (Eysenck, Derakshan, Santos, & Calvo, ). However, previous research using the n-back working memory task suggests that working memory load also reduces state anxiety. Assuming that similar mechanisms underlie the effect of anxiety on cognition, and the effect of cognition on anxiety, one possible implication of the ACT would suggest that the reduction of state anxiety with increasing working memory load is driven by activation of central executive attentional control processes. We tested this hypothesis using the Sternberg working memory paradigm, where maintenance processes can be isolated from central executive processes (Altamura et al., ; Sternberg, ). Consistent with the n-back results, subjects showed decreased state anxiety during the maintenance period of high-load trials relative to low-load trials, suggesting that maintenance processes alone are sufficient to achieve this state anxiety reduction. Given that the Sternberg task does not require central executive engagement, these results are not consistent with an implication of the ACT where the cognition/anxiety relationship and anxiety/cognition relationship are mediated by similar central executive mechanisms. Instead, we propose an extension of the ACT such that engaging working memory maintenance suppresses state anxiety in a load-dependent manner. Furthermore, we hypothesize that the efficacy of this effect may moderate the effect of trait anxiety on cognition.
Ashcraft, M H; Kirk, E P
Individuals with high math anxiety demonstrated smaller working memory spans, especially when assessed with a computation-based span task. This reduced working memory capacity led to a pronounced increase in reaction time and errors when mental addition was performed concurrently with a memory load task. The effects of the reduction also generalized to a working memory-intensive transformation task. Overall, the results demonstrated that an individual difference variable, math anxiety, affects on-line performance in math-related tasks and that this effect is a transitory disruption of working memory. The authors consider a possible mechanism underlying this effect--disruption of central executive processes--and suggest that individual difference variables like math anxiety deserve greater empirical attention, especially on assessments of working memory capacity and functioning.
Sprowles, Jenna L N; Hufgard, Jillian R; Gutierrez, Arnold; Bailey, Rebecca A; Jablonski, Sarah A; Williams, Michael T; Vorhees, Charles V
Selective serotonin reuptake inhibitors (SSRIs) block the serotonin (5-HT) reuptake transporter (SERT) and increase synaptic 5-HT. 5-HT is also important in brain development; hence when SSRIs are taken during pregnancy there exists the potential for these drugs to affect CNS ontogeny. Prenatal SSRI exposure has been associated with an increased prevalence of autism spectrum disorder (ASD), and peripheral 5-HT is elevated in some ASD patients. Perinatal SSRI exposure in rodents has been associated with increased depression and anxiety-like behavior, decreased sociability, and impaired learning in the offspring, behaviors often seen in ASD. The present study investigated whether perinatal exposure to citalopram causes persistent neurobehavioral effects. Gravid Sprague-Dawley rats were assigned to two groups and subcutaneously injected twice per day with citalopram (10mg/kg; Cit) or saline (Sal) 6h apart on embryonic day (E)6-21, and then drug was given directly to the pups after delivery from postnatal day (P)1-20. Starting on P60, one male/female from each litter was tested in the Cincinnati water maze (CWM) and open-field before and after MK-801. A second pair from each litter was tested in the Morris water maze (MWM) and open-field before and after (+)-amphetamine. A third pair was tested as follows: elevated zero-maze, open-field, marble burying, prepulse inhibition of acoustic startle, social preference, and forced swim. Cit-exposed rats were impaired in the MWM during acquisition and probe, but not during reversal, shift, or cued trials. Cit-exposed rats also showed increased marble burying, decreased time in the center of the open-field, decreased latency to immobility in forced swim, and increased acoustic startle across prepulse intensities with no effects on CWM. The results are consistent with citalopram inducing several ASD-like effects. The findings add to concerns about use of SSRIs during pregnancy. Further research on different classes of
Crespo, Iris; Santos, Alicia; Valassi, Elena; Pires, Patricia; Webb, Susan M; Resmini, Eugenia
Evaluation of cognitive function in acromegaly has revealed contradictory findings; some studies report normal cognition in patients with long-term cured acromegaly, while others show attention and memory deficits. Moreover, the presence of affective disorders in these patients is common. Our aim was to evaluate memory and decision making in acromegalic patients and explore their relationship with affective disorders like anxiety and depressive symptoms. Thirty-one patients with acromegaly (mean age 49.5 ± 8.5 years, 14 females and 17 males) and thirty-one healthy controls participated in this study. The Iowa Gambling Task (IGT), Rey Auditory Verbal Learning Test, State-Trait Anxiety Inventory, and Beck Depression Inventory-II (BDI-II) were used to evaluate decision making, verbal memory, anxiety, and depressive symptoms, respectively. Acromegalic patients showed impairments in delayed verbal memory (p < 0.05) and more anxiety and depressive symptoms (p < 0.05) than controls. In the IGT, acromegalic patients presented an altered decision-making strategy compared to controls, choosing a lower number of the safer cards (p < 0.05) and higher number of the riskier cards (p < 0.05). Moreover, multiple correlations between anxiety and depressive symptoms and performance in memory and decision making were found. Impaired delayed memory and decision making observed in acromegalic patients are related to anxiety and depressive symptoms. Providing emotional support to the patients could improve their cognitive function. A key clinical application of this research is the finding that depressive symptoms and anxiety are essentially modifiable factors.
Dorfman, Julia; Benson, Brenda; Farber, Madeline; Pine, Daniel; Ernst, Monique
Anxiety disorders are among the most common psychiatric disorders of adolescence. Behavioral and task-based imaging studies implicate altered reward system function, including striatal dysfunction, in adolescent anxiety. However, no study has yet examined alterations of the striatal intrinsic functional connectivity in adolescent anxiety disorders. The current study examines striatal intrinsic functional connectivity (iFC), using six bilateral striatal seeds, among 35 adolescents with anxiety disorders and 36 healthy comparisons. Anxiety is associated with abnormally low iFC within the striatum (e.g., between nucleus accumbens and caudate nucleus), and between the striatum and prefrontal regions, including subgenual anterior cingulate cortex, posterior insula and supplementary motor area. The current findings extend prior behavioral and task-based imaging research, and provide novel data implicating decreased striatal iFC in adolescent anxiety. Alterations of striatal neurocircuitry identified in this study may contribute to the perturbations in the processing of motivational, emotional, interoceptive, and motor information seen in pediatric anxiety disorders. This pattern of the striatal iFC perturbations can guide future research on specific mechanisms underlying anxiety. PMID:27004799
Kutlu, Munir Gunes; Gould, Thomas J.
Anxiety disorders are a group of crippling mental diseases affecting millions of Americans with a 30% lifetime prevalence and costs associated with healthcare of $42.3 billion. While anxiety disorders show high levels of co-morbidity with smoking (45.3% vs. 22.5% in healthy individuals), anxiety disorders are also more common among the smoking population (22% vs. 11.1% in the non-smoking population). Moreover, there is clear evidence that smoking modulates symptom severity in patients with anxiety disorders. In order to better understand this relationship, several animal paradigms are used to model several key symptoms of anxiety disorders; these include fear conditioning and measures of anxiety. Studies clearly demonstrate that nicotine mediates acquisition and extinction of fear as well as anxiety through the modulation of specific subtypes of nicotinic acetylcholine receptors (nAChRs) in brain regions involved in emotion processing such as the hippocampus. However, the direction of nicotine’s effects on these behaviors is determined by several factors that include the length of administration, hippocampus-dependency of the fear learning task, and source of anxiety (novelty-driven vs. social anxiety). Overall, the studies reviewed here suggest that nicotine alters behaviors related to fear and anxiety and that nicotine contributes to the development, maintenance, and reoccurrence of anxiety disorders. PMID:26231942
Prevatt, Frances; Welles, Theresa L.; Li, Huijun; Proctor, Briley
The impact of memory and anxiety on math performance was analyzed in a sample of 115 college undergraduates, all of whom had a diagnosed learning disability. The direct effects of memory and anxiety on math performance were first examined, followed by an examination of whether anxiety moderates the relationship between memory and math. Both memory…
Waldhauser, Gerd T; Johansson, Mikael; Bäckström, Martin; Mecklinger, Axel
We aimed at replicating the finding that humans are able to suppress unwanted memories, and tested whether this ability varies with individual differences in working memory capacity, trait anxiety and defensiveness. In a think/no-think experiment, participants either recalled or suppressed previously learned words for 0, 8 or 16 times. Suppression did not have an overall detrimental effect on later recall performance. However, higher recall rates after repeated suppression were exclusively predicted by higher trait anxiety. These results are discussed in relation to current theories on anxiety and executive control.
Gross, Thomas F.
Two experiments investigated relationships between state anxiety, memory processes, and children's performance on problem-solving tasks. Participants were second and sixth graders in a private elementary school in Redlands, California. In both experiments, subjects responded to three training and eight test problems presented in the introtact…
Bedard, Anne-Claude; Tannock, Rosemary
Objective: To investigate the effects of methylphenidate (MPH) on components of working memory (WM) in children with ADHD and determine whether MPH produces differential effects on WM in children with comorbid anxiety (ANX). Method: Participants were a clinical sample of 130 children with ADHD, aged 6 to 12 years old (32% comorbid ANX). Each child…
Kutlu, Munir Gunes; Gould, Thomas J
Anxiety disorders are a group of crippling mental diseases affecting millions of Americans with a 30% lifetime prevalence and costs associated with healthcare of $42.3 billion. While anxiety disorders show high levels of co-morbidity with smoking (45.3% vs. 22.5% in healthy individuals), they are also more common among the smoking population (22% vs. 11.1% in the non-smoking population). Moreover, there is clear evidence that smoking modulates symptom severity in patients with anxiety disorders. In order to better understand this relationship, several animal paradigms are used to model several key symptoms of anxiety disorders; these include fear conditioning and measures of anxiety. Studies clearly demonstrate that nicotine mediates acquisition and extinction of fear as well as anxiety through the modulation of specific subtypes of nicotinic acetylcholine receptors (nAChRs) in brain regions involved in emotion processing such as the hippocampus. However, the direction of nicotine's effects on these behaviors is determined by several factors that include the length of administration, hippocampus-dependency of the fear learning task, and source of anxiety (novelty-driven vs. social anxiety). Overall, the studies reviewed here suggest that nicotine alters behaviors related to fear and anxiety and that nicotine contributes to the development, maintenance, and reoccurrence of anxiety disorders.
Shi, Zhan; Liu, Peiru
Sixty-one high-math-anxious persons and sixty-one low-math-anxious persons completed a modified working memory capacity task, designed to measure working memory capacity under a dysfunctional math-related context and working memory capacity under a valence-neutral context. Participants were required to perform simple tasks with emotionally benign material (i.e., lists of letters) over short intervals while simultaneously reading and making judgments about sentences describing dysfunctional math-related thoughts or sentences describing emotionally-neutral facts about the world. Working memory capacity for letters under the dysfunctional math-related context, relative to working memory capacity performance under the valence-neutral context, was poorer overall in the high-math-anxious group compared with the low-math-anxious group. The findings show a particular difficulty employing working memory in math-related contexts in high-math-anxious participants. Theories that can provide reasonable interpretations for these findings and interventions that can reduce anxiety-induced worrying intrusive thoughts or improve working memory capacity for math anxiety are discussed.
Shi, Zhan; Liu, Peiru
Sixty-one high-math-anxious persons and sixty-one low-math-anxious persons completed a modified working memory capacity task, designed to measure working memory capacity under a dysfunctional math-related context and working memory capacity under a valence-neutral context. Participants were required to perform simple tasks with emotionally benign material (i.e., lists of letters) over short intervals while simultaneously reading and making judgments about sentences describing dysfunctional math-related thoughts or sentences describing emotionally-neutral facts about the world. Working memory capacity for letters under the dysfunctional math-related context, relative to working memory capacity performance under the valence-neutral context, was poorer overall in the high-math-anxious group compared with the low-math-anxious group. The findings show a particular difficulty employing working memory in math-related contexts in high-math-anxious participants. Theories that can provide reasonable interpretations for these findings and interventions that can reduce anxiety-induced worrying intrusive thoughts or improve working memory capacity for math anxiety are discussed. PMID:27788235
Grimley, Michael; Dahraei, Hassan; Riding, Richard J.
While prior research indicates that relationships exist between anxiety-stability and working memory, and cognitive style and anxiety-stability, they have not been considered together. The aim of this study was to consider how anxiety-stability is related to working memory, gender and style in interaction. The sample consisted of 179…
Visu-Petra, Laura; Cheie, Lavinia; Benga, Oana; Alloway, Tracy Packiam
The relationship between trait anxiety and memory functioning in young children was investigated. Two studies were conducted, using tasks tapping verbal and visual-spatial short-term memory (Study 1) and working memory (Study 2) in preschoolers. On the verbal storage tasks, there was a detrimental effect of anxiety on processing efficiency…
Shi, Zhan; Gao, Xin; Zhou, Renlai
Previous studies have shown that working memory (WM) processes are related to frontal-midline theta (FM-theta) activity (4-8 Hz) and test anxiety impairs WM performance. However, the effect of test anxiety on FM-theta activity during WM has not been investigated as yet. To examine this question, 37 undergraduates were asked to complete a modified reading span task involving neutral working memory capacity (WMC) and emotional WMC while their electroencephalography was measured. The results showed that relative to neutral WMC performance (the ability to remember the letter lists in the context of valence-neutral sentences), emotional WMC performance (the ability to remember the letter lists in the context of test-related sentences) was poorer for highly test anxious participants compared with lowly test anxious participants. Relative to FM-theta activity during remembering the letter lists in the valence-neutral context, FM-theta activity was weaker during remembering the letter lists in the test-related context for highly test anxious participants compared with lowly test anxious participants. These findings indicate that FM-theta is an index not only for successful WM manipulation but also for efficient prefrontal cortex functioning during WM.
Zielinski, Mark R; Davis, J Mark; Fadel, James R; Youngstedt, Shawn D
Sleep deprivation can have deleterious effects on cognitive function and mental health. Moderate exercise training has myriad beneficial effects on cognition and mental health. However, physiological and behavioral effects of chronic moderate sleep restriction and its interaction with common activities, such as moderate exercise training, have received little investigation. The aims of this study were to examine the effects of chronic moderate sleep restriction and moderate exercise training on anxiety-related behavior, spatial memory, and neurobiological correlates in mice. Male mice were randomized to one of four 11-week treatments in a 2 [sleep restriction (∼4h loss/day) vs. ad libitum sleep] × 2 [exercise (1h/day/6 d/wk) vs. sedentary activity] experimental design. Anxiety-related behavior was assessed with the elevated-plus maze, and spatial learning and memory were assessed with the Morris water maze. Chronic moderate sleep restriction did not alter anxiety-related behavior, but exercise training significantly attenuated anxiety-related behavior. Spatial learning and recall, hippocampal cell activity (i.e., number of c-Fos positive cells), and brain derived neurotrophic factor were significantly lower after chronic moderate sleep restriction, but higher after exercise training. Further, the benefit of exercise training for some memory variables was evident under normal sleep, but not chronic moderate sleep restriction conditions. These data indicate clear detrimental effects of chronic moderate sleep restriction on spatial memory and that the benefits of exercise training were impaired after chronic moderate sleep restriction.
Bowman, R E; Micik, R; Gautreaux, C; Fernandez, L; Luine, V N
Chronic restraint stress alters performance of rats on cognitive tasks, and anxiety measurements, and these stress-induced behavioral alterations are sexually dimorphic. Following a long stress period (21 days restraint) males show cognitive impairments while females are either not affected or enhanced on the same tasks. The current study examined whether sexually differentiated responses are also induced following shorter restraint stress durations. Male and female Sprague Dawley rats, aged 2.5 months, served as controls or received restraint stress (6 h/day, 7 days) and were tested for anxiety (plus maze), non-spatial memory (object recognition), and spatial memory (object placement). Plus maze performance was altered by sex and stress exposure. Stress impaired male object recognition but did not affect female performance. Stress did not affect male spatial memory; however, control females could not significantly discriminate between the old and new locations, but stress exposure enhanced female performance. Following behavioral testing, monoamines and metabolites were measured in prefrontal cortex (PFC), hippocampus (CA1, CA3), and amygdala. Notably, PFC and CA3 indices for noradrenergic activity (MHPG levels and MHPG/NE ratios) were increased in stress females, but decreased in males, and similar changes were found in CA1 and BLA dopaminergic indices. Thus, these sexually dimorphic neurochemical changes following stress may underlie the behavioral differences. Current results show that short-term restraint elicits sex-dependent behavioral and neural changes different from those previously reported for longer term stresses and suggest that the temporal relationship between the change from adaptive to maladaptive responses to stress is shorter in male than female rats.
Darcet, Flavie; Mendez-David, Indira; Tritschler, Laurent; Gardier, Alain M; Guilloux, Jean-Philippe; David, Denis J
Cognitive disturbances are often reported as serious incapacitating symptoms by patients suffering from major depressive disorders (MDDs). Such deficits have been observed in various animal models based on environmental stress. Here, we performed a complete characterization of cognitive functions in a neuroendocrine mouse model of depression based on a chronic (4 weeks) corticosterone administration (CORT). Cognitive performances were assessed using behavioral tests measuring episodic (novel object recognition test, NORT), associative (one-trial contextual fear conditioning, CFC), and visuo-spatial (Morris water maze, MWM; Barnes maze, BM) learning/memory. Altered emotional phenotype after chronic corticosterone treatment was confirmed in mice using tests predictive of anxiety or depression-related behaviors. In the NORT, CORT-treated mice showed a decrease in time exploring the novel object during the test session and a lower discrimination index compared to control mice, characteristic of recognition memory impairment. Associative memory was also impaired, as observed with a decrease in freezing duration in CORT-treated mice in the CFC, thus pointing out the cognitive alterations in this model. In the MWM and in the BM, spatial learning performance but also short-term spatial memory were altered in CORT-treated mice. In the MWM, unlike control animals, CORT-treated animals failed to learn a new location during the reversal phase, suggesting a loss of cognitive flexibility. Finally, in the BM, the lack of preference for the target quadrant during the recall probe trial in animals receiving corticosterone regimen demonstrates that long-term retention was also affected in this paradigm. Taken together, our results highlight that CORT-induced anxio-depressive-like phenotype is associated with a cognitive deficit affecting all aspects of memory tested.
Darcet, Flavie; Mendez-David, Indira; Tritschler, Laurent; Gardier, Alain M.; Guilloux, Jean-Philippe; David, Denis J.
Cognitive disturbances are often reported as serious incapacitating symptoms by patients suffering from major depressive disorders (MDDs). Such deficits have been observed in various animal models based on environmental stress. Here, we performed a complete characterization of cognitive functions in a neuroendocrine mouse model of depression based on a chronic (4 weeks) corticosterone administration (CORT). Cognitive performances were assessed using behavioral tests measuring episodic (novel object recognition test, NORT), associative (one-trial contextual fear conditioning, CFC), and visuo-spatial (Morris water maze, MWM; Barnes maze, BM) learning/memory. Altered emotional phenotype after chronic corticosterone treatment was confirmed in mice using tests predictive of anxiety or depression-related behaviors. In the NORT, CORT-treated mice showed a decrease in time exploring the novel object during the test session and a lower discrimination index compared to control mice, characteristic of recognition memory impairment. Associative memory was also impaired, as observed with a decrease in freezing duration in CORT-treated mice in the CFC, thus pointing out the cognitive alterations in this model. In the MWM and in the BM, spatial learning performance but also short-term spatial memory were altered in CORT-treated mice. In the MWM, unlike control animals, CORT-treated animals failed to learn a new location during the reversal phase, suggesting a loss of cognitive flexibility. Finally, in the BM, the lack of preference for the target quadrant during the recall probe trial in animals receiving corticosterone regimen demonstrates that long-term retention was also affected in this paradigm. Taken together, our results highlight that CORT-induced anxio-depressive-like phenotype is associated with a cognitive deficit affecting all aspects of memory tested. PMID:24822041
Owens, Matthew; Stevenson, Jim; Norgate, Roger; Hadwin, Julie A
Working memory skills are positively associated with academic performance. In contrast, high levels of trait anxiety are linked with educational underachievement. Based on Eysenck and Calvo's (1992) processing efficiency theory (PET), the present study investigated whether associations between anxiety and educational achievement were mediated via poor working memory performance. Fifty children aged 11-12 years completed verbal (backwards digit span; tapping the phonological store/central executive) and spatial (Corsi blocks; tapping the visuospatial sketchpad/central executive) working memory tasks. Trait anxiety was measured using the State-Trait Anxiety Inventory for Children. Academic performance was assessed using school administered tests of reasoning (Cognitive Abilities Test) and attainment (Standard Assessment Tests). The results showed that the association between trait anxiety and academic performance was significantly mediated by verbal working memory for three of the six academic performance measures (math, quantitative and non-verbal reasoning). Spatial working memory did not significantly mediate the relationship between trait anxiety and academic performance. On average verbal working memory accounted for 51% of the association between trait anxiety and academic performance, while spatial working memory only accounted for 9%. The findings indicate that PET is a useful framework to assess the impact of children's anxiety on educational achievement.
Castelhano, Adelisandra Silva Santos; Cassane, Gustavo dos Santos Teada; Scorza, Fulvio Alexandre; Cysneiros, Roberta Monterazzo
Neonatal seizures are the most common manifestation of neurological dysfunction in the neonate. The prognosis of neonatal seizures is highly variable, and the controversy remains whether the severity, duration, or frequency of seizures may contribute to brain damage independently of its etiology. Animal data indicates that seizures during development are associated with a high probability of long-term adverse effects such as learning and memory impairment, behavioral changes and even epilepsy, which is strongly age dependent, as well as the severity, duration, and frequency of seizures. In preliminary studies, we demonstrated that adolescent male rats exposed to one-single neonatal status epilepticus (SE) episode showed social behavior impairment, and we proposed the model as relevant for studies of developmental disorders. Based on these facts, the goal of this study was to verify the existence of a persistent deficit and if the anxiety-related behavior could be associated with that impairment. To do so, male Wistar rats at 9 days postnatal were submitted to a single episode of SE by pilocarpine injection (380 mg/kg, i.p.) and control animals received saline (0.9%, 0.1 mL/10 g). It was possible to demonstrate that in adulthood, animals exposed to neonatal SE displayed low preference for social novelty, anxiety-related behavior, and increased stereotyped behavior in anxiogenic environment with no locomotor activity changes. On the balance, these data suggests that neonatal SE in rodents leads to altered anxiety-related and abnormal social behaviors. PMID:23675329
Klados, Manousos A.; Simos, Panagiotis; Micheloyannis, Sifis; Margulies, Daniel; Bamidis, Panagiotis D.
There have been several attempts to account for the impact of Mathematical Anxiety (MA) on brain activity with variable results. The present study examines the effects of MA on ERP amplitude during performance of simple arithmetic calculations and working memory tasks. Data were obtained from 32 university students as they solved four types of arithmetic problems (one- and two-digit addition and multiplication) and a working memory task comprised of three levels of difficulty (1, 2, and 3-back task). Compared to the Low-MA group, High-MA individuals demonstrated reduced ERP amplitude at frontocentral (between 180–320 ms) and centroparietal locations (between 380–420 ms). These effects were independent of task difficulty/complexity, individual performance, and general state/trait anxiety levels. Results support the hypothesis that higher levels of self-reported MA are associated with lower cortical activation during the early stages of the processing of numeric stimuli in the context of cognitive tasks. PMID:26578912
Moon, Chung-Man; Jeong, Gwang-Woo
Background The neuroanatomical abnormalities associated with behavioral dysfunction on explicit memory in patients generalized anxiety disorder (GAD) have not yet been clearly identified. Purpose To investigate the regional gray matter (GM) and white matter (WM) volume alterations over the whole brain in patients with GAD, as well as the correlation between the brain structural abnormality and explicit memory dysfunction. Material and Methods Twenty patients with GAD and 20 healthy controls matched for age, sex, and education level underwent high-resolution T1-weighted magnetic resonance imaging (MRI). The participants performed the explicit memory tasks with the neutral and anxiety-inducing words. Results Patients with GAD showed significantly reduced GM volumes in the midbrain (MB), thalamus, hippocampus (Hip), insula, and superior temporal gyrus (STG); and reduced WM volumes in the MB, anterior limb of the internal capsule (ALIC), dorsolateral prefrontal cortex (DLPFC), and precentral gyrus (PrG). It is important to note that the GM volume of the Hip and the WM volume of the DLPFC were positively correlated with the recognition accuracy (%) in the explicit memory tasks with neutral and anxiety-inducing words, respectively. On the other hand, the WM volume of the PrG was negatively correlated with the reaction time in the same memory tasks. Conclusion This study demonstrated the regional volume changes on whole-brain GM and WM and the correlation between the brain structural alteration and explicit memory dysfunction in GAD patients. These findings would be helpful to understand the association between the brain structure abnormality and the functional deficit in the explicit memory in GAD.
Bellani, Rudy; Luecken, Linda J; Conrad, Cheryl D
We tested the hypothesis that peripubertal anxiety levels are predictive of the detrimental effects of chronic stress on hippocampal-dependent spatial memory. The anxiety levels of peripubertal male Sprague-Dawley rats (43 days old) were characterized using open field and elevated plus mazes, followed by chronic restraint stress for 6 h/day/21 days beginning in young adulthood (75 days). Following chronic stress treatment, rats were tested on the spatial Y-maze using two inter-trial interval levels of difficulty (4 h: 1 day post-chronic stress; 1 min: 2 days post-chronic stress). As expected, all groups displayed intact spatial memory in the less difficult 1 min version of the Y-maze. However, in the 4 h version of the Y-maze, chronically stressed high anxiety rats showed impaired spatial memory, while chronically stressed low anxiety and control (low and high anxiety) rats displayed intact spatial memory. Moreover, a month after chronic stress ended, high anxiety rats had significantly higher basal corticosterone levels than low anxiety rats (control and stress). These results indicate that peripubertal anxiety and chronic stress interact to influence hippocampal-dependent spatial memory in adulthood.
Hopko, D R; Ashcraft, M H; Gute, J; Ruggiero, K J; Lewis, C
A current theory of anxiety effects in cognition claims that anxiety disrupts normal processing within the working memory system. We examined this theory in the context of a reading task, for participants who were high or low in assessed mathematics anxiety. The task was designed to measure the ability to inhibit attention to distracting information and the effects of this ability on explicit memory performance. The results suggested that math-anxious individuals have a deficient inhibition mechanism whereby working memory resources are consumed by task-irrelevant distracters. A consequence of this deficiency was that explicit memory performance was poorer for high-anxious individuals. Based on these results, the recommendation is made that Eysenck and Calvo's (1992) processing efficiency theory be integrated with Connelly, Hasher, and Zack's (1991) inhibition theory to portray more comprehensively the relation between anxiety and performance.
Watts, Sarah E.; Weems, Carl F.
The purpose of this study was to examine the linkages among selective attention, memory bias, cognitive errors, and anxiety problems by testing a model of the interrelations among these cognitive variables and childhood anxiety disorder symptoms. A community sample of 81 youth (38 females and 43 males) aged 9-17 years and their parents completed…
Ganley, Colleen M.; Vasilyeva, Marina
This research examined a potential mechanism underlying gender differences in math performance by testing a mediation model in which women's higher anxiety taxes their working memory resources, leading to underperformance on a mathematics test. Participants for the 2 studies were college students (N = 87, N = 118) who completed an anxiety measure,…
Mazerolle, Marie; Régner, Isabelle; Rigalleau, François; Huguet, Pascal
There is now evidence that negative age-related stereotypes about memory reduce older adults' memory performance, and inflate age differences in this domain. Here, we examine whether stereotype threat may also influence the basic feeling that one is more or less able to remember. Using the Remember/Know paradigm, we demonstrated that stereotype threat conducted older adults to a greater feeling of familiarity with events, while failing to retrieve any contextual detail. This finding indicates that stereotype threat alters older adults' subjective experience of memory, and strengthens our understanding of the mechanisms underlying stereotype threat effects.
Machado, M L; Lelong-Boulouard, V; Smith, P F; Freret, T; Philoxene, B; Denise, P; Besnard, S
It is now well established that vestibular information plays an important role in spatial memory processes. Although vestibular lesions induce anxiety in humans, this finding remains controversial in rodents. However, it is possible that anxiety-related behavior is associated with spatial memory impairments after vestibular lesions. We aimed to evaluate anxiety-like behavior and the effect of an anxiolytic treatment during a complex spatial memory task in a rat model of compensated bilateral vestibular lesions. Adult rats were divided into four groups, with or without vestibular lesions and, treated or untreated by diazepam. The vestibular lesion was performed by transtympanic injection of arsanilate and compared to transtympanic saline injection. Diazepam or saline was administered 1h before each test or learning session. Vestibular-lesioned rats exhibited anxiety-like behavior which was decreased with diazepam. Spatial memory performance was similar in control-treated and untreated groups, suggesting no effect on memory at the dose of diazepam used. Spatial memory performances were not modified by anxiolytic drug treatment in vestibular-lesioned rats compared to vestibular-lesioned rats without drug treatment. We conclude that bilateral vestibular lesions in rats induced anxiety-like behavior which was unrelated to spatial memory impairment and was probably specifically related to the loss of vestibular information.
Using a large sample and the confirmatory factor analysis, the study investigated the relationships between anxiety, working memory (WM) and (fluid) intelligence. The study showed that the negative impact of anxiety on WM functioning diminishes with increasing intelligence, and that anxiety can significantly affect WM only in people below average intelligence. This effect could not be fully explained by the sheer differences in WM capacity (WMC), suggesting the importance of higher-level cognition in coping with anxiety. Although intelligence moderated the impact of anxiety on WM, it was only weakly related to anxiety. In contrast to previous studies, anxiety explained the substantial amount of WMC variance (17.8%) in less intelligent participants, but none of the variance in more intelligent ones. These results can be explained in terms of either increased motivation of intelligent but anxious people to cope with a WM task, or their ability to compensate decrements in WM.
Nakashima, Satoshi F; Morimoto, Yuko; Takano, Yuji; Yoshikawa, Sakiko; Hugenberg, Kurt
In the current research, we extend past work on the effects of ambient darkness and threat to the domain of memory for expressive faces. In one study, we examined the effects of ambient darkness and individual differences in state anxiety on memory of unfamiliar expressive faces. Here, participants were seated in either a dark or light room and encoded a set of unfamiliar faces with angry, happy, and neutral facial expressions. A subsequent recognition task revealed an interactive effect of ambient darkness, anxiety, and target expression. Highly anxious participants in ambient darkness had worse memory for angry faces than did low-anxiety participants. On the other hand, the recognition performance for happy faces was affected neither by the darkness nor state anxiety. The results suggest not only that ambient darkness has its strongest effect on anxious perceivers, but also that person × situation effects should be considered in face recognition research.
Drugs acting through 5-hydroxytryptamine (serotonin or 5-HT) systems modulate memory and its alterations, although the mechanisms involved are poorly understood. 5-HT drugs may present promnesic and/or antiamnesic (or even being amnesic) effects. Key questions regarding 5-HT markers include whether receptors directly or indirectly participate and/or contribute to the physiological and pharmacological basis of memory and its pathogenesis; hence, the major aim of this article was to examine recent advances in emergent targets of the 5-HT systems for memory formation and memory alterations. Recent reviews and findings are summarized, mainly in the context of the growing notion of memory deficits in brain disorders (e.g., posttraumatic stress disorder, mild cognitive impairment, consumption of drugs, poststroke cognitive dysfunctions, schizophrenia, Parkinson disease, and infection-induced memory impairments). Mainly, mammalian and (some) human data were the focus. At least agonists and antagonists for 5-HT1A/1B, 5-HT2A/2B/2C, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors as well as serotonin uptake inhibitors seem to have a promnesic and/or antiamnesic effect in different conditions and 5-HT markers seem to be associated to neural changes. Available evidence offers clues about the possibilities, but the exact mechanisms remain unclear. For instance, 5-HT transporter expression seems to be a reliable neural marker related to memory mechanisms and its alterations.
Hawley, Wayne R; Grissom, Elin M; Dohanich, Gary P
Rodents learn to navigate mazes using various strategies that are governed by specific regions of the brain. The type of strategy used when learning to navigate a spatial environment is moderated by a number of factors including emotional states. Heightened anxiety states, induced by exposure to stressors or administration of anxiogenic agents, have been found to bias male rats toward the use of a striatum-based stimulus-response strategy rather than a hippocampus-based place strategy. However, no study has yet examined the relationship between natural anxiety levels, or trait anxiety, and the type of learning strategy used by rats on a dual-solution task. In the current experiment, levels of inherent anxiety were measured in an open field and compared to performance on two separate cognitive tasks, a Y-maze task that assessed place recognition memory, and a visible platform water maze task that assessed learning strategy. Results indicated that place recognition memory on the Y-maze correlated with the use of place learning strategy on the water maze. Furthermore, lower levels of trait anxiety correlated positively with better place recognition memory and with the preferred use of place learning strategy. Therefore, competency in place memory and bias in place strategy are linked to the levels of inherent anxiety in male rats.
Zeitlin, Ross; Patel, Sagar; Solomon, Rosalynn; Tran, John; Weeber, Edwin J; Echeverria, Valentina
Posttraumatic stress disorder (PTSD) is an anxiety disorder triggered by traumatic events. Symptoms include anxiety, depression and deficits in fear memory extinction (FE). PTSD patients show a higher prevalence of cigarette smoking than the general population. The present study investigated the effects of cotinine, a tobacco-derived compound, over anxiety and contextual fear memory after fear conditioning (FC) in mice, a model for inducing PTSD-like symptoms. Two-month-old C57BL/6J mice were separated into three experimental groups. These groups were used to investigate the effect of pretreatment with cotinine on contextual fear memory and posttreatment on extinction and stability or retrievability of the fear memory. Also, changes induced by cotinine on the expression of extracellular signal-regulated kinase (ERK)1/2 were assessed after extinction in the hippocampus. An increase in anxiety and corticosterone levels were found after fear conditioning. Cotinine did not affect corticosterone levels but enhanced the extinction of contextual fear, decreased anxiety and the stability and/or retrievability of contextual fear memory. Cotinine-treated mice showed higher levels of the active forms of ERK1/2 than vehicle-treated mice after FC. This evidence suggests that cotinine is a potential new pharmacological treatment to reduce symptoms in individuals with PTSD.
Sanders, Ashley F P; Hobbs, Diana A; Stephenson, David D; Laird, Robert D; Beaton, Elliott A
Stress and anxiety have a negative impact on working memory systems by competing for executive resources and attention. Broad memory deficits, anxiety, and elevated stress have been reported in individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS). We investigated anxiety and physiological stress reactivity in relation to visuospatial working memory impairments in 20 children with 22q11.2DS and 32 typically developing (TD) children ages 7 to 16. Children with 22q11.2DS demonstrated poorer working memory, reduced post-stress respiratory sinus arrhythmia recovery, and overall increased levels of cortisol in comparison to TD children. Anxiety, but not physiological stress responsivity, mediated the relationship between 22q11.2DS diagnosis and visuospatial working memory impairment. Findings indicate that anxiety exacerbates impaired working memory in children with 22q11.2DS.
Vytal, Katherine E; Cornwell, Brian R; Letkiewicz, Allison M; Arkin, Nicole E; Grillon, Christian
Anxiety can be distracting, disruptive, and incapacitating. Despite problems with empirical replication of this phenomenon, one fruitful avenue of study has emerged from working memory (WM) experiments where a translational method of anxiety induction (risk of shock) has been shown to disrupt spatial and verbal WM performance. Performance declines when resources (e.g., spatial attention, executive function) devoted to goal-directed behaviors are consumed by anxiety. Importantly, it has been shown that anxiety-related impairments in verbal WM depend on task difficulty, suggesting that cognitive load may be an important consideration in the interaction between anxiety and cognition. Here we use both spatial and verbal WM paradigms to probe the effect of cognitive load on anxiety-induced WM impairment across task modality. Subjects performed a series of spatial and verbal n-back tasks of increasing difficulty (1, 2, and 3-back) while they were safe or at risk for shock. Startle reflex was used to probe anxiety. Results demonstrate that induced-anxiety differentially impacts verbal and spatial WM, such that low and medium-load verbal WM is more susceptible to anxiety-related disruption relative to high-load, and spatial WM is disrupted regardless of task difficulty. Anxiety impacts both verbal and spatial processes, as described by correlations between anxiety and performance impairment, albeit the effect on spatial WM is consistent across load. Demanding WM tasks may exert top-down control over higher-order cortical resources engaged by anxious apprehension, however high-load spatial WM may continue to experience additional competition from anxiety-related changes in spatial attention, resulting in impaired performance. By describing this disruption across task modalities, these findings inform current theories of emotion-cognition interactions and may facilitate development of clinical interventions that seek to target cognitive impairments associated with anxiety.
Sieber, Joan E.; Kameya, Lawrence I.
Forty fifth and sixth graders, matched on sex and measures of test anxiety, defensiveness, and IQ, were divided into two groups, each of which solved Porteus maze tasks and a marble puzzle, with and without memory support, respectively. An anxiety-by-memory support interaction occurred in the number of errors made prior to solving the marble…
Owens, Matthew; Stevenson, Jim; Hadwin, Julie A; Norgate, Roger
Cognitive interference theories (e.g. attentional control theory, processing efficiency theory) suggest that high levels of trait anxiety predict adverse effects on the performance of cognitive tasks, particularly those that make high demands on cognitive resources. We tested an interaction hypothesis to determine whether a combination of high anxiety and low working memory capacity (WMC) would predict variance in demanding cognitive test scores. Ninety six adolescents (12- to 14-years-old) participated in the study, which measured self-report levels of trait anxiety, working memory, and cognitive test performance. As hypothesized, we found that the anxiety-WMC interaction explained a significant amount of variance in cognitive test performance (ΔR(2) .07, p < .01). Trait anxiety was unrelated to cognitive test performance for those adolescents with average WMC scores (β = .13, p > .10). In contrast, trait anxiety was negatively related to test performance in adolescents with low WMC (β = -.35, p < .05) and positively related to test performance in those with high WMC (β = .49, p < .01). The results of this study suggest that WMC moderates the relationship between anxiety and cognitive test performance and may be a determinant factor in explaining some discrepancies found in the literature. Further research is needed to fully understand the mechanisms involved.
Aasvik, Julie K.; Woodhouse, Astrid; Jacobsen, Henrik B.; Borchgrevink, Petter C.; Stiles, Tore C.; Landrø, Nils I.
Objective: The aim of this study was to identify symptoms associated with subjective memory complaints (SMCs) among subjects who are currently on sick leave due to symptoms of chronic pain, fatigue, depression, anxiety, and insomnia. Methods: This was a cross-sectional study, subjects (n = 167) who were currently on sick leave were asked to complete an extensive survey consisting of the following: items addressing their sociodemographics, one item from the SF-8 health survey measuring pain, Chalder Fatigue Questionnaire, Hospital Anxiety and Depression Scale, Insomnia Severity Index, and Everyday Memory Questionnaire – Revised. General linear modeling was used to analyze variables associated with SMCs. Results: Symptoms of fatigue (p-value < 0.001) and anxiety (p-value = 0.001) were uniquely and significantly associated with perceived memory failures. The associations with symptoms of pain, depression, and insomnia were not statistically significant. Conclusions: Subjective memory complaints should be recognized as part of the complex symptomatology among patients who report multiple symptoms, especially in cases of fatigue and anxiety. Self-report questionnaires measuring perceived memory failures may be a quick and easy way to incorporate and extend this knowledge into clinical practice. PMID:26441716
Vanmierlo, Tim; Rutten, Kris; van Vark-van der Zee, Leonie C; Friedrichs, Silvia; Bloks, Vincent W; Blokland, Arjan; Ramaekers, Frans C; Sijbrands, Eric; Steinbusch, Harry; Prickaerts, Jos; Kuipers, Folkert; Lütjohann, Dieter; Mulder, Monique
Plant sterols such as sitosterol and campesterol are frequently applied as functional food in the prevention of atherosclerosis. Recently, it became clear that plasma derived plant sterols accumulate in murine brains. We questioned whether plant sterols in the brain are associated with alterations in brain cholesterol homeostasis and subsequently with brain functions. ATP binding cassette (Abc)g5-/- mice, a phytosterolemia model, were compared to Abcg5+/+ mice for serum and brain plant sterol accumulation and behavioral and cognitive performance. Serum and brain plant sterol concentrations were respectively 35-70-fold and 5-12-fold increased in Abcg5-/- mice (P<0.001). Plant sterol accumulation resulted in decreased levels of desmosterol (P<0.01) and 24(S)-hydroxycholesterol (P<0.01) in the hippocampus, the brain region important for learning and memory functions, and increased lanosterol levels (P<0.01) in the cortex. However, Abcg5-/- and Abcg5+/+ displayed no differences in memory functions or in anxiety and mood related behavior. The swimming speed of the Abcg5-/- mice was slightly higher compared to Abcg5+/+ mice (P<0.001). In conclusion, plant sterols in the brains of Abcg5-/- mice did have consequences for brain cholesterol metabolism, but did not lead to an overt phenotype of memory or anxiety related behavior. Thus, our data provide no contra-indication for nutritional intake of plant sterol enriched nutrition.
Amorós-Aguilar, Laura; Portell-Cortés, Isabel; Costa-Miserachs, David; Torras-Garcia, Meritxell; Coll-Andreu, Margalida
The consequences of traumatic brain injury (TBI) sustained during late adolescence (7 weeks old) on spontaneous object recognition memory and on anxiety-like behaviors in the elevated plus maze were tested in rats during adulthood. Testing took place at 2 different postinjury times, in separate groups: 3 and 6 weeks, when animals were 10 and 13 weeks old, respectively. The rats were either submitted to controlled cortical impact injury, an experimental model of focal TBI with contusion, or were sham-operated. TBI animals failed to remember the familiar object and had a significantly lower performance than sham-operated animals, indicating memory disruption, when the retention delay was 24 hr, but not when it was 3 hr. TBI did not have any significant effect on the main anxiety-related behaviors, but it reduced time in the central platform of the elevated plus maze. The effects of TBI on memory and on anxiety-like behaviors were similar at the 2 postinjury times. In both TBI and sham-operated groups, animals tested 6 weeks after surgery had lower anxiety-related indices than those tested at 3 weeks, an effect that might be indicative of reduced anxiety levels with increasing age. In summary, focal TBI with contusion sustained during late adolescence led to object recognition memory deficits in a 24-hr test during adulthood but did not have a major impact on anxiety-like behaviors. Memory deficits persisted for at least 6 weeks after injury, indicating that spontaneous modifications of these functional disturbances did not take place along this time span.
Bagci, Eyup; Aydin, Emel; Ungureanu, Eugen; Hritcu, Lucian
Anthriscus nemorosa (Bieb.) Sprengel is used for medicinal purposes in traditional medicine around the world, including Turkey. Ethnobotanical studies suggest that Anthriscus essential oil could improve memory in Alzheimer's disease. The current study was hypothesized to investigate the beneficial effects of inhaled Anthriscus nemorosa essential oil on memory, anxiety and depression in scopolamine-treated rats. Anthriscus nemorosa essential oil was administered by inhalation in the doses of 1% and 3% for 21 continuous days and scopolamine (0.7mg/kg) was injected intraperitoneally 30min before the behavioral testing. Y-maze and radial arm-maze tests were used for assessing memory processes. Also, the anxiety and depressive responses were studied by elevated plus-maze and forced swimming tests. As expected, the scopolamine alone-treated rats exhibited the following: decrease the percentage of the spontaneous alternation in Y-maze test, increase the number of working and reference memory errors in radial arm-maze test, decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. However, dual scopolamine and Anthriscus nemorosa essential oil-treated rats showed significant improvement of memory formation and exhibited anxiolytic- and antidepressant-like effects in scopolamine-treated rats. These results suggest that Anthriscus nemorosa essential oil inhalation can prevent scopolamine-induced memory impairment, anxiety and depression.
Passolunghi, Maria C; Caviola, Sara; De Agostini, Ruggero; Perin, Chiara; Mammarella, Irene C
Mathematics anxiety (MA) has been defined as "a feeling of tension and anxiety that interferes with the manipulation of numbers and the solving of math problems in a wide variety of ordinary life and academic situations." Previous studies have suggested that a notable proportion of children in primary and secondary school suffer from MA, which is negatively correlated with calculation skills. The processing efficiency and attentional control theories suggest that working memory (WM) also plays an important part in such anxious feelings. The present study aimed to analyze the academic achievement and cognitive profiles of students with high math anxiety (HMA) and low math anxiety (LMA). Specifically, 32 students with HMA and 34 with LMA matched for age, gender, generalized anxiety, and vocabulary attending sixth to eighth grades were selected from a larger sample. The two groups were tested on reading decoding, reading comprehension, mathematics achievement, and on verbal short-term memory and WM. Our findings showed that HMA students were weak in several measures of mathematics achievement, but not in reading and writing skills, and that students with HMA reported lower scores on short-term memory and WM performances (with associated difficulties in inhibiting irrelevant information) than children with LMA. In addition, a logistic regression showed that weaknesses in inhibitory control and fact retrieval were the strongest variables for classifying children as having HMA or LMA.
Passolunghi, Maria C.; Caviola, Sara; De Agostini, Ruggero; Perin, Chiara; Mammarella, Irene C.
Mathematics anxiety (MA) has been defined as “a feeling of tension and anxiety that interferes with the manipulation of numbers and the solving of math problems in a wide variety of ordinary life and academic situations.” Previous studies have suggested that a notable proportion of children in primary and secondary school suffer from MA, which is negatively correlated with calculation skills. The processing efficiency and attentional control theories suggest that working memory (WM) also plays an important part in such anxious feelings. The present study aimed to analyze the academic achievement and cognitive profiles of students with high math anxiety (HMA) and low math anxiety (LMA). Specifically, 32 students with HMA and 34 with LMA matched for age, gender, generalized anxiety, and vocabulary attending sixth to eighth grades were selected from a larger sample. The two groups were tested on reading decoding, reading comprehension, mathematics achievement, and on verbal short-term memory and WM. Our findings showed that HMA students were weak in several measures of mathematics achievement, but not in reading and writing skills, and that students with HMA reported lower scores on short-term memory and WM performances (with associated difficulties in inhibiting irrelevant information) than children with LMA. In addition, a logistic regression showed that weaknesses in inhibitory control and fact retrieval were the strongest variables for classifying children as having HMA or LMA. PMID:26869951
Hadwin, Julie A.; Brogan, Joanna; Stevenson, Jim
This study investigated the effect of individual differences in state anxiety on tasks tapping the central executive, phonological, and visuo-spatial components of working memory (WM). It was designed to test Eysenck and Calvo's processing efficiency theory (PET) which suggests that the phonological and executive components of WM may be important…
Visu-Petra, Laura; Miclea, Mircea; Cheie, Lavinia; Benga, Oana
In self-paced auditory memory span tasks, the microanalysis of response timing measures represents a developmentally sensitive measure, providing insights into the development of distinct processing rates during recall performance. The current study first examined the effects of age and trait anxiety on span accuracy (effectiveness) and response…
Calvo, M G; Eysenck, M W
Texts were presented sentence by sentence (Experiment 1) or word by word (Experiment 2) at a fixed rate to subjects high or low in test anxiety, under various conditions: no interference, concurrent articulatory suppression, and concurrent irrelevant speech (presented auditorily). High-anxiety subjects produced overt articulation more frequently than low-anxiety subjects, especially in the irrelevant speech condition. The most salient finding was an interaction between anxiety and interference on comprehension performance: under word-by-word-but not under sentence-by-sentence-presentation, anxious subjects showed poorer comprehension than non-anxious subjects in both conditions known to interfere with the articulatory loop (i.e. articulatory suppression, and irrelevant speech), but equivalent comprehension in the no interference condition. These findings suggest (a) that the articulatory loop has a special compensatory role for anxious individuals in reading comprehension, and (b) that the importance of this auxiliary mechanism is enhanced when other strategies, such as regressive fixations and control of reading speed, cannot be used.
Lenaert, Bert; Boddez, Yannick; Vervliet, Bram; Schruers, Koen; Hermans, Dirk
Associative learning plays an important role in the development of anxiety disorders, but a thorough understanding of the variables that impact such learning is still lacking. We investigated whether individual differences in autobiographical memory specificity are related to discrimination learning and generalization. In an associative learning task, participants learned the association between two pictures of female faces and a non-aversive outcome. Subsequently, six morphed pictures functioning as generalization stimuli (GSs) were introduced. In a sample of healthy participants (Study 1), we did not find evidence for differences in discrimination learning as a function of memory specificity. In a sample of anxiety disorder patients (Study 2), individuals who were characterized by low memory specificity showed deficient discrimination learning relative to high specific individuals. In contrast to previous findings, results revealed no effect of memory specificity on generalization. These results indicate that impaired discrimination learning, previously shown in patients suffering from an anxiety disorder, may be—in part—due to limited memory specificity. Together, these studies emphasize the importance of incorporating cognitive variables in associative learning theories and their implications for the development of anxiety disorders. In addition, re-analyses of the data (Study 3) showed that patients suffering from panic disorder showed higher outcome expectancies in the presence of the stimulus that was never followed by an outcome during discrimination training, relative to patients suffering from other anxiety disorders and healthy participants. Because we used a neutral, non-aversive outcome (i.e., drawing of a lightning bolt), these data suggest that learning abnormalities in panic disorder may not be restricted to fear learning, but rather reflect a more general associative learning deficit that also manifests in fear irrelevant contexts. PMID
Lenaert, Bert; Boddez, Yannick; Vervliet, Bram; Schruers, Koen; Hermans, Dirk
Associative learning plays an important role in the development of anxiety disorders, but a thorough understanding of the variables that impact such learning is still lacking. We investigated whether individual differences in autobiographical memory specificity are related to discrimination learning and generalization. In an associative learning task, participants learned the association between two pictures of female faces and a non-aversive outcome. Subsequently, six morphed pictures functioning as generalization stimuli (GSs) were introduced. In a sample of healthy participants (Study 1), we did not find evidence for differences in discrimination learning as a function of memory specificity. In a sample of anxiety disorder patients (Study 2), individuals who were characterized by low memory specificity showed deficient discrimination learning relative to high specific individuals. In contrast to previous findings, results revealed no effect of memory specificity on generalization. These results indicate that impaired discrimination learning, previously shown in patients suffering from an anxiety disorder, may be-in part-due to limited memory specificity. Together, these studies emphasize the importance of incorporating cognitive variables in associative learning theories and their implications for the development of anxiety disorders. In addition, re-analyses of the data (Study 3) showed that patients suffering from panic disorder showed higher outcome expectancies in the presence of the stimulus that was never followed by an outcome during discrimination training, relative to patients suffering from other anxiety disorders and healthy participants. Because we used a neutral, non-aversive outcome (i.e., drawing of a lightning bolt), these data suggest that learning abnormalities in panic disorder may not be restricted to fear learning, but rather reflect a more general associative learning deficit that also manifests in fear irrelevant contexts.
White, Corey N; Ratcliff, Roger; Vasey, Michael W
Individuals with high anxiety show bias for threatening information, but it is unclear whether this bias affects memory. Recognition memory studies have shown biases for recognising and rejecting threatening items in anxiety, prompting the need to identify moderating factors of this effect. This study focuses on the role of semantic similarity: the use of many semantically related threatening words could increase familiarity for those items and obscure anxiety-related differences in memory. To test this, two recognition memory experiments varied the proportion of threatening words in lists to manipulate the semantic-similarity effects. When similarity effects were reduced, participants with high trait anxiety were biased to respond "new" to threatening words, whereas when similarity effects were strong there was no effect of anxiety on memory bias. Analysis of the data with the drift diffusion model showed that the bias was due to differences in processing of the threatening stimuli rather than a simple response bias. These data suggest that the semantic similarity of the threatening words significantly affects the presence or absence of anxiety-related threat bias in recognition memory. The results indicate that trait anxiety is associated with a bias to decide that threatening stimuli were not previously studied, but only when semantic-similarity effects are controlled. Implications for theories of anxiety and future studies in this domain are discussed.
Hamilton, Trevor James; Kwan, Garfield T.; Gallup, Joshua; Tresguerres, Martin
Aggression and responsiveness to noxious stimuli are adaptable traits that are ubiquitous throughout the animal kingdom. Like vertebrate animals, some invertebrates have been shown to exhibit anxiety-like behaviour and altered levels of aggression that are modulated by the neurotransmitter serotonin. To investigate whether this influence of serotonin is conserved in crabs and whether these behaviours are sensitive to human antidepressant drugs; the striped shore crab, Pachygrapsus crassipes, was studied using anxiety (light/dark test) and aggression (mirror test) paradigms. Crabs were individually exposed to acute doses of the selective serotonin reuptake inhibitor, fluoxetine (5 or 25 mg/L), commonly known as Prozac®, followed by behavioural testing. The high dose of fluoxetine significantly decreased anxiety-like behaviour but had no impact on mobility or aggression. These results suggest that anxiety-like behaviour is more sensitive to modulation of serotonin than is aggressiveness in the shore crab. PMID:26806870
Hamilton, Trevor James; Kwan, Garfield T; Gallup, Joshua; Tresguerres, Martin
Aggression and responsiveness to noxious stimuli are adaptable traits that are ubiquitous throughout the animal kingdom. Like vertebrate animals, some invertebrates have been shown to exhibit anxiety-like behaviour and altered levels of aggression that are modulated by the neurotransmitter serotonin. To investigate whether this influence of serotonin is conserved in crabs and whether these behaviours are sensitive to human antidepressant drugs; the striped shore crab, Pachygrapsus crassipes, was studied using anxiety (light/dark test) and aggression (mirror test) paradigms. Crabs were individually exposed to acute doses of the selective serotonin reuptake inhibitor, fluoxetine (5 or 25 mg/L), commonly known as Prozac®, followed by behavioural testing. The high dose of fluoxetine significantly decreased anxiety-like behaviour but had no impact on mobility or aggression. These results suggest that anxiety-like behaviour is more sensitive to modulation of serotonin than is aggressiveness in the shore crab.
Hamilton, Trevor James; Holcombe, Adam; Tresguerres, Martin
The average surface pH of the ocean is dropping at a rapid rate due to the dissolution of anthropogenic CO2, raising concerns for marine life. Additionally, some coastal areas periodically experience upwelling of CO2-enriched water with reduced pH. Previous research has demonstrated ocean acidification (OA)-induced changes in behavioural and sensory systems including olfaction, which is due to altered function of neural gamma-aminobutyric acid type A (GABAA) receptors. Here, we used a camera-based tracking software system to examine whether OA-dependent changes in GABAA receptors affect anxiety in juvenile Californian rockfish (Sebastes diploproa). Anxiety was estimated using behavioural tests that measure light/dark preference (scototaxis) and proximity to an object. After one week in OA conditions projected for the next century in the California shore (1125 ± 100 µatm, pH 7.75), anxiety was significantly increased relative to controls (483 ± 40 µatm CO2, pH 8.1). The GABAA-receptor agonist muscimol, but not the antagonist gabazine, caused a significant increase in anxiety consistent with altered Cl(-) flux in OA-exposed fish. OA-exposed fish remained more anxious even after 7 days back in control seawater; however, they resumed their normal behaviour by day 12. These results show that OA could severely alter rockfish behaviour; however, this effect is reversible.
Hamilton, Trevor James; Holcombe, Adam; Tresguerres, Martin
The average surface pH of the ocean is dropping at a rapid rate due to the dissolution of anthropogenic CO2, raising concerns for marine life. Additionally, some coastal areas periodically experience upwelling of CO2-enriched water with reduced pH. Previous research has demonstrated ocean acidification (OA)-induced changes in behavioural and sensory systems including olfaction, which is due to altered function of neural gamma-aminobutyric acid type A (GABAA) receptors. Here, we used a camera-based tracking software system to examine whether OA-dependent changes in GABAA receptors affect anxiety in juvenile Californian rockfish (Sebastes diploproa). Anxiety was estimated using behavioural tests that measure light/dark preference (scototaxis) and proximity to an object. After one week in OA conditions projected for the next century in the California shore (1125 ± 100 µatm, pH 7.75), anxiety was significantly increased relative to controls (483 ± 40 µatm CO2, pH 8.1). The GABAA-receptor agonist muscimol, but not the antagonist gabazine, caused a significant increase in anxiety consistent with altered Cl− flux in OA-exposed fish. OA-exposed fish remained more anxious even after 7 days back in control seawater; however, they resumed their normal behaviour by day 12. These results show that OA could severely alter rockfish behaviour; however, this effect is reversible. PMID:24285203
Olsen, Reid H J; Johnson, Lance A; Zuloaga, Damian G; Limoli, Charles L; Raber, Jacob
Oxidative stress (OS) and reactive oxygen species (ROS) play a modulatory role in synaptic plasticity and signaling pathways. Mitochondria (MT), a major source of ROS because of their involvement in energy metabolism, are important for brain function. MT-generated ROS are proposed to be responsible for a significant proportion of OS and are associated with developmental abnormalities and aspects of cellular aging. The role of ROS and MT function in cognition of healthy individuals is relatively understudied. In this study, we characterized behavioral and cognitive performance of 5- to 6-month-old mice over-expressing mitochondrial catalase (MCAT). MCAT mice showed enhancements in hippocampus-dependent spatial learning and memory in the water maze and contextual fear conditioning, and reduced measures of anxiety in the elevated zero maze. Catalase activity was elevated in MCAT mice in all brain regions examined. Measures of oxidative stress (glutathione, protein carbonyl content, lipid peroxidation, and 8-hydroxyguanine) did not significantly differ between the groups. The lack of differences in these markers of oxidative stress suggests that the differences observed in this study may be due to altered redox signaling. Catalase over-expression might be sufficient to enhance cognition and reduce measures of anxiety even in the absence of alteration in levels of OS.
Aarts, Kristien; Pourtois, Gilles
Anxiety has profound influences on a wide range of cognitive processes, including action monitoring. Event-related brain potential (ERP) studies have shown that anxiety can boost early error detection mechanisms, as reflected by an enhanced error-related negativity (ERN) following errors in high-anxious, as compared with low-anxious, participants. This observation is consistent with the assumption of a gain control mechanism exerted by anxiety onto error-related brain responses within the dorsal anterior cingulate cortex (ACC). However, whether anxiety simply enhances or, rather, alters early error detection mechanisms remains unsolved. In this study, we compared the performance of low- versus high-trait-anxious participants during a go/no-go task while high-density EEG was recorded. The two groups showed comparable behavioral performance, although levels of state anxiety increased following the task for high-anxious participants only. ERP results confirmed that the ERN/Ne to errors was enhanced for high-anxious, relative to low-anxious, participants. However, complementary topographic analyses revealed that the scalp map of the ERN/Ne was not identical between the two groups, suggesting that anxiety did not merely increase early error detection mechanisms, but also led to a qualitative change in the early appraisal of errors. Inverse solution results confirmed a shift within the ACC for the localization of neural generators underlying the ERN/Ne scalp map in high-anxious participants, corroborating the assumption of an early effect of anxiety on early error-monitoring functions. These results shed new light on the dynamic interplay between anxiety and error-monitoring functions in the human brain.
Hoshino, Takatoshi; Tanno, Yoshihiko
The present study investigated whether the control of reflective attention in working memory (WM) is impaired in high trait anxiety individuals. We focused on the consequences of refreshing-a simple reflective process of thinking briefly about a just-activated representation in mind-on the subsequent processing of verbal stimuli. Participants performed a selective refreshing task, in which they initially refreshed or read one word from a three-word set, and then refreshed a non-selected item from the initial phrase or read aloud a new word. High trait anxiety individuals exhibited greater latencies when refreshing a word after experiencing the refreshing of a word from the same list of semantic associates. The same pattern was observed for reading a new word after prior refreshing. These findings suggest that high trait anxiety individuals have difficulty resolving interference from active distractors when directing reflective attention towards contents in WM or processing a visually presented word.
Owens, Matthew; Stevenson, Jim; Hadwin, Julie A.; Norgate, Roger
Anxiety and depression are linked to lower academic performance. It is proposed that academic performance is reduced in young people with high levels of anxiety or depression as a function of increased test-specific worry that impinges on working memory central executive processes. Participants were typically developing children (12 to…
Zhang, Kun; Li, Yu-jiao; Feng, Dan; Zhang, Peng; Wang, Ya-tao; Li, Xiang; Liu, Shui-bing; Wu, Yu-mei; Zhao, Ming-gao
Sleep disorder is becoming a widespread problem in current society, and is associated with impaired cognition and emotional disorders. Progranulin (PGRN), also known as granulin epithelin precursor, promotes neurite outgrowth and cell survival, and is encoded by the GRN gene. It is a tumor necrosis factor α receptor (TNFR) ligand which is implicated in many central nervous system diseases. However, the role PGRN in sleep disorder remains unclear. In the present study, we found that sleep deprivation (S-DEP) impaired the memory and produced thigmotaxis/anxiety-like behaviors in mice. S-DEP increased the levels of TNFα but decreased PGRN levels in the hippocampus. The intracerebroventricular (ICV) injection of PGRN or intraperitoneal injection of TNFα synthesis blocker thalidomide (25 mg/kg), prevented the memory impairment and anxiety behaviors induced by S-DEP. PGRN treatment also restored dendritic spine density in the hippocampus CA1 region and neurogenesis in hippocampus dentate gyrus (DG). These results indicate that an imbalance between TNFα and PGRN contributes to memory impairment and thigmotaxis/anxiety caused by sleep deprivation. PMID:28300056
Zhang, Kun; Li, Yu-Jiao; Feng, Dan; Zhang, Peng; Wang, Ya-Tao; Li, Xiang; Liu, Shui-Bing; Wu, Yu-Mei; Zhao, Ming-Gao
Sleep disorder is becoming a widespread problem in current society, and is associated with impaired cognition and emotional disorders. Progranulin (PGRN), also known as granulin epithelin precursor, promotes neurite outgrowth and cell survival, and is encoded by the GRN gene. It is a tumor necrosis factor α receptor (TNFR) ligand which is implicated in many central nervous system diseases. However, the role PGRN in sleep disorder remains unclear. In the present study, we found that sleep deprivation (S-DEP) impaired the memory and produced thigmotaxis/anxiety-like behaviors in mice. S-DEP increased the levels of TNFα but decreased PGRN levels in the hippocampus. The intracerebroventricular (ICV) injection of PGRN or intraperitoneal injection of TNFα synthesis blocker thalidomide (25 mg/kg), prevented the memory impairment and anxiety behaviors induced by S-DEP. PGRN treatment also restored dendritic spine density in the hippocampus CA1 region and neurogenesis in hippocampus dentate gyrus (DG). These results indicate that an imbalance between TNFα and PGRN contributes to memory impairment and thigmotaxis/anxiety caused by sleep deprivation.
Wingo, Aliza P.; Gibson, Greg
Prospective epidemiological studies found that generalized anxiety disorder (GAD) can impair immune function and increase risk for cardiovascular disease or events. Mechanisms underlying the physiological reverberations of anxiety, however, are still elusive. Hence, we aimed to investigate molecular processes mediating effects of anxiety on physical health using blood gene expression profiles of 336 community participants (157 anxious and 179 control). We examined genome-wide differential gene expression in anxiety, as well as associations between nine major modules of co-regulated transcripts in blood gene expression and anxiety. No significant differential expression was observed in women, but 631 genes were differentially expressed between anxious and control men at the false discovery rate of 0.1 after controlling for age, body mass index, race, and batch effect. Gene set enrichment analysis (GSEA) revealed that genes with altered expression levels in anxious men were involved in response of various immune cells to vaccination and to acute viral and bacterial infection, and in a metabolic network affecting traits of metabolic syndrome. Further, we found one set of 260 co-regulated genes to be significantly associated with anxiety in men after controlling for the relevant covariates, and demonstrate its equivalence to a component of the stress-related conserved transcriptional response to adversity profile. Taken together, our results suggest potential molecular pathways that can explain negative effects of GAD observed in epidemiological studies. Remarkably, even mild anxiety, which most of our participants had, was associated with observable changes in immune-related gene expression levels. Our findings generate hypotheses and provide incremental insights into molecular mechanisms mediating negative physiological effects of GAD. PMID:25300922
Wingo, Aliza P; Gibson, Greg
Prospective epidemiological studies found that generalized anxiety disorder (GAD) can impair immune function and increase risk for cardiovascular disease or events. Mechanisms underlying the physiological reverberations of anxiety, however, are still elusive. Hence, we aimed to investigate molecular processes mediating effects of anxiety on physical health using blood gene expression profiles of 336 community participants (157 anxious and 179 control). We examined genome-wide differential gene expression in anxiety, as well as associations between nine major modules of co-regulated transcripts in blood gene expression and anxiety. No significant differential expression was observed in women, but 631 genes were differentially expressed between anxious and control men at the false discovery rate of 0.1 after controlling for age, body mass index, race, and batch effect. Gene set enrichment analysis (GSEA) revealed that genes with altered expression levels in anxious men were involved in response of various immune cells to vaccination and to acute viral and bacterial infection, and in a metabolic network affecting traits of metabolic syndrome. Further, we found one set of 260 co-regulated genes to be significantly associated with anxiety in men after controlling for the relevant covariates, and demonstrate its equivalence to a component of the stress-related conserved transcriptional response to adversity profile. Taken together, our results suggest potential molecular pathways that can explain negative effects of GAD observed in epidemiological studies. Remarkably, even mild anxiety, which most of our participants had, was associated with observable changes in immune-related gene expression levels. Our findings generate hypotheses and provide incremental insights into molecular mechanisms mediating negative physiological effects of GAD.
Moseley, Amy E; Williams, Michael T; Schaefer, Tori L; Bohanan, Cynthia S; Neumann, Jon C; Behbehani, Michael M; Vorhees, Charles V; Lingrel, Jerry B
Several disorders have been associated with mutations in Na,K-ATPase alpha isoforms (rapid-onset dystonia parkinsonism, familial hemiplegic migraine type-2), as well as reduction in Na,K-ATPase content (depression and Alzheimer's disease), thereby raising the issue of whether haploinsufficiency or altered enzymatic function contribute to disease etiology. Three isoforms are expressed in the brain: the alpha1 isoform is found in many cell types, the alpha2 isoform is predominantly expressed in astrocytes, and the alpha3 isoform is exclusively expressed in neurons. Here we show that mice heterozygous for the alpha2 isoform display increased anxiety-related behavior, reduced locomotor activity, and impaired spatial learning in the Morris water maze. Mice heterozygous for the alpha3 isoform displayed spatial learning and memory deficits unrelated to differences in cued learning in the Morris maze, increased locomotor activity, an increased locomotor response to methamphetamine, and a 40% reduction in hippocampal NMDA receptor expression. In contrast, heterozygous alpha1 isoform mice showed increased locomotor response to methamphetamine and increased basal and stimulated corticosterone in plasma. The learning and memory deficits observed in the alpha2 and alpha3 heterozygous mice reveal the Na,K-ATPase to be an important factor in the functioning of pathways associated with spatial learning. The neurobehavioral changes seen in heterozygous mice suggest that these mouse models may be useful in future investigations of the associated human CNS disorders.
Patro, Ganesh; Kumar Bhattamisra, Subrat; Kumar Mohanty, Bijay
Objective: The present study was carried out to investigate the neuropharmacological activities of ethyl acetate extract of Mimosa pudica (EAMP) leaves on anxiety, depression and memory in a mouse model. Materials and Methods: Anti-anxiety potential of EAMP was evaluated by elevated plus maze (EPM), light-dark box (LDB) and social interaction (SI) tests in mice.Anti-depressant potential of EAMP was evaluated by forced swimming (FST), tail suspension (TST), and open field tests (OFT). The behavioral findings were further corroborated with estimation of neurotransmitters and their metabolites from mouse brain homogenate. Effect on learning and memory was evaluated by EPM, passive avoidance (PA) tests. Further, it was confirmed with assessment of acetylcholinesterase and caspase-3 activity in brain homogenate. Results: EAMP showed significant anti-anxiety activity by increasing the time spent in open arm of EPM, light box of LDB. Social interaction time was increased significantly (p<0.01) as compared to vehicle control. There was also significant reduction of immobility time in both FST and TST without any changes in locomotor activity in the OFT. Monoamine neurotransmitters (dopamine and norepinephrine) concentrations were increased significantly (p<0.01) after 4 weeks of treatment as compared to stress control and substantiated the anti-depressant activity. Step down latency was increased (p<0.01) in PA test and transfer latency was decreased (p<0.01) in EPM test of EAMP-treated mice. Acetylcholinesterase and caspase-3 activity was significantly (p<0.05) changed in mice treated with EAMP (200 and 400 mg/kg). Conclusion: The results revealed that EAMP has anti-anxiety, anti-depressant and memory enhancing activities that are mediated through multiple mechanisms. PMID:28078250
Pietrzak, Robert H; Scott, J Cobb; Neumeister, Alexander; Lim, Yen Ying; Ames, David; Ellis, Kathryn A; Harrington, Karra; Lautenschlager, Nicola T; Szoeke, Cassandra; Martins, Ralph N; Masters, Colin L; Villemagne, Victor L; Rowe, Christopher C; Maruff, Paul
Although beta-amyloid, anxiety and depression have linked cross-sectionally to reduced memory function in healthy older adults without dementia, prospective data evaluating these associations are lacking. Using data an observational cohort study of 178 healthy older adults without dementia followed for 3 years, we found that anxiety symptoms significantly moderated the relationship between beta-amyloid level and decline in verbal (Cohen's d = 0.65) and episodic (Cohen's d = 0.38) memory. Anxiety symptoms were additionally linked to greater decline in executive function, irrespective of beta-amyloid and other risk factors. These findings suggest that interventions to mitigate anxiety symptoms may help delay memory decline in otherwise healthy older adults with elevated beta-amyloid.
Desai, N; Taylor-Davies, A; Barnett, D B
1 The effect of oral doses of diazepam (5 mg) and oxprenolol (80 mg) on short term memory of normal individuals stratified for 'state' anxiety levels has been investigated. 2 Normal student volunteers were stratified into high and low anxiety groups on the basis of responses to the Spielberger 'A-state' scale. Subjects were then randomly administered active drug or placebo and given a form of running memory test performed under a variety of conditions in which variable rate of item presentation and articulatory suppression were used. 3 Diazepam significantly reduced the errors of recall in the running memory test in the high anxiety group and produced a distinct separation of response from the low anxiety group under the test conditions of slow item presentation with articulatory suppression. Oxprenolol had no effect on the short term memory test in either high or low anxiety groups in any experimental test situation. 4 These results are compared to previous work in which generally a deleterious effect of diazepam on short term memory in normal volunteers has been reported. The implications of these findings are further discussed in relationship to possible models of memory function. PMID:6849754
Lachman, Margie E.; Agrigoroaei, Stefan
Low perceived control is considered a risk factor for poor cognitive functioning, but the mechanisms are unclear. The goal of this study was to analyze anxiety and task interference as sequential mediators of the association between control beliefs and episodic memory. Cognitive-specific control beliefs were assessed prior to the lab session. State anxiety was assessed in the lab followed by a word list recall task. The frequency of intrusive thoughts during the memory task was reported by the participants as a measure of task interference after the completion of the cognitive testing. The results for 152 participants aged 22 to 84 years supported the predicted three-path mediation model. Lower levels of control beliefs were associated with higher state anxiety, which in turn affected episodic memory performance by increasing the likelihood of task interference, with age, sex, and verbal abilities as covariates. The implications of the results for developing interventions to improve memory performance are considered. PMID:21918911
Nelson, Jason M; Lindstrom, Will; Foels, Patricia A
Test anxiety and its correlates were examined with college students with and without specific reading disability (RD; n = 50 in each group). Results indicated that college students with RD reported higher test anxiety than did those without RD, and the magnitude of these differences was in the medium range on two test anxiety scales. Relative to college students without RD, up to 5 times as many college students with RD reported clinically significant test anxiety. College students with RD reported significantly higher cognitively based test anxiety than physically based test anxiety. Reading skills, verbal ability, and processing speed were not correlated with test anxiety. General intelligence, nonverbal ability, and working memory were negatively correlated with test anxiety, and the magnitude of these correlations was medium to large. When these three cognitive constructs were considered together in multiple regression analyses, only working memory and nonverbal ability emerged as significant predictors and varied based on the test anxiety measure. Implications for assessment and intervention are discussed.
Ramirez, Gerardo; Gunderson, Elizabeth A; Levine, Susan C; Beilock, Sian L
Spatial ability is a strong predictor of students' pursuit of higher education in science and mathematics. However, very little is known about the affective factors that influence individual differences in spatial ability, particularly at a young age. We examine the role of spatial anxiety in young children's performance on a mental rotation task. We show that even at a young age, children report experiencing feelings of nervousness at the prospect of engaging in spatial activities. Moreover, we show that these feelings are associated with reduced mental rotation ability among students with high but not low working memory (WM). Interestingly, this WM × spatial anxiety interaction was only found among girls. We discuss these patterns of results in terms of the problem-solving strategies that boys versus girls use in solving mental rotation problems.
Sampedro-Piquero, P; Zancada-Menendez, C; Begega, A; Rubio, S; Arias, J L
We have studied the effect of an environmental enrichment (EE) protocol in adult Wistar rats on the activity in the elevated zero-maze (EZM), performance in the radial-arm water maze (RAWM) and we have also examined the changes in the neuronal metabolic activity of several brain regions related to anxiety response and spatial memory through cytochrome c oxidase histochemistry (COx). Our EE protocol had anxiolytic effect in the EZM; the animals spent more time and made more entries into the open quadrants, they had lower latency to enter into the open quadrant and lower levels of defecation. Also, the EE group showed fewer working memory and reference memory errors, as well as lesser distance travelled in the first day of the spatial training. In relation to the neuronal metabolic activity, EE reduced the COx activity in brain regions related to anxiety response, such as the infralimbic cortex, the paraventricular thalamic and hypothalamic nucleus, the basolateral amygdala, and the ventral hippocampus. Interestingly, there were no significant differences between groups in the dorsal hippocampus, more related to spatial cognition. These results suggest a beneficial effect of EE on spatial memory as a result of reducing anxiety levels and the COx activity in brain regions involved in anxiety response. We also found a differential pattern of activation inside the hippocampus, suggesting that the dorsal hippocampus has a preferential involvement in spatial learning and memory, whereas the ventral hippocampus has a role in anxiety response.
It is argued that a Jean Piaget anecdote about an alleged memory implanted in a young child leading to both a visual and semantic memory that persists despite disconfirming evidence is entirely different than the recovered memory debate, which is about the alleged introduction of memories to grown adults. (CR)
Andreotti, Charissa; Thigpen, Jennifer E; Dunn, Madeleine J; Watson, Kelly; Potts, Jennifer; Reising, Michelle M; Robinson, Kristen E; Rodriguez, Erin M; Roubinov, Danielle; Luecken, Linda; Compas, Bruce E
The current study examined the relations of measures of cognitive reappraisal and secondary control coping with working memory abilities, positive and negative affect, and symptoms of anxiety and depression in young adults (N=124). Results indicate significant relations between working memory abilities and reports of secondary control coping and between reports of secondary control coping and cognitive reappraisal. Associations were also found between measures of secondary control coping and cognitive reappraisal and positive and negative affect and symptoms of depression and anxiety. Further, the findings suggest that reports of cognitive reappraisal may be more strongly predictive of positive affect whereas secondary control coping may be more strongly predictive of negative affect and symptoms of depression and anxiety. Overall, the results suggest that current measures of secondary control coping and cognitive reappraisal capture related but distinct constructs and suggest that the assessment of working memory may be more strongly related to secondary control coping in predicting individual differences in distress.
Patki, Gaurav; Solanki, Naimesh; Atrooz, Fatin; Allam, Farida; Salim, Samina
In the present study, we have examined the behavioral and biochemical effect of induction of psychological stress using a modified version of the resident-intruder model for social stress (social defeat). At the end of the social defeat protocol, body weights, food and water intake were recorded, depression and anxiety-like behaviors as well as memory function was examined. Biochemical analysis including oxidative stress measurement, inflammatory markers and other molecular parameters, critical to behavioral effects were examined. We observed a significant decrease in the body weight in the socially defeated rats as compared to the controls. Furthermore, social defeat increased anxiety-like behavior and caused memory impairment in rats (P<0.05). Socially defeated rats made significantly more errors in long term memory tests (P<0.05) as compared to control rats. Furthermore, brain extracellular signal-regulated kinase-1/2 (ERK1/2), and an inflammatory marker, interleukin (IL)-6 were activated (P<0.05), while the protein levels of glyoxalase (GLO)-1, glutathione reductase (GSR)-1, calcium/calmodulin-dependent protein kinase type (CAMK)-IV, cAMP-response-element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were significantly less (P<0.05) in the hippocampus, but not in the prefrontal cortex and amygdala of socially defeated rats, when compared to control rats. We suggest that social defeat stress alters ERK1/2, IL-6, GLO1, GSR1, CAMKIV, CREB, and BDNF levels in specific brain areas, leading to oxidative stress-induced anxiety-depression-like behaviors and as well as memory impairment in rats.
Muse, Kate; McManus, Freda; Hackmann, Ann; Williams, Matthew; Williams, Mark
Increased understanding of the nature and role of intrusive imagery has contributed to the development of effective treatment protocols for some anxiety disorders. However, intrusive imagery in severe health anxiety (hypochondriasis) has been comparatively neglected. Hence, the current study investigates the prevalence, nature and content of intrusive imagery in 55 patients who met DSM-IV-TR (APA, 2000) criteria for the diagnosis of hypochondriasis. A semi-structured interview was used to assess the prevalence, nature and possible role of intrusive imagery in this disorder. Over 78% of participants reported experiencing recurrent, distressing intrusive images, the majority (72%) of which either were a memory of an earlier event or were strongly associated with a memory. The images tended to be future orientated, and were reliably categorised into four themes: i) being told 'the bad news' that you have a serious/life threatening-illness (6.9%), ii) suffering from a serious or life-threatening illness (34.5%), iii) death and dying due to illness (22.4%) and iv) impact of own death or serious illness on loved ones (36.2%). Participants reported responding to experiencing intrusive images by engaging in avoidance, checking, reassurance seeking, distraction and rumination. Potential treatment implications and links to maintenance cycles are considered.
Silva, Anatildes Feitosa; Sousa, Diego Silveira; Medeiros, André Macêdo; Macêdo, Priscila Tavares; Leão, Anderson Henrique; Ribeiro, Alessandra Mussi; Izídio, Geison Souza; Silva, Regina Helena
Studies with rodents and humans show the relationship between female sex hormones and cognitive/emotional tasks. However, despite the greater incidence of anxiety disorders in women, the data are still inconclusive regarding the mechanisms related to this phenomenon. We evaluated the effects of a classical anxiolytic/amnestic drug (diazepam; DZP) on female (at different estrous cycle phases) and male rats tested in the plus-maze discriminative avoidance task (PMDAT), that allows the concomitant evaluation of memory and anxiety-like behavior. Further, in order to investigate the role of progesterone and its metabolites in the effects of DZP in the PMDAT, female rats were pre-treated with the progesterone receptor antagonist mifepristone or the 5-alpha-reductase inhibitor finasteride. The main findings were: (1) DZP caused memory impairment and anxiolysis in both sexes, but only the highest dose induced the anxiolytic effect in females; (2) females in proestrus did not present the amnestic and anxiolytic effects of DZP (at 2.0 and 4.0mg/kg, respectively) and (3) the co-administration of mifepristone reestablished both amnestic and anxiolytic effects of DZP, while finasteride reinstated the amnestic effect in proestrus female rats. These results suggest that changes in the endogenous levels of progesterone and its metabolites are important in the modulation of emotional/cognitive behavior in female rats. Based on the influence on different aspects of DZP action, the mechanisms related to this modulation are probably linked to GABAergic transmission, but this point remains to be investigated. Further, the variation in therapeutic and adverse effects of DZP depending on sex and hormonal state is of great relevance considering the higher prevalence of anxiety disorders in women.
Dias, Gisele Pereira; Bevilaqua, Mário Cesar do Nascimento; da Luz, Anna Claudia Domingos Silveira; Fleming, Renata Lopes; de Carvalho, Lítia Alves; Cocks, Graham; Beckman, Danielle; Hosken, Lucas Costa; de Sant'Anna Machado, William; Corrêa-e-Castro, Ana Carolina; Mousovich-Neto, Felippe; de Castro Gomes, Vítor; Bastos, Gilmara de Nazareth Tavares; Kubrusly, Regina Célia Cussa; da Costa, Vânia Maria Corrêa; Srivastava, Deepak; Landeira-Fernandez, Jesus; Nardi, Antonio Egidio; Thuret, Sandrine; Gardino, Patricia Franca
Generalized anxiety disorder (GAD) is highly prevalent and incapacitating. Here we used the Carioca High-Conditioned Freezing (CHF) rats, a previously validated animal model for GAD, to identify biomarkers and structural changes in the hippocampus that could be part of the underlying mechanisms of their high-anxiety profile. Spatial and fear memory was assessed in the Morris water maze and passive avoidance test. Serum corticosterone levels, immunofluorescence for glucocorticoid receptors (GR) in the dentate gyrus (DG), and western blotting for hippocampal brain derived neurotrophic factor (BDNF) were performed. Immunohistochemistry for markers of cell proliferation (bromodeoxiuridine/Ki-67), neuroblasts (doublecortin), and cell survival were undertaken in the DG, along with spine staining (Golgi) and dendritic arborization tracing. Hippocampal GABA release was assessed by neurochemical assay. Fear memory was higher among CHF rats whilst spatial learning was preserved. Serum corticosterone levels were increased, with decreased GR expression. No differences were observed in hippocampal cell proliferation/survival, but the number of newborn neurons was decreased, along with their number and length of tertiary dendrites. Increased expression of proBDNF and dendritic spines was observed; lower ratio of GABA release in the hippocampus was also verified. These findings suggest that generalized anxiety/fear could be associated with different hippocampal biomarkers, such as increased spine density, possibly as a compensatory mechanism for the decreased hippocampal number of neuroblasts and dendritic arborization triggered by high corticosterone. Disruption of GABAergic signaling and BDNF impairment are also proposed as part of the hippocampal mechanisms possibly underlying the anxious phenotype of this model.
Klann, Eric; Sweatt, J. David
Summary There is ongoing debate concerning whether new protein synthesis is necessary for, or even contributes to, memory formation and storage. This review summarizes a contemporary model proposing a role for altered protein synthesis in memory formation and its subsequent stabilization. One defining aspect of the model is that altered protein synthesis serves as a trigger for memory consolidation. Thus, we propose that specific alterations in the pattern of neuronal protein translation serve as an initial event in long-term memory formation. These specific alterations in protein read-out result in the formation of a protein complex that then serves as a nidus for subsequent perpetuating reinforcement by a positive feedback mechanism. The model proposes this scenario as a minimal but requisite component for long-term memory formation. Our description specifies three aspects of prevailing scenarios for the role of altered protein synthesis in memory that we feel will help clarify what, precisely, is typically proposed as the role for protein translation in memory formation. First, that a relatively short initial time window exists wherein specific alterations in the pattern of proteins translated (not overall protein synthesis) is involved in initializing the engram. Second, that a self-perpetuating positive feedback mechanism maintains the altered pattern of protein expression (synthesis or recruitment) locally. Third, that other than the formation and subsequent perpetuation of the unique initializing proteins, ongoing constitutive protein synthesis is all that is minimally necessary for formation and maintenance of the engram. We feel that a clear delineation of these three principles will assist in interpreting the available experimental data, and propose that the available data are consistent with a role for protein synthesis in memory. PMID:17919940
Smelser, Lisa K; Walker, Callum; Burns, Erin M; Curry, Michael; Black, Nathanael; Metzler, Jennifer A; McDowell, Susan A; Bruns, Heather A
Statins are potent modulators of immune responses, resulting in their ability to enhance host survival from primary bacterial infections. Alterations in primary immune responses that may be beneficial for survival following infection may also result in alterations in the generation of the immunologic memory response and subsequently affect immune responses mounted during secondary bacterial infection. In this study, we report that levels of total serum IgG2c, following primary infection, were decreased in simvastatin pretreated mice, and investigate the effect of simvastatin treatment, prior to primary infection, on immune responses activated during secondary S. aureus infection. A secondary infection model was implemented whereby simvastatin pretreated and control mice were reinfected with S. aureus 14 days after primary infection, with no additional simvastatin treatment, and assessed for survival and alterations in immune function. While survivability to secondary S. aureus infection was not different between simvastatin pretreated and control mice, memory B and T lymphocyte functions were altered. Memory B cells, isolated 14 days after secondary infection, from simvastatin pretreated mice and stimulated ex vivo produced increased levels of IgG1 compared to memory B cells isolated from control mice, while levels of IgM and IgG2c remained similar. Furthermore, memory B and T lymphocytes from simvastatin pretreated mice exhibited a decreased proliferative response when stimulated ex vivo compared to memory cells isolated from control mice. These findings demonstrate the ability of a short term, low dose simvastatin treatment to modulate memory immune function.
Nielsen, Shawn E; Segal, Sabrina K; Worden, Ian V; Yim, Ilona S; Cahill, Larry
Emotionally arousing material is typically better remembered than neutral material. Since norepinephrine and cortisol interact to modulate emotional memory, sex-related influences on stress responses may be related to sex differences in emotional memory. Two groups of healthy women - one naturally cycling (NC women, n=42) and one using hormonal contraceptives (HC women, n=36) - viewed emotionally arousing and neutral images. Immediately after, they were assigned to Cold Pressor Stress (CPS) or a control procedure. One week later, participants received a surprise free recall test. Saliva samples were collected and later assayed for salivary alpha-amylase (biomarker for norepinephrine) and cortisol. Compared to NC women, HC women exhibited significantly blunted stress hormone responses to the images and CPS. Recall of emotional images differed between HC and NC women depending on noradrenergic and cortisol responses. These findings may have important implications for understanding the neurobiology of emotional memory disorders, especially those that disproportionately affect women.
... include Panic disorder Obsessive-compulsive disorder Post-traumatic stress disorder Phobias Generalized anxiety disorder Treatment can involve medicines, therapy or both. NIH: National Institute of Mental Health
Boutwell, Richard C.
The intent of this study was to determine the relationship of the independent variables of task difficulty and memory support for high and low anxious subjects on certain dependent variables: correct task performances, measured anxiety level, and self-estimated competency rating. A further purpose was to investigate the relationship of obtained…
Cheie, Lavinia; Miclea, Mircea; Visu-Petra, Laura
Prospective memory (PM) refers to remembering to perform a previously planned action at the appropriate time or in the appropriate context. The present study investigated the effects of individual differences in age and trait anxiety on PM performance in 3-5- and 5-7-year-olds. Two types of PM measures were used: an event-based task, requiring…
Electroencephalographic ( EEG ) measures demonstrate that a mere 90 seconds of left hand clenching increases right hemisphere activity, and similar right...However, to our knowledge no research has examined cognition , and in particular memory processing, as a function of hemispheric activation induced via...contraction of hand muscles. Cortex 30: 247–254. 5. Davidson RJ (2002) Anxiety and affective style : Role of prefrontal cortex and amygdala. Biol Psychiatry
Rostami, Amin; Shahani, Minoo; Zarrindast, Mohammad Reza; Semnanian, Saeed; Rahmati Roudsari, Mohammad; Rezaei Tavirani, Mostafa; Hasanzadeh, Hadi
Introduction: The effects of electromagnetic fields on biological organisms have been a controversial and also interesting debate over the past few decades, despite the wide range of investigations, many aspects of extremely low frequency electromagnetic fields (ELF/EMFs) effects including mechanism of their interaction with live organisms and also their possible biological applications still remain ambiguous. In the present study, we investigated whether the exposures of ELF/EMF with frequencies of 3 Hz and 60 Hz can affect the memory, anxiety like behaviors, electrophysiological properties and brain’s proteome in rats. Methods: Male rats were exposed to 3 Hz and 60 Hz ELF/EMFs in a protocol consisting of 2 cycles of 2 h/day exposure for 4 days separated with a 2-day interval. Short term memory and anxiety like behaviors were assessed immediately, 1 and 2 weeks after the exposures. Effects of short term exposure were also assessed using electrophysiological approach immediately after 2 hours exposure. Results: Behavioral test revealed that immediately after the end of exposures, locomotor activity of both 3 Hz and 60 Hz exposed groups significantly decreased compared to sham group. This exposure protocol had no effect on anxiety like behavior during the 2 weeks after the treatment and also on short term memory. A significant reduction in firing rate of locus coeruleus (LC) was found after 2 hours of both 3 Hz and 60 Hz exposures. Proteome analysis also revealed global changes in whole brain proteome after treatment. Conclusion: Here, some evidence regarding the fact that such exposures can alter locomotor activity and neurons firing rate in male rats were presented. PMID:27330708
Moon, Chung-Man; Sundaram, Thirunavukkarasu; Choi, Nam-Gil; Jeong, Gwang-Woo
Generalized anxiety disorder (GAD) is associated with brain functional and morphological changes in connected with emotional dysregulation and cognitive deficit. This study dealt with the neural functional deficits and metabolic abnormalities in working memory (WM) task with emotion-inducing distractors in patients with GAD. Fourteen patients with GAD and 14 healthy controls underwent functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy ((1)H-MRS) at 3T. In response to the emotional distractors in WM tasks, the patients concurrently showed higher activity in the hippocampus and lower activities in the superior occipital gyrus, superior parietal gyrus, dorsolateral prefrontal cortex (DLPFC) and precentral gyrus compared to the controls. MRS revealed significantly lower choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) ratios in the DLPFC. In particular, the Cho ratios were positively correlated with the brain activities based on blood oxygenation level-dependent signal change in the DLPFC. This study provides the first evidence for the association between the metabolic alterations and functional deficit in WM processing with emotion-inducing distractors in GAD. These findings will be helpful to understand the neural dysfunction in connection with WM impairment in GAD.
Huang, Max P; Radadia, Kushan; Macone, Brian W; Auerbach, Sanford H; Datta, Subimal
At present, eszopiclone and zolpidem are the most commonly prescribed drugs for treating insomnia. Despite the established relationship between sleep disturbance and anxiety, it remains unknown whether targeted treatment for insomnia may affect acute anxiety. Therefore, the objective of this study was to examine the effects of three different doses (1, 3, and 10mg/kg) of eszopiclone and zolpidem on the states of sleep and wakefulness, levels of anxiety-like behavior, and long-term contextual memory in footshock-induced anxious rats. The results of this study demonstrated that the administration of eszopiclone and zolpidem both were equally effective in attenuating footshock stressor-induced suppression of slow-wave sleep (SWS). The administration of eszopiclone at 1mg/kg or zolpidem at 1 and 3mg/kg doses showed a tendency for attenuating stressor-induced suppression of REM sleep. However, the REM sleep attenuating effects of these drugs disappeared when they were administered at higher doses. The administration of eszopiclone at 3 and 10mg/kg doses and zolpidem at all three doses reduced the power of electroencephalographic theta band frequencies during wakefulness. In addition, the administration of eszopiclone at 1 and 3mg/kg doses suppressed stressor-induced anxiety-like behavior. The administration of zolpidem at 1, 3, or 10mg/kg doses was not effective in attenuating stressor-induced anxiety-like behavior. Contextual memory after administration of eszopiclone at 1mg/kg dose had no effects, but was reduced significantly with increased dosage. Contextual memory after administration of zolpidem, at all three doses, was severely disrupted. The results of this study suggest that eszopiclone at a low dose could be used effectively to control anxiety and anxiety-induced insomnia.
Huang, Max P.; Radadia, Kushan; Macone, Brian W.; Auerbach, Sanford H.; Datta, Subimal
At present, eszopiclone and zolpidem are the most commonly prescribed drugs for treating insomnia. Despite the established relationship between sleep disturbance and anxiety, it remains unknown whether targeted treatment for insomnia may affect acute anxiety. Therefore, the objective of this study was to examine the effects of three different doses (1, 3, and 10 mg/kg) of eszopiclone and zolpidem on the states of sleep and wakefulness, levels of anxiety-like behavior, and long-term contextual memory in footshock-induced anxious rats. The results of this study demonstrated that the administration of eszopiclone and zolpidem both were equally effective in attenuating footshock stressor-induced suppression of slow-wave sleep (SWS). The administration of eszopiclone at 1 mg/kg or zolpidem at 1 and 3 mg/kg doses showed a tendency for attenuating stressor-induced suppression of REM sleep. However, the REM sleep attenuating effects of these drugs disappeared when they were administered at higher doses. The administration of eszopiclone at 3 and 10 mg/kg doses and zolpidem at all three doses reduced the power of electroencephalographic theta band frequencies during wakefulness. In addition, the administration of eszopiclone at 1 and 3 mg/kg doses suppressed stressor-induced anxiety-like behavior. The administration of zolpidem at 1, 3, or 10 mg/kg doses was not effective in attenuating stressor-induced anxiety-like behavior. Contextual memory after administration of eszopiclone at 1 mg/kg dose had no effects, but was reduced significantly with increased dosage. Contextual memory after administration of zolpidem, at all three doses, was severely disrupted. The results of this study suggest that eszopiclone at a low dose could be used effectively to control anxiety and anxiety-induced insomnia. PMID:20153782
Aydin, Emel; Hritcu, Lucian; Dogan, Gulden; Hayta, Sukru; Bagci, Eyup
In the present study, we identified the effects of inhaled Pimpinella peregrina essential oil (1 and 3 %, for 21 continuous days) on scopolamine-induced memory impairment, anxiety, and depression in laboratory rats. Y-maze and radial arm-maze tests were used for assessing memory processes. Also, the anxiety and depressive responses were studied by means of the elevated plus-maze and forced swimming tests. The scopolamine alone-treated rats exhibited the following: decrease of the spontaneous alternation percentage in Y-maze test, increase of the number of working and reference memory errors in radial arm-maze test, along with decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. Inhalation of the P. peregrina essential oil significantly improved memory formation and exhibited anxiolytic- and antidepressant-like effects in scopolamine-treated rats. Our results suggest that the P. peregrina essential oil inhalation ameliorates scopolamine-induced memory impairment, anxiety, and depression. Moreover, studies on the P. peregrina essential oil may open a new therapeutic window for the prevention of neurological abnormalities closely related to Alzheimer's disease.
Luine, Victoria N.; Frankfurt, Maya
Estrogens exert sustained, genomically mediated effects on memory throughout the female life cycle, but here we review new studies documenting rapid effects of estradiol on memory, which are exerted through membrane-mediated mechanisms. Use of recognition memory tasks in rats, shows that estrogens enhance memory consolidation within one hour. 17α-estradiol is more potent than 17β-estradiol, and the dose response relationship between estrogens and memory is an inverted U shape. Use of specific estrogen receptor (ER) agonists suggests mediation by an ERβ-like membrane receptor. Enhanced memory is associated with increased spine density and altered noradrenergic activity in the medial prefrontal cortex and hippocampus within 30 min. of administration. The environmental chemical, bisphenol-A, rapidly antagonizes enhancements in memory in both sexes possibly through actions on spines. Thus, estradiol and related compounds exert rapid alterations in cognition through non-genomic mechanisms, a finding which may provide a basis for better understanding and treating memory impairments. PMID:22981654
Greenstein, Michael; Franklin, Nancy; Martins, Mariana; Sewack, Christine; Meier, Markus A
Threat frequently leads to the prioritization of survival-relevant processes. Much of the work examining threat-related processing advantages has focused on the detection of static threats or long-term memory for details. In the present study, we examined immediate memory for dynamic threatening situations. We presented participants with visually neutral, dynamic stimuli using a representational momentum (RM) paradigm, and manipulated threat conceptually. Although the participants in both the threatening and nonthreatening conditions produced classic RM effects, RM was stronger for scenarios involving threat (Exps. 1 and 2). Experiments 2 and 3 showed that this effect does not generalize to the nonthreatening objects within a threatening scene, and that it does not extend to arousing happy situations. Although the increased RM effect for threatening objects by definition reflects reduced accuracy, we argue that this reduced accuracy may be offset by a superior ability to predict, and thereby evade, a moving threat.
Agonists and antagonists of the 5-hydroxytryptamine (serotonin) receptor6 (5-HT6) or receptor7 (5-HT7) might improve memory and/or reverse amnesia, although the mechanisms involved are poorly understood. Hence, the current work summarizes recent reviews and findings involving these receptors. Evidence indicates that diverse 5-HT6 receptor antagonists produce promnesic and/or antiamnesic effect in conditions, such as memory formation, age-related cognitive impairments and memory deficit in preclinical studies, as well as in diseases such as schizophrenia, Parkinson's, and Alzheimer's disease (AD). Memory, aging, and AD modify 5-HT6 receptors and signaling cascades; likewise, the modulation of 5-HT6 drugs on memory seems to be accompanied with neural changes. Moreover, 5-HT7 receptors are localized in brain areas mediating memory, including the cortex, hippocampus (e.g., Zola-Morgan and Squire, 1993) and raphe nuclei; however, the role of these receptors on memory has yet to be fully explored. Hence, findings and reviews are summarized in this work. Evidence suggests that both 5-HT7 receptor agonists and antagonists might have promnesic and anti-amnesic effects. These effects seem to be dependent on the basal level of performance, i.e., normal or impaired. Available evidence suggests that a potential utility of 5-HT6 and 5-HT7 receptor in mild-to-moderate AD patients and other memory dysfunctions as therapeutic targets.
Sweeney, Fabian F; O'Leary, Olivia F; Cryan, John F
Although the underlying pathophysiology of anxiety disorders is unknown it is clear that a combination of genetic and environmental factors in early life predispose to disease risk. Preclinical research increasingly suggests an important role for the GABAB receptor in modulating anxiety behaviour, with GABAB receptor deficient mice having increased anxiety behaviour. Previous studies have highlighted critical windows during development where adult anxiety behaviour is primed. However, little is known regarding the role played by the GABAB receptors in the developmental processes that underlie adult anxiety behaviour. To this end, we treated male BALB/c mouse pups with the either the selective GABAB receptor agonist, R-baclofen (2 mg/kg, s.c), the GABAB receptor antagonist CGP 52432 (10 mg/kg and 30 mg/kg) or vehicle from postnatal days (P) 14-28. The anxiety behaviour of these mice was then assessed in adulthood (P62 onwards) in a battery of behavioural tests comprising; the stress induced hyperthermia (SIH) test, defensive marble burying (DMB), elevated-plus maze (EPM) and the forced swim test (FST). Postnatal R-baclofen treatment resulted in increased anxiety-like behaviour in the EPM as shown by approach-avoidance and ethological measures. Other behavioural measures were not significantly altered. Interestingly, blockade of GABAB receptors with CGP52432 in early life caused no alterations in emotional behaviour. These data suggest that during early life GABAB receptor signalling can play a functional role in programing anxiety behaviour in adulthood. The underlying neurodevelopmental processes underlying these effects remain to be discovered.
Gao, Chuanji; Hermiller, Molly S.; Voss, Joel L.; Guo, Chunyan
It is difficult to pinpoint the border between perceptual and conceptual processing, despite their treatment as distinct entities in many studies of recognition memory. For instance, alteration of simple perceptual characteristics of a stimulus can radically change meaning, such as the color of bread changing from white to green. We sought to better understand the role of perceptual and conceptual processing in memory by identifying the effects of changing a basic perceptual feature (color) on behavioral and neural correlates of memory in circumstances when this change would be expected to either change the meaning of a stimulus or to have no effect on meaning (i.e., to influence conceptual processing or not). Abstract visual shapes (“squiggles”) were colorized during study and presented during test in either the same color or a different color. Those squiggles that subjects found to resemble meaningful objects supported behavioral measures of conceptual priming, whereas meaningless squiggles did not. Further, changing color from study to test had a selective effect on behavioral correlates of priming for meaningful squiggles, indicating that color change altered conceptual processing. During a recognition memory test, color change altered event-related brain potential (ERP) correlates of memory for meaningful squiggles but not for meaningless squiggles. Specifically, color change reduced the amplitude of frontally distributed N400 potentials (FN400), implying that these potentials indicated conceptual processing during recognition memory that was sensitive to color change. In contrast, color change had no effect on FN400 correlates of recognition for meaningless squiggles, which were overall smaller in amplitude than for meaningful squiggles (further indicating that these potentials signal conceptual processing during recognition). Thus, merely changing the color of abstract visual shapes can alter their meaning, changing behavioral and neural correlates of
Carlini, V P; Ghersi, M; Gabach, L; Schiöth, H B; Pérez, M F; Ramirez, O A; Fiol de Cuneo, M; de Barioglio, S R
A 13-amino acid peptide named neuronostatin (NST) encoded in the somatostatin pro-hormone has been recently reported. It is produced throughout the body, particularly in brain areas that have significant actions over the metabolic and autonomic regulation. The present study was performed in order to elucidate the functional role of NST on memory, anxiety-like behavior and food intake and the hippocampal participation in these effects. When the peptide was intra-hippocampally administered at 3.0 nmol/μl, it impaired memory retention in both, object recognition and step-down test. Also, this dose blocked the hippocampal long-term potentiation (LTP) generation. When NST was intra-hippocampally administered at 0.3 nmol/μl and 3.0 nmol/μl, anxiolytic effects were observed. Also, the administration in the third ventricle at the higher dose (3.0 nmol/μl) induced similar effects, and both doses reduced food intake. The main result of the present study is the relevance of the hippocampal formation in the behavioral effects induced by NST, and these effects could be associated to a reduced hippocampal synaptic plasticity.
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The reported experiment investigated memory of unfamiliar faces and how it is influenced by race, facial expression, direction of gaze, and observers' level of social anxiety. Eighty- seven Japanese participants initially memorized images of Oriental and Caucasian faces displaying either happy or angry expressions with direct or averted gaze. They then saw the previously seen faces and additional distractor faces displaying neutral expressions, and judged if they had seen them before. Their level of social anxiety was measured with a questionnaire. Regardless of gaze or race of the faces, recognition for faces studied with happy expressions was more accurate than for those studied with angry expressions (happiness advantage), but this tendency weakened for people with higher levels of social anxiety, possibly due to their increased anxiety for positive feedback regarding social interactions. Interestingly, the reduction of the happiness advantage observed for the highly anxious participants was more prominent for the own-race faces than for the other-race faces. The results suggest that angry expression disrupts processing of identity-relevant features of the faces, but the memory for happy faces is affected by the social anxiety traits, and the magnitude of the impact may depend on the importance of the face.
Gatica, Rafael Ignacio; Pérez-Valenzuela, Enzo; Sierra-Mercado, Demetrio; Fuentealba, José Antonio
The repeated administration of amphetamine can lead to locomotor sensitization. Although the repeated administration of amphetamine has been associated with anxiety and impaired working memory, it is uncertain if expression of amphetamine sensitization is associated with modifications of emotional memories. To address this issue, rats were injected once daily with amphetamine for five consecutive days (1.5mg/kg). After four days of withdrawal, rats were delivered an acute amphetamine injection to assess the expression of sensitization. A single exposure to an elevated plus maze (EPM), 24h after the last injection of amphetamine, showed that amphetamine sensitization is not accompanied by anxiety. Next, aversive memory was assessed using an 11day inter-trial interval between the EPM Trial 1 and EPM Trial 2. Rats administered with saline showed a percentage of open arms time (% OAT) in Trial 2 that was comparable to Trial 1, demonstrating a reduction in the retrieval of aversive memory. However, rats sensitized after the EPM Trial 1 showed a significant decrease in the % OAT in Trial 2. Importantly, a decrease in the % OAT in Trial 2 compared to Trial 1 was also observed after a single injection of amphetamine 24h before Trial 2. These results show a facilitation in the retrieval of aversive memory, and suggest that a previous amphetamine injection is enough to produce a protracted activation of neural circuits necessary for the retrieval of aversive memory.
Zou, D; Chen, L; Deng, D; Jiang, D; Dong, F; McSweeney, C; Zhou, Y; Liu, L; Chen, G; Wu, Y; Mao, Y
Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PVpositive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3DGq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.
Zou, D.; Chen, L.; Deng, D.; Jiang, D.; Dong, F.; McSweeney, C.; Zhou, Y.; Liu, L.; Chen, G.; Wu, Y.; Mao, Y.
Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PV-positive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3D-Gq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus. PMID:26733123
Fernandez, Sebastian P; Muzerelle, Aude; Scotto-Lomassese, Sophie; Barik, Jacques; Gruart, Agnès; Delgado-García, José M; Gaspar, Patricia
Serotonin (5-HT) deficiency occurs in a number of brain disorders that affect cognitive function. However, a direct causal relationship between 5-HT hypo-transmission and memory and underlying mechanisms has not been established. We used mice with a constitutive depletion of 5-HT brain levels (Pet1KO mice) to analyze the contribution of 5-HT to different forms of learning and memory. Pet1KO mice exhibited a striking deficit in novel object recognition memory, a hippocampal-dependent task. No alterations were found in tasks for social recognition, procedural learning, or fear memory. Viral delivery of designer receptors exclusively activated by designer drugs was used to selectively silence the activity of 5-HT neurons in the raphe. Inhibition of 5-HT neurons in the median raphe, but not the dorsal raphe, was sufficient to impair object recognition in adult mice. In vivo electrophysiology in behaving mice showed that long-term potentiation in the hippocampus of 5-HT-deficient mice was altered, and administration of the 5-HT1A agonist 8-OHDPAT rescued the memory deficits. Our data suggest that hyposerotonergia selectively affects declarative hippocampal-dependent memory. Serotonergic projections from the median raphe are necessary to regulate object memory and hippocampal synaptic plasticity processes, through an inhibitory control mediated by 5-HT1A receptors.
Qi, Senqing; Ding, Cody; Li, Hong
Research has indicated that highly trait-anxious (HTA) individuals exhibit a specific deficit in filtering threat-related distractors from visual-spatial working memory (WM). Prior demonstrations of impaired inhibition control in HTA individuals have mainly focused on tasks that required the inhibition of prepotent response tendencies. Studies on the suppression of emotionally neutral distractors from WM in trait anxiety have also been minimal. In this article, we present a study on the manifestation of general inefficient filtering of neutral distractors during visual-spatial WM maintenance stages in HTA individuals. Female participants performed a visual-spatial WM task while event-related potentials were recorded. They were made to remember the orientations of red rectangles within half of the screen and to ignore all salient green rectangles. As predicted, no significant main effect of group and no interaction between group and condition were found in the N2pc component, suggesting that group differences did not manifest in the initial process of object individuation. During the subsequent WM maintenance phase, HTA individuals were highly inefficient at filtering the irrelevant items from WM, as reflected not only by parallel late contralateral delay activity (CDA; 450 to 900 ms) amplitudes for the distractor condition and the four red items, but also by a smaller filtering efficiency score in the HTA group than in the low-trait-anxiety group. Extending previous studies, our findings verify a general filtering impairment in HTA individuals for task-irrelevant salient distractors during a WM maintenance phase.
Bottini, Roberto; Mattioni, Stefania; Collignon, Olivier
Several studies suggest that serial order in working memory (WM) is grounded on space. For a list of ordered items held in WM, items at the beginning of the list are associated with the left side of space and items at the end of the list with the right side. This suggests that maintaining items in verbal WM is performed in strong analogy to writing these items down on a physical whiteboard for later consultation (The Mental Whiteboard Hypothesis). What drives this spatial mapping of ordered series in WM remains poorly understood. In the present study we tested whether visual experience is instrumental in establishing the link between serial order in WM and spatial processing. We tested early blind (EB), late blind (LB) and sighted individuals in an auditory WM task. Replicating previous studies, left-key responses were faster for early items in the list whereas later items facilitated right-key responses in the sighted group. The same effect was observed in LB individuals. In contrast, EB participants did not show any association between space and serial position in WM. These results suggest that early visual experience plays a critical role in linking ordered items in WM and spatial representations. The analogical spatial structure of WM may depend in part on the actual experience of using spatially organized devices (e.g., notes, whiteboards) to offload WM. These practices are largely precluded to EB individuals, who instead rely to mnemonic devices that are less spatially organized (e.g., recordings, vocal notes). The way we habitually organize information in the external world may bias the way we organize information in our WM.
Karl, T; Duffy, L; Scimone, A; Harvey, R P; Schofield, P R
Human genetic studies have shown that neuregulin 1 (NRG1) is a potential susceptibility gene for schizophrenia. Nrg1 influences various neurodevelopmental processes, which are potentially related to schizophrenia. The neurodevelopmental theory of schizophrenia suggests that interactions between genetic and environmental factors are responsible for biochemical alterations leading to schizophrenia. To investigate these interactions and to match experimental design with the pathophysiology of schizophrenia, we applied a comprehensive behavioural phenotyping strategy for motor activity, exploration and anxiety in a heterozygous Nrg1 transmembrane domain mutant mouse model (Nrg1 HET) using different housing conditions and age groups. We observed a locomotion- and exploration-related hyperactive phenotype in Nrg1 HETs. Increased age had a locomotion- and exploration-inhibiting effect, which was significantly attenuated in mutant mice. Environmental enrichment (EE) had a stimulating influence on locomotion and exploration. The impact of EE was more pronounced in Nrg1 hypomorphs. Our study also showed a moderate task-specific anxiolytic-like phenotype for Nrg1 HETs, which was influenced by external factors. The behavioural phenotype detected in heterozygous Nrg1 mutant mice is not specific to schizophrenia per se, but the increased sensitivity of mutant mice to exogenous factors is consistent with the pathophysiology of schizophrenia and the neurodevelopmental theory. Our findings reinforce the importance of carefully controlling experimental designs for external factors and of comprehensive, integrative phenotyping strategies. Thus, Nrg1 HETs may, in combination with other genetic and drug models, help to clarify pathophysiological mechanisms behind schizophrenia.
Santin, L.J.; Bilbao, A.; Pedraza, C.; Matas-Rico, E.; López-Barroso, D.; Castilla-Ortega, E.; Sánchez-López, J.; Riquelme, R.; Varela-Nieto, I.; de la Villa, P.; Suardíaz, M.; Chun, J.; De Fonseca, F. Rodriguez; Estivill-Torrús, G.
Lysophosphatidic acid (LPA) has emerged as a new regulatory molecule in the brain. Recently, some studies have demonstrated a role for this molecule and its LPA1 receptor in the regulation of plasticity and neurogenesis in the adult brain. However, no systematic studies have been conducted to investigate whether the LPA1 receptor is involved in behavior. Here we studied the phenotype of maLPA1–null mice, which bear a targeted deletion at the lpa1 locus, in a battery of tests examining neurologic performance, habituation in exploratory behavior in response to low and mild anxiety environments and spatial memory. MaLPA1-null mutants showed deficits in both olfaction and somesthesis, but not in retinal or auditory functions. Sensorimotor coordination was impaired only in the equilibrium and grasping reflexes. The mice also showed impairments in neuromuscular strength and analgesic response. No additional differences were observed in the rest of the tests used to study sensoriomotor orientation, limb reflexes, and coordinated limb use. At behavioral level, maLPA1-null mice showed an impaired exploration in the open field and increased anxiety-like response when exposed to the elevated plus maze. Furthermore, the mice exhibit impaired spatial memory retention and reduced use of spatial strategies in the Morris water maze. We propose that the LPA1 receptor may play a major role in both spatial memory and response to anxiety-like conditions. PMID:19689455
Dworkin, Sebastian; Auden, Alana; Partridge, Darren D; Daglas, Maria; Medcalf, Robert L; Mantamadiotis, Theo; Georgy, Smitha R; Darido, Charbel; Jane, Stephen M; Ting, Stephen B
The highly conserved Grainyhead-like (Grhl) family of transcription factors, comprising three members in vertebrates (Grhl1-3), play critical regulatory roles during embryonic development, cellular proliferation and apoptosis. Although loss of Grhl function leads to multiple neural abnormalities in numerous animal models, a comprehensive analysis of Grhl expression and function in the mammalian brain has not been reported. Here we show that only Grhl3 expression is detectable in the embryonic mouse brain; particularly within the habenula, an organ known to modulate repressive behaviours. Using both Grhl3-knockout mice (Grhl3(-/-) ), and brain-specific conditional deletion of Grhl3 in adult mice (Nestin-Cre/Grhl3(flox/flox) ), we performed histological expression analyses and behavioural tests to assess long-term effects of Grhl3 loss on motor co-ordination, spatial memory, anxiety and stress. We found that complete deletion of Grhl3 did not lead to noticeable structural or cell-intrinsic defects in the embryonic brain, however aged Grhl3 conditional knockout (cKO) mice showed enlarged lateral ventricles and displayed marked changes in motor function and behaviours suggestive of decreased fear and anxiety. We conclude that loss of Grhl3 in the brain leads to significant alterations in locomotor activity and decreased self-inhibition, and as such, these mice may serve as a novel model of human conditions of impulsive behaviour or hyperactivity. This article is protected by copyright. All rights reserved.
Wall, P M; Messier, C
The present report investigated the contributions of the ventromedial prefrontal cortex to the control of spontaneous alternation/working memory and anxiety-related behaviour. In Experiment 1, we examined the effects of microinjections of the selective kappa(1) receptor agonist, U-69,593, in the infralimbic cortex (IL) of CD-1 mice on several ethologically-derived anxiety indices in the elevated plus-maze (EPM) and defensive/withdrawal (D/W) anxiety in the open field, as well as on memory in the EPM transfer-latency (T-L) test and implicit spontaneous alternation memory (SAP) in the Y-maze. In week 1, pretreatment with one injection of vehicle, 1, 10 or 25 nmol/1.0 microliter U-69,593 in the IL dose-dependently prolonged T-L and produced a dose-dependent anxiolytic behavioural profile in the first EPM trial. Following a 24-h delay, the same mice were given a drug-free second trial in the EPM tests of T-L memory and anxiety. Whereas T-L memory was not disturbed, small but detectable carry-over effects were observed in trial-2 EPM behaviour relative to vehicle-treated animals. In week 2, the same groups of mice were again pretreated with one injection of the same doses of U-69,593 in the IL and given a D/W test in an open field, followed immediately by an 8-min SAP trial in the Y-maze. The smallest U-69,593 dose was anxiolytic in the D/W test, and SAP/working memory was dose-dependently enhanced in the Y-maze. In Experiment 2, we evaluated whether 0.5 microliter volume microinjections would produce comparable behavioural and carry-over effects in the IL of three new groups of CD-1 mice, in the event that the 1.0 microl volume injections used in Experiment 1 diffused beyond the IL and therefore may have confounded some effects. Experiment 2 procedures were carried out in the same manner as in Experiment 1, except the animals were tested in reverse order. Thus in week 1, SAP memory was tested in the Y-maze followed by D/W anxiety in the open field for half of the
Parikh, Ishita; Guo, Janet; Chuang, Kai-Hsiang; Zhong, Yu; Rempe, Ralf G.; Hoffman, Jared D.; Armstrong, Rachel; Bauer, Björn; Hartz, Anika M.S.; Lin, Ai-Ling
Neurovascular integrity plays an important role in protecting cognitive and mental health in aging. Lifestyle interventions that sustain neurovascular integrity may thus be critical on preserving brain functions in aging and reducing the risk for age-related neurodegenerative disorders. Here we show that caloric restriction (CR) had an early effect on neurovascular enhancements, and played a critical role in preserving vascular, cognitive and mental health in aging. In particular, we found that CR significantly enhanced cerebral blood flow (CBF) and blood-brain barrier function in young mice at 5-6 months of age. The neurovascular enhancements were associated with reduced mammalian target of rapamycin expression, elevated endothelial nitric oxide synthase signaling, and increased ketone bodies utilization. With age, CR decelerated the rate of decline in CBF. The preserved CBF in hippocampus and frontal cortex were highly correlated with preserved memory and learning, and reduced anxiety, of the aging mice treated with CR (18-20 months of age). Our results suggest that dietary intervention started in the early stage (e.g., young adults) may benefit cognitive and mental reserve in aging. Understanding nutritional effects on neurovascular functions may have profound implications in human brain aging and age-related neurodegenerative disorders. PMID:27829242
Otto, Michael W; Eastman, Abraham; Lo, Stephen; Hearon, Bridget A; Bickel, Warren K; Zvolensky, Michael; Smits, Jasper A J; Doan, Stacey N
Understanding the nature and influence of specific risk profiles is increasingly important for health behavior promotion. The purpose of this article is to document the value of two factors-anxiety sensitivity (AS) and working memory capacity (WMC)-for enhancing risk for the initiation and/or maintenance of a range of negative health behaviors. AS is a distress-related risk factor that potentiates avoidance/coping motivations for negative health behaviors. Stress provides the conditions for negative somatic and affective states, and AS amplifies the aversiveness of these experiences and correspondingly hinders adaptive functioning. In contrast, low WMC is hypothesized to exert its effect by decreasing the capacity to filter out current temptations, attenuating a focus on longer-term goals and impairing the application of relevant coping skills at times of stress. In this review, we provide conceptual models for the separate roles of high AS and low WMC in negative health behaviors, review the influence of these factors on specific health behavior exemplars (eating behaviors/obesity, physical activity, smoking, alcohol use, and sleep promotion), provide preliminary evidence for their value as independent treatment targets for health-behavior promotion, and encourage specific research directions in relation to these variables.
Ramirez, Gerardo; Gunderson, Elizabeth A.; Levine, Susan C.; Beilock, Sian L.
Although math anxiety is associated with poor mathematical knowledge and low course grades (Ashcraft & Krause, 2007), research establishing a connection between math anxiety and math achievement has generally been conducted with young adults, ignoring the emergence of math anxiety in young children. In the current study, we explored whether…
Hellemans, Kim G. C.; Verma, Pamela; Yoon, Esther; Yu, Wayne K.; Young, Allan H.; Weinberg, Joanne
Background Fetal Alcohol Spectrum Disorder (FASD) is associated with numerous neuro behavioral alterations, as well as disabilities in a number of domains, including a high incidence of depression and anxiety disorders. Prenatal alcohol exposure (PAE) also alters hypothalamic-pituitary-adrenal (HPA) function, resulting in increased responsiveness to stressors and HPA dysregulation in adulthood. Interestingly, data suggest that pre-existing HPA abnormalities may be a major contributory factor to some forms of depression, particularly when an individual is exposed to stressors later in life. We tested the hypothesis that exposure to stressors in adulthood may unmask an increased vulnerability to depressive- and anxiety-like behaviors in PAE animals. Methods Male and female offspring from prenatal alcohol (PAE), pair-fed (PF), and ad libitumfed control (C) treatment groups were tested in adulthood. Animals were exposed to 10 consecutive days of chronic mild stress (CMS), and assessed in a battery of well-validated tasks sensitive to differences in depressive- and / or anxiety-like behaviors. Results We report here that the combination of PAE and CMS in adulthood increases depressive- and anxiety-like behaviors in a sexually dimorphic manner. PAE males showed impaired hedonic responsivity (sucrose contrast test), locomotor hyperactivity (open field), and alterations in affiliative and nonaffiliative social behaviors (social interaction test) compared to control males. By contrast, PAE and, to a lesser extent, PF, females showed greater levels of “behavioral despair” in the forced swim test, and PAE females showed altered behavior in the final 5 minutes of the social interaction test compared to control females. Conclusions These data support the possibility that stress may be a mediating or contributing factor in the psychopathologies reported in FASD populations. PMID:20102562
Bachiller, Sara; Del-Pozo-Martín, Yaiza; Carrión, Ángel Manuel
Somatic LINE-1 (L1) retrotransposition is a source of genomic mosaicism and potential phenotypic diversity among neurons during brain development. In the adult brain, L1 expression can be triggered by different environmental alterations, but its functional role in this context remains unknown. Here we demonstrate a neural activation-dependent increase in the number of L1 retrotransposon insertions in the hippocampus. Using both pharmacologic and genetic approaches in mice, we demonstrate that L1 expression in the adult hippocampus enables long-term memory formation. These results provide experimental evidence that L1 retrotransposition-induced genomic mosaicism is involved in cognitive processes such as memory formation.
Chepulis, Lynne M; Starkey, Nicola J; Waas, Joseph R; Molan, Peter C
Sucrose is considered by many to be detrimental to health, giving rise to deterioration of the body associated with ageing. This study was undertaken to determine whether replacing sucrose in the diet long-term with honey that has a high antioxidant content could decrease deterioration in brain function during ageing. Forty-five 2-month old Sprague Dawley rats were fed ad libitum for 52 weeks on a powdered diet that was either sugar-free or contained 7.9% sucrose or 10% honey (which is the equivalent amount of sugar). Anxiety levels were assessed using an Elevated Plus Maze, whilst a Y maze and an Object Recognition task were used to assess memory. Locomotor activity was also measured using an Open Field task to ensure that differences in activity levels did not bias results in the other tasks. Anxiety generally decreased overall from 3 to 12 months, but the honey-fed rats showed significantly less anxiety at all stages of ageing compared with those fed sucrose. Honey-fed animals also displayed better spatial memory throughout the 12-month period: at 9 and 12 months a significantly greater proportion of honey-fed rats recognised the novel arm as the unvisited arm of the maze compared to rats on a sugar-free or sucrose-based diet. No significant differences among groups were observed in the Object Recognition task, and there appeared to be no differences in locomotor activity among groups at either 6 or 12 months. In conclusion, it appears that consumption of honey may reduce anxiety and improve spatial memory in middle age.
Traumatic brain injuries (TBIs) are generally recognized to affect episodic memory. However, less is known regarding how external force altered the way functionally connected brain structures of the episodic memory system interact. To address this issue, we adopted an effective connectivity based analysis, namely, multivariate Granger causality approach, to explore causal interactions within the brain network of interest. Results presented that TBI induced increased bilateral and decreased ipsilateral effective connectivity in the episodic memory network in comparison with that of normal controls. Moreover, the left anterior superior temporal gyrus (aSTG, the concept forming hub), left hippocampus (the personal experience binding hub), and left parahippocampal gyrus (the contextual association hub) were no longer network hubs in TBI survivors, who compensated for hippocampal deficits by relying more on the right hippocampus (underlying perceptual memory) and the right medial frontal gyrus (MeFG) in the anterior prefrontal cortex (PFC). We postulated that the overrecruitment of the right anterior PFC caused dysfunction of the strategic component of episodic memory, which caused deteriorating episodic memory in mTBI survivors. Our findings also suggested that the pattern of brain network changes in TBI survivors presented similar functional consequences to normal aging. PMID:28074162
Ya, Bai-liu; Liu, Wen-yan; Ge, Feng; Zhang, Yan-xia; Zhu, Bao-liang; Bai, Bo
Cholesterol plays an important role in synaptic plasticity, learning and memory. To better explore how dietary cholesterol contributes to learning and memory and the related changes in synaptic structural plasticity, rats were categorized into a regular diet (RD) group and a cholesterol-enriched diet (CD) group, and were fed with respective diet for 2 months. Dietary cholesterol impacts on learning and memory, hippocampal synaptic ultrastructure, expression levels of postsynaptic density-95 (PSD-95), synaptophysin (SYP) and cannabinoid receptor type 1 (CB1R) were investigated. We found CD rats had better performances in learning and memory using Morris water maze and object recognition test than RD rats. The memory improvement was accompanied with alterations of synaptic ultrastructure in the CA1 area of the hippocampus evaluated by electron microscopy, enhanced immunoreactivity of SYP, a presynaptic marker in hippocampus detected by immunocytochemistry, as well as increased levels of PSD-95, SYP and decreased level of CB1R in brains of CD rats determined by Western blot. Taken together, the results suggest that the improvement of learning and memory abilities of the young adult rats induced by dietary cholesterol may be linked with changes in synaptic structural plasticity in the brain.
Sansom-Daly, Ursula M; Bryant, Richard A; Cohn, Richard J; Wakefield, Claire E
Individuals with health anxiety experience catastrophic fears relating to future illness. However, little research has explored cognitive processes involved in how health anxious individuals picture the future. Ruminative thinking has been shown to impede the ability to recall specific autobiographical memories, which in turn is related to maladaptive, categoric future thinking processes. This study examined the impact of rumination on memory and future thinking among 60 undergraduate participants with varying health anxiety (35% clinical-level health anxiety). Participants were randomized to experiential/ruminative self-focus conditions, then completed an Autobiographical Memory Test and Future Imaginings Task. Responses were coded for specificity and the presence of illness concerns. Rumination led to more specific illness-concerned memories overall, yet at the same time led to more categoric illness-related future imaginings. Rumination and health anxiety together best predicted overgeneral illness-related future imaginings. Highly specific illness-related memories may be maintained due to their personal salience. However, more overgeneral illness-related future imaginings may reflect cognitive avoidance in response to the threat of future illness. This divergent pattern of results between memory and future imaginings may exacerbate health anxiety, and may also serve to maintain maladaptive responses among individuals with realistic medical concerns, such as individuals living with chronic illness.
Gangarossa, Giuseppe; Laffray, Sophie; Bourinet, Emmanuel; Valjent, Emmanuel
The fine-tuning of neuronal excitability relies on a tight control of Ca2+ homeostasis. The low voltage-activated (LVA) T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3 isoforms) play a critical role in regulating these processes. Despite their wide expression throughout the central nervous system, the implication of T-type Cav3.2 isoform in brain functions is still poorly characterized. Here, we investigate the effect of genetic ablation of this isoform in affective disorders, including anxiety, cognitive functions as well as sensitivity to drugs of abuse. Using a wide range of behavioral assays we show that genetic ablation of the cacna1h gene results in an anxiety-like phenotype, whereas novelty-induced locomotor activity is unaffected. Deletion of the T-type channel Cav3.2 also triggers impairment of hippocampus-dependent recognition memories. Acute and sensitized hyperlocomotion induced by d-amphetamine and cocaine are dramatically reduced in T-type Cav3.2 deficient mice. In addition, the administration of the T-type blocker TTA-A2 prevented the expression of locomotor sensitization observed in wildtype mice. In conclusion, our data reveal that physiological activity of this specific Ca2+ channel is required for affective and cognitive behaviors. Moreover, our work highlights the interest of T-type channel blockers as therapeutic strategies to reverse drug-associated alterations. PMID:24672455
Cui, Lixia; Shi, Guangyuan; He, Fan; Zhang, Qin; Oei, Tian P. S.; Guo, Chunyan
The interaction between recognition memory and emotion has become a research hotspot in recent years. Dual process theory posits that familiarity and recollection are two separate processes contributing to recognition memory, but further experimental evidence is needed. The present study explored the emotional context effects on successful and unsuccessful source retrieval amongst 15 high-trait-anxiety college students by using event-related potentials (ERPs) measurement. During study, a happy, fearful, or neutral face picture first was displayed, then a Chinese word was superimposed centrally on the picture and subjects were asked to remember the word and the corresponding type of picture. During the test participants were instructed to press one of four buttons to indicate whether the displayed word was an old or new word. And then, for the old word, indicate whether it had been shown with a fearful, happy, or neutral face during the study. ERPs were generally more positive for remembered words than for new words and the ERP difference was termed as an old/new effect. It was found that, for successful source retrieval (it meant both the item and the source were remembered accurately) between 500 and 700 ms (corresponding to a late positive component, LPC), there were significant old/new effects in all contexts. However, for unsuccessful source retrieval (it meant the correct recognition of old items matched with incorrect source attribution), there were no significant old/new effects in happy and neutral contexts, though significant old/new effects were observed in the fearful context. Between 700 and 1200 ms (corresponding to a late slow wave, LSW), there were significant old/new effects for successful source retrieval in happy and neutral contexts. However, in the fearful context, the old/new effects were reversed, ERPs were more negative for successful source retrieval compared to correct rejections. Moreover, there were significant emotion effects for
Pittman, Julian T; Lott, Chad S
Zebrafish (Danio rerio) are rapidly becoming a popular animal model for neurobehavioral and psychopharmacological research. While startle testing is a well-established assay to investigate anxiety-like behaviors in different species, screening of the startle response and its habituation in zebrafish is a new direction of translational biomedical research. This study focuses on a novel behavioral protocol to assess a tapping-induced startle response and its habituation in adult zebrafish that have been pharmacologically-induced to exhibit anxiety/depression-like behaviors. We demonstrated that zebrafish exhibit robust learning performance in a task adapted from the mammalian literature, a modified plus maze, and showed that ethanol and fluoxetine impair memory performance in this maze when administered after training at a dose that does not impair motor function, however, leads to significant upregulation of hippocampal serotoninergic neurons. These results suggest that the maze associative learning paradigm has face and construct validity and that zebrafish may become a translationally relevant study species for the analysis of the mechanisms of learning and memory changes associated with psychopharmacological treatment of anxiety/depression.
Sivamaruthi, Bhagavathi S.; Madhumita, Rajkumar; Balamurugan, Krishnaswamy; Rajan, Koilmani E.
It is well established that Cronobacter sakazakii infection cause septicemia, necrotizing enterocolitis and meningitis. In the present study, we tested whether the C. sakazakii infection alter the learning and memory through serotonin transporter (SERT). To investigate the possible effect on SERT, on postnatal day-15 (PND-15), wistar rat pups were administered with single dose of C. sakazakii culture (infected group; 107 CFU) or 100 μL of Luria-Bertani broth (medium control) or without any treatment (naïve control). All the individuals were subjected to passive avoidance test on PND-30 to test their fear memory. We show that single dose of C. sakazakii infection improved fear memory retention. Subsequently, we show that C. sakazakii infection induced the activation of toll-like receptor-3 and heat-shock proteins-90 (Hsp-90). On the other hand, level of serotonin (5-hydroxytryptamine) and SERT protein was down-regulated. Furthermore, we show that C. sakazakii infection up-regulate microRNA-16 (miR-16) expression. The observed results highlight that C. sakazakii infections was responsible for improved fear memory retention and may have reduced the level of SERT protein, which is possibly associated with the interaction of up-regulated Hsp-90 with SERT protein or miR-16 with SERT mRNA. Taken together, observed results suggest that C. sakazakii infection alter the fear memory possibly through SERT. Hence, this model may be effective to test the C. sakazakii infection induced changes in synaptic plasticity through SERT and effect of other pharmacological agents against pathogen induced memory disorder. PMID:26388777
Ly, Martina; Adluru, Nagesh; Destiche, Daniel J.; Lu, Sharon Y.; Oh, Jennifer M.; Hoscheidt, Siobhan M.; Alexander, Andrew L.; Okonkwo, Ozioma C.; Rowley, Howard A.; Sager, Mark A.; Johnson, Sterling C.; Bendlin, Barbara B.
Objective The purpose of this study was to assess whether age-related differences in white matter microstructure are associated with altered task-related connectivity during episodic recognition. Method Using functional magnetic resonance imaging and diffusion tensor imaging from 282 cognitively healthy middle-to-late aged adults enrolled in the Wisconsin Registry for Alzheimer's Prevention, we investigated whether fractional anisotropy (FA) within white matter regions known to decline with age was associated with task-related connectivity within the recognition network. Results There was a positive relationship between fornix FA and memory performance, both of which negatively correlated with age. Psychophysiological interaction analyses revealed that higher fornix FA was associated with increased task-related connectivity amongst the hippocampus, caudate, precuneus, middle occipital gyrus, and middle frontal gyrus. In addition, better task performance was associated with increased task-related connectivity between the posterior cingulate gyrus, middle frontal gyrus, cuneus, and hippocampus. Conclusions The findings indicate that age has a negative effect on white matter microstructure, which in turn has a negative impact on memory performance. However, fornix microstructure did not significantly mediate the effect of age on performance. Interestingly, dynamic functional connectivity was associated with better memory performance. The results of the psychophysiological interaction analysis further revealed that alterations in fornix microstructure explain–at least in part–connectivity among cortical regions in the recognition memory network. Our results may further elucidate the relationship between structural connectivity, neural function, and cognition. PMID:26888616
Davies, Daniel R.; Olson, Dawne; Meyer, Danielle L.; Scholl, Jamie L.; Watt, Michael J.; Manzerra, Pasquale; Renner, Kenneth J.; Forster, Gina L.
Mild traumatic brain injury (mTBI) produces symptoms similar to those typifying posttraumatic stress disorder (PTSD) in humans. We sought to determine whether a rodent model of stress concurrent with mTBI produces characteristics of PTSD such as impaired contextual fear extinction, while also examining concurrent alterations to limbic monoamine activity in brain regions relevant to fear and anxiety states. Male rats were exposed to social stress or control conditions immediately prior to mTBI induction, and 6 days later were tested either for anxiety-like behavior using the elevated plus maze (EPM), or for contextual fear conditioning and extinction. Brains were collected 24 h after EPM testing, and tissue from various limbic regions analyzed for content of monoamines, their precursors and metabolites using HPLC with electrochemical detection. Either social defeat or mTBI alone decreased time spent in open arms of the EPM, indicating greater anxiety-like behavior. However, this effect was enhanced by the combination of treatments. Further, rats exposed to both social defeat and mTBI exhibited greater freezing within extinction sessions compared to all other groups, suggesting impaired contextual fear extinction. Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning. The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes. PMID:27147992
Hirjak, Dusan; Wolf, Robert C; Remmele, Barbara; Seidl, Ulrich; Thomann, Anne K; Kubera, Katharina M; Schröder, Johannes; Maier-Hein, Klaus H; Thomann, Philipp A
Autobiographical memory (AM) is part of declarative memory and includes both semantic and episodic aspects. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. Previous MRI studies in AD patients have showed that deficits in semantic and episodic AM are associated with hippocampal alterations. However, the question which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits of AM in individuals with mild cognitive impairment (MCI) and AD patients has not been investigated so far. Hundred and seven participants (38 AD patients, 38 MCI individuals and 31 healthy controls [HC]) underwent MRI at 3 Tesla. AM was assessed with a semi-structured interview (E-AGI). FreeSurfer 5.3 was used for hippocampal parcellation. Semantic and episodic AM scores were related to the volume of 5 hippocampal subfields and cortical thickness in the parahippocampal and entorhinal cortex. Both semantic and episodic AM deficits were associated with bilateral hippocampal alterations. These associations referred mainly to CA1, CA2-3, presubiculum, and subiculum atrophy. Episodic, but not semantic AM loss was associated with cortical thickness reduction of the bilateral parahippocampal and enthorinal cortex. In MCI individuals, episodic, but not semantic AM deficits were associated with alterations of the CA1, presubiculum and subiculum. Our findings support the crucial role of CA1, presubiculum, and subiculum in episodic memory. The present results implicate that in MCI individuals, semantic and episodic AM deficits are subserved by distinct neuronal systems.
Pajak, Rosanna; Kamboj, Sunjeev K.
Bowel and bladder obsession [bowel/bladder-control anxiety (BBCA)] is a viscerally centered phobic syndrome involving a specific concern about losing control of bowel or bladder functioning in a public place. Like other anxiety disorders, BBCA is characterized by intrusive imagery. We have previously described the nature of intrusive mental imagery in BBCA and found imagery themes to be linked to actual experiences of loss of control or to “near misses.” A causal role for imagery in symptom maintenance can be inferred by examining the effects of imagery rescripting. Moreover, successful rescripting may point to a potentially efficacious avenue for treatment development. Three cases of imagery rescripting are described here with pre-, post-, and follow-up (1-week) data reported. After rescripting, two participants experienced pronounced reductions in imagery vividness, distress, shame, disgust, and belief conviction. Most importantly, all three participants experienced a reduction in fear-associated bladder and/or bowel sensations. The results support a causal role for mental imagery in bowel-bladder-control anxiety and suggest that rescripting of distressing intrusive memories linked to recurrent images may be a useful avenue for development of cognitive-behavioral treatments of bladder/bowel-control anxiety. PMID:25566101
Glassman, Lisa Hayley
Individuals with public speaking phobia experience fear and avoidance that can cause extreme distress, impaired speaking performance, and associated problems in psychosocial functioning. Most extant interventions for public speaking phobia focus on the reduction of anxiety and avoidance, but neglect performance. Additionally, very little is known about the relationship between verbal working memory and social performance under conditions of high anxiety. The current study compared the efficacy of two cognitive behavioral treatments, traditional Cognitive Behavioral Therapy (tCBT) and acceptance-based behavior therapy (ABBT), in enhancing public speaking performance via coping with anxiety. Verbal working memory performance, as measured by the backwards digit span (BDS), was measured to explore the relationships between treatment type, anxiety, performance, and verbal working memory. We randomized 30 individuals with high public speaking anxiety to a 90-minute ABBT or tCBT intervention. As this pilot study was underpowered, results are examined in terms of effect sizes as well as statistical significance. Assessments took place at pre and post-intervention and included self-rated and objective anxiety measurements, a behavioral assessment, ABBT and tCBT process measures, and backwards digit span verbal working memory tests. In order to examine verbal working memory during different levels of anxiety and performance pressure, we gave each participant a backwards digit span task three times during each assessment: once under calm conditions, then again while experiencing anticipatory anxiety, and finally under conditions of acute social performance anxiety in front of an audience. Participants were asked to give a video-recorded speech in front of the audience at pre- and post-intervention to examine speech performance. Results indicated that all participants experienced a very large and statistically significant decrease in anxiety (both during the speech and BDS
Hescham, Sarah; Jahanshahi, Ali; Meriaux, Céline; Lim, Lee Wei; Blokland, Arjan; Temel, Yasin
Deep brain stimulation (DBS) has gained interest as a potential therapy for advanced treatment-resistant dementia. However, possible targets for DBS and the optimal stimulation parameters are not yet clear. Here, we compared the effects of DBS of the CA1 sub-region of the hippocampus, mammillothalamic tract, anterior thalamic nucleus, and entorhinal cortex in an experimental rat model of dementia. Rats with scopolamine-induced amnesia were assessed in the object location task with different DBS parameters. Moreover, anxiety-related side effects were evaluated in the elevated zero maze and open field. After sacrifice, we applied c-Fos immunohistochemistry to assess which memory-related regions were affected by DBS. When comparing all structures, DBS of the entorhinal cortex and CA1 sub-region was able to restore memory loss when a specific set of stimulation parameters was used. No anxiety-related side effects were found following DBS. The beneficial behavioral performance of CA1 DBS rats was accompanied with an activation of cells in the anterior cingulate gyrus. Therefore, we conclude that acute CA1 DBS restores memory loss possibly through improved attentional and cognitive processes in the limbic cortex.
Ménard, Caroline; Quirion, Rémi; Bouchard, Sylvain; Ferland, Guylaine; Gaudreau, Pierrette
The LOU/C/Jall (LOU) rat strain is considered a model of healthy aging due to its increased longevity, maintenance of stable body weight (BW) throughout life and low incidence of age-related diseases. However, aging LOU rat cognitive and anxiety status has yet to be investigated. In the present study, male and female LOU rat cognitive performances (6–42 months) were assessed using novel object recognition and Morris Water Maze tasks. Recognition memory remained intact in all LOU rats up to 42 months of age. As for spatial memory, old LOU rat performed similarly as young animals for learning acquisition, reversal learning, and retention. While LOU rat BW remained stable despite aging, 20-month-old ad-libitum-fed (OAL) male Sprague Dawley rats become obese. We determined if long-term caloric restriction (LTCR) prevents age-related BW increase and cognitive deficits in this rat strain, as observed in the obesity-resistant LOU rats. Compared to young animals, recognition memory was impaired in OAL but intact in 20-month-old calorie-restricted (OCR) rats. Similarly, OAL spatial learning acquisition was impaired but LTCR prevented the deficits. Exacerbated stress responses may favor age-related cognitive decline. In the elevated plus maze and open field tasks, LOU and OCR rats exhibited high levels of exploratory activity whereas OAL rats displayed anxious behaviors. Expression of prodynorphin (Pdyn), an endogenous peptide involved in stress-related memory impairments, was increased in the hippocampus of OAL rats. Group 1 metabotropic glutamate receptor 5 and immediate early genes Homer 1a and Arc expression, both associated with successful cognitive aging, were unaltered in aging LOU rats but lower in OAL than OCR rats. Altogether, our results, supported by principal component analysis and correlation matrix, suggest that intact memory and low anxiety are associated with glutamatergic signaling and low Pdyn expression in the hippocampus of non-obese aging rats. PMID
Li, Zhihao; Coles, Claire D; Lynch, Mary Ellen; Hamann, Stephan; Peltier, Scott; LaConte, Stephen; Hu, Xiaoping
While prenatal cocaine exposure (PCE) has been associated with arousal dysregulation and attentional impairments in both human and animal studies, the neurobiological bases of these teratogenic effects have not been well characterized. In the current study, we report functional neuroimaging observations of these effects in exposed youth. Using functional magnetic resonance imaging (fMRI), we embedded task-irrelevant emotional distracters in a working memory task to examine the interaction of emotional arousal and memory in 33 PCE and 23 non-exposed adolescents. Though with similar behavioral performance, the two groups exhibited different activation patterns associated with emotion-memory interactions. On the one hand, higher memory load attenuated emotion-related amygdala activation in controls but not in the exposed adolescents; on the other hand, prefrontal activation associated with memory load decreased in the presence of emotional distraction in the controls but increased in the exposed group. These group interaction differences suggest neurobiological substrates for arousal-associated neuronal alterations related to prenatal cocaine exposure. Consistent with previous findings in behavioral and physiological studies, the present neuroimaging data provided more in-depth evidence supporting the view that PCE has significant long-term teratogenic effect on arousal regulation system.
Li, Zhihao; Coles, Claire D.; Lynch, Mary Ellen; Hamann, Stephan; Peltier, Scott; LaConte, Stephen; Hu, Xiaoping
While prenatal cocaine exposure (PCE) has been associated with arousal dysregulation and attentional impairments in both human and animal studies, the neurobiological bases of these teratogenic effects have not been well characterized. In the current study, we report functional neuroimaging observations of these effects in exposed youth. Using functional magnetic resonance imaging (fMRI), we embedded task-irrelevant emotional distracters in a working memory task to examine the interaction of emotional arousal and memory in 33 PCE and 23 non-exposed adolescents. Though with similar behavioral performance, the two groups exhibited different activation patterns associated with emotion-memory interactions. On the one hand, higher memory load attenuated emotion-related amygdala activation in controls but not in the exposed adolescents; on the other hand, prefrontal activation associated with memory load decreased in the presence of emotional distraction in the controls but increased in the exposed group. These group interaction differences suggest neurobiological substrates for arousal-associated neuronal alterations related to prenatal cocaine exposure. Consistent with previous findings in behavioral and physiological studies, the present neuroimaging data provided more in-depth evidence supporting the view that PCE has significant long-term teratogenic effect on arousal regulation system. PMID:19699795
Basu, Amrita; McFarlane, Hewlet G; Kopchick, John J
Growth hormone (GH) has a significant influence on cognitive performance in humans and other mammals. To understand the influence of altered GH action on cognition, we assessed spatial learning and memory using a Barnes maze (BM) comparing twelve-month old, male, bovine GH (bGH) and GH receptor antagonist (GHA) transgenic mice and their corresponding wild type (WT) littermates. During the acquisition training period in the BM, bGH mice showed increased latency, traveled longer path lengths and made more errors to reach the target than WT mice indicating significantly poorer learning. Short-term memory (STM) and long-term memory (LTM) trials showed significantly suppressed memory retention in bGH mice when compared to the WT group. Conversely, GHA mice showed significantly better learning parameters (latency, path length and errors) and increased use of an efficient search strategy than WT mice. Our study indicates a negative impact of GH excess and a beneficial effect of the inhibition of GH action on spatial learning and memory and, therefore, cognitive performance in male mice. Further research to elucidate GH's role in brain function will facilitate identifying therapeutic applications of GH or GHA for neuropathological and neurodegenerative conditions.
Hofmann, Tobias; Weibert, Elena; Ahnis, Anne; Obbarius, Alexander; Elbelt, Ulf; Rose, Matthias; Klapp, Burghard F; Stengel, Andreas
In addition to its anorexigenic properties in the neuroendocrine regulation of hunger and satiety, mounting evidence indicates a role for NUCB2/nesfatin-1 in the regulation of emotional stress responses which seems to occur in a sex-specific way. In the present study, we investigated the association of NUCB2/nesfatin-1 plasma levels with anxiety, depressiveness and perceived stress in obese men and women and their alterations during inpatient treatment. We expected a decrease of NUCB2/nesfatin-1 levels in female and an increase in male patients reporting a relevant alleviation of anxiety. We analyzed 69 inpatients (44 female, 25 male; body mass index, mean: 50.2±9.5kg/m(2), range: 31.8-76.5kg/m(2); mean age: 45.0±12.4years) hospitalized due to morbid obesity with mental (not necessarily anxiety disorders) and somatic comorbidities. NUCB2/nesfatin-1 plasma levels were measured by ELISA. Anxiety (GAD-7), depressiveness (PHQ-9) and perceived stress (PSQ-20) were concurrently determined as patient-reported outcomes. All measurements were carried out at the initiation of and during inpatient treatment when a clinically meaningful improvement of anxiety was achieved (≥5 points on GAD-7) or missed (±1 point). NUCB2/nesfatin-1 was positively correlated with anxiety scores in women at the beginning of (r=0.411; p=0.006) and during (r=0.301; p=0.047) inpatient treatment. In men, a significant negative correlation was observed following treatment (r=-0.469; p=0.018), while at the outset of treatment only a trend was observed (r=-0.381; p=0.059). Unexpectedly, neither women (n=19; at beginning vs. during treatment; 0.49±1.00ng/ml vs. 0.38±0.72ng/ml; p=0.687) nor men (n=9; 0.17±0.31ng/ml vs. 0.19±0.36ng/ml; p=0.427) who improved in anxiety scores (p<0.001) displayed significant changes of NUCB2/nesfatin-1 plasma levels, although the direction of change was as expected with a decrease in women (-23.3%) and an increase in men (+12.4%). In addition, the change of NUCB2
Roberts-Wolfe, Douglas; Sacchet, Matthew D.; Hastings, Elizabeth; Roth, Harold; Britton, Willoughby
Objectives: While mindfulness-based interventions have received widespread application in both clinical and non-clinical populations, the mechanism by which mindfulness meditation improves well-being remains elusive. One possibility is that mindfulness training alters the processing of emotional information, similar to prevailing cognitive models of depression and anxiety. The aim of this study was to investigate the effects of mindfulness training on emotional information processing (i.e., memory) biases in relation to both clinical symptomatology and well-being in comparison to active control conditions. Methods: Fifty-eight university students (28 female, age = 20.1 ± 2.7 years) participated in either a 12-week course containing a “meditation laboratory” or an active control course with similar content or experiential practice laboratory format (music). Participants completed an emotional word recall task and self-report questionnaires of well-being and clinical symptoms before and after the 12-week course. Results: Meditators showed greater increases in positive word recall compared to controls [F(1, 56) = 6.6, p = 0.02]. The meditation group increased significantly more on measures of well-being [F(1, 56) = 6.6, p = 0.01], with a marginal decrease in depression and anxiety [F(1, 56) = 3.0, p = 0.09] compared to controls. Increased positive word recall was associated with increased psychological well-being (r = 0.31, p = 0.02) and decreased clinical symptoms (r = −0.29, p = 0.03). Conclusion: Mindfulness training was associated with greater improvements in processing efficiency for positively valenced stimuli than active control conditions. This change in emotional information processing was associated with improvements in psychological well-being and less depression and anxiety. These data suggest that mindfulness training may improve well-being via changes in emotional information processing. Future
Rudenko, Andrii; Seo, Jinsoo; Hu, Ji; Su, Susan C; de Anda, Froylan Calderon; Durak, Omer; Ericsson, Maria; Carlén, Marie; Tsai, Li-Huei
Perturbations in fast-spiking parvalbumin (PV) interneurons are hypothesized to be a major component of various neuropsychiatric disorders; however, the mechanisms regulating PV interneurons remain mostly unknown. Recently, cyclin-dependent kinase 5 (Cdk5) has been shown to function as a major regulator of synaptic plasticity. Here, we demonstrate that genetic ablation of Cdk5 in PV interneurons in mouse brain leads to an increase in GABAergic neurotransmission and impaired synaptic plasticity. PVCre;fCdk5 mice display a range of behavioral abnormalities, including decreased anxiety and memory impairment. Our results reveal a central role of Cdk5 expressed in PV interneurons in gating inhibitory neurotransmission and underscore the importance of such regulation during behavioral tasks. Our findings suggest that Cdk5 can be considered a promising therapeutic target in a variety of conditions attributed to inhibitory interneuronal dysfunction, such as epilepsy, anxiety disorders, and schizophrenia.
Park, Jong-Il; Kim, Gwang-Won; Jeong, Gwang-Woo; Chung, Gyung Ho; Yang, Jong-Chul
Few studies have assessed the neural mechanisms of the effects of emotion on cognition in generalized anxiety disorder (GAD) patients. In this functional MRI (fMRI), we investigated the effects of emotional interference on working memory (WM) maintenance in GAD patients. Fifteen patients with GAD participated in this study. Event-related fMRI data were obtained while the participants performed a WM task (face recognition) with neutral and anxiety-provoking distracters. The GAD patients showed impaired performance in WM task during emotional distracters and showed greater activation on brain regions such as DLPFC, VLPFC, amygdala, hippocampus which are responsible for the active maintenance of goal relevant information in WM and emotional processing. Although our results are not conclusive, our finding cautiously suggests the cognitive-affective interaction in GAD patients which shown interfering effect of emotional distracters on WM maintenance.
Spangler, Derek P.; Friedman, Bruce H.
Anxiety impairs both inhibition of distraction and attentional focus. It is unclear whether these impairments are reduced or exacerbated when loading working memory with non-affective information. Cardiac vagal control has been related to top–down regulation of anxiety; therefore, vagal control may reflect load-related inhibition of distraction under anxiety. The present study examined whether: (1) the enhancing and impairing effects of load on inhibition exist together in a non-linear function, (2) there is a similar association between inhibition and concurrent vagal control under anxiety. During anxiogenic threat-of-noise, 116 subjects maintained a digit series of varying lengths (0, 2, 4, and 6 digits) while completing a visual flanker task. The task was broken into four blocks, with a baseline period preceding each. Electrocardiography was acquired throughout to quantify vagal control as high-frequency heart rate variability (HRV). There were significant quadratic relations of working memory load to flanker performance and to HRV, but no associations between HRV and performance. Results indicate that low load was associated with relatively better inhibition and increased HRV. These findings suggest that attentional performance under anxiety depends on the availability of working memory resources, which might be reflected by vagal control. These results have implications for treating anxiety disorders, in which regulation of anxiety can be optimized for attentional focus. PMID:28217091
André, Caroline; Dinel, Anne-Laure; Ferreira, Guillaume; Layé, Sophie; Castanon, Nathalie
Obesity is associated with a high prevalence of mood symptoms and cognitive dysfunctions that emerges as significant risk factors for important health complications such as cardiovascular diseases and type 2 diabetes. It is therefore important to identify the dynamic of development and the pathophysiological mechanisms underlying these neuropsychiatric symptoms. Obesity is also associated with peripheral low-grade inflammation and increased susceptibility to immune-mediated diseases. Excessive production of proinflammatory cytokines and the resulting activation of the brain tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) have been shown to promote neurobehavioral complications, particularly depression. In that context, questions arise about the impact of diet-induced obesity on the onset of neuropsychiatric alterations and the increased susceptibility to immune-mediated diseases displayed by obese patients, particularly through brain IDO activation. To answer these questions, we used C57Bl/6 mice exposed to standard diet or western diet (WD; consisting of palatable energy-dense food) since weaning and for 20 weeks. We then measured inflammatory and behavioral responses to a systemic immune challenge with lipopolysaccharide (LPS) in experimental conditions known to alter cognitive and emotional behaviors independently of any motor impairment. We first showed that in absence of LPS, 9 weeks of WD is sufficient to impair spatial recognition memory (in the Y-maze). On the other hand, 18 weeks of WD increased anxiety-like behavior (in the elevated plus-maze), but did not affect depressive-like behavior (in the tail-suspension and forced-swim tests). However, 20 weeks of WD altered LPS-induced depressive-like behavior compared to LPS-treated lean mice and exacerbated hippocampal and hypothalamic proinflammatory cytokine expression and brain IDO activation. Taken together, these results show that WD exposure alters cognition and anxiety in unstimulated
Jeppesen, Elisabeth; Pedersen, Carsten M.; Larsen, Klaus R.; Rehl, Anne; Bartholdy, Karen; Walsted, Emil S.; Backer, Vibeke
Background The use of music to relieve anxiety has been examined in various studies, but the results are inconclusive. Methods From April to October 2015, 160 patients undergoing examination of pulmonary nodules were randomly assigned to MusiCure or no music. MusiCure was administered through earplugs to ensure blinding of the staff and was played from admission to the operating theatre to the end of the bronchoscopy. Spielberger’s State-Trait Anxiety Inventory (STAI) was administered on admission, immediately before bronchoscopy, and on discharge. Secondary outcomes were p-cortisol, physiological variables, dosage of sedatives, movements measured by Actigraph, bronchoscopy duration, number of re-examinations, and overall perception of the sounds in the operating theatre measured by Visual analogue scale. Results The STAI scores were similar on admission, but after a 10-min wait in the operating theatre, scores varied significantly between patients with and without music, with lower scores in the music group [median (interquartile range, IQR) 35 (18) vs. 43 (25); p=0.03]. Post hoc multiple regression revealed treatment group as insignificant when adjusting for sex and baseline anxiety. However, there was a significantly more positive perception of the sounds in the operating theatre in the music group (median (IQR) 8.2 (1.8) vs. 5.4 (6.8); p<0.0001) and fewer re-examinations in the music group (19.2% vs. 7.7%, p<0.032). Conclusions Ten minutes with MusiCure does not alter anxiety when adjusting for baseline anxiety and sex. The current study indicates that this field of research has many confounders. PMID:27814780
Mantua, Janna; Mahan, Keenan M; Henry, Owen S; Spencer, Rebecca M C
Individuals with a history of traumatic brain injury (TBI) often report sleep disturbances, which may be caused by changes in sleep architecture or reduced sleep quality (greater time awake after sleep onset, poorer sleep efficiency, and sleep stage proportion alterations). Sleep is beneficial for memory formation, and herein we examine whether altered sleep physiology following TBI has deleterious effects on sleep-dependent declarative memory consolidation. Participants learned a list of word pairs in the morning or evening, and recall was assessed 12-h later, following an interval awake or with overnight sleep. Young adult participants (18-22 years) were assigned to one of four experimental groups: TBI Sleep (n = 14), TBI Wake (n = 12), non-TBI Sleep (n = 15), non-TBI Wake (n = 15). Each TBI participant was >1 year post-injury. Sleep physiology was measured with polysomnography. Memory consolidation was assessed by comparing change in word-pair recall over 12-h intersession intervals. The TBI group spent a significantly greater proportion of the night in SWS than the non-TBI group at the expense of NREM1. The TBI group also had marginally lower EEG delta power during SWS in the central region. Intersession changes in recall were greater for intervals with sleep than without sleep in both groups. However, despite abnormal sleep stage proportions for individuals with a TBI history, there was no difference in the intersession change in recall following sleep for the TBI and non-TBI groups. In both Sleep groups combined, there was a positive correlation between Intersession Change and the proportion of the night in NREM2 + SWS. Overall, sleep composition is altered following TBI but such deficits do not yield insufficiencies in sleep-dependent memory consolidation.
Simmons, Alan; Stein, Murray B.; Strigo, Irina A; Arce, Estibaliz; Hitchcock, Carla; Paulus, Martin P.
Prior neuroimaging studies support the hypothesis that anticipation, an important component of anxiety, may be mediated by activation within the insular and medial prefrontal cortices including the anterior cingulate cortex. However, there is an insufficient understanding of how affective anticipation differs across anxiety groups in emotional brain loci and networks. We examined 14 anxiety positive (AP) and 14 anxiety normative (AN) individuals completing an affective picture anticipation task during functional magnetic resonance imaging (fMRI). Brain activation was examined across groups for cued anticipation (to aversive or pleasant stimuli). Both groups showed greater activation in the bilateral anterior insula during cued differential anticipation (i.e., aversive vs. pleasant) and activation on the right was significantly higher in AP compared to AN subjects. Functional connectivity showed that the left anterior insula was involved in a similar network during pleasant anticipation in both groups. The left anterior insula during aversive and the right anterior insula during all anticipation conditions co-activated with a cortical network consisting of frontal and parietal lobes in the AP group to a greater degree. These results are consistent with the hypothesis that anxiety is related to greater anticipatory reactivity in the brain and that there may be functional asymmetries in the brain that interact with psychiatric traits. PMID:21181800
Egloff, Boris; Schmukle, Stefan C; Burns, Lawrence R; Schwerdtfeger, Andreas
In these studies, the correlates of spontaneously using expressive suppression and cognitive reappraisal during stressful speeches were examined. Spontaneous emotion regulation means that there were no instructions of how to regulate emotions during the speech. Instead, participants indicated after the speech to what extent they used self-motivated expressive suppression or reappraisal during the task. The results show that suppression is associated with less anxiety expression, greater physiological responding, and less memory for the speech while having no impact on negative affect. In contrast, reappraisal has no impact on physiology and memory while leading to less expression and affect. Taken together, spontaneous emotion regulation in active coping tasks has similar consequences as experimentally induced emotion regulation in passive tasks.
Toschi-Dias, Edgar; Trombetta, Ivani C; da Silva, Valdo José Dias; Maki-Nunes, Cristiane; Alves, Maria Janieire N N; Angelo, Luciana F; Cepeda, Felipe X; Martinez, Daniel G; Negrão, Carlos Eduardo; Rondon, Maria Urbana P B
Previous investigations show that metabolic syndrome (MetSyn) causes sympathetic hyperactivation. Symptoms of anxiety and mood disturbance (AMd) provoke sympatho-vagal imbalance. We hypothesized that AMd would alter even further the autonomic function in patients with MetSyn. Twenty-six never-treated patients with MetSyn (ATP-III) were allocated to two groups, according to the levels of anxiety and mood disturbance: (1) with AMd (MetSyn + AMd, n = 15), and (2) without AMd (MetSyn, n = 11). Ten healthy control subjects were also studied (C, n = 10). AMd was determined using quantitative questionnaires. Muscle sympathetic nerve activity (MSNA, microneurography), blood pressure (oscillometric beat-to-beat basis), and heart rate (ECG) were measured during a baseline 10-min period. Spectral analysis of RR interval and systolic arterial pressure were analyzed, and the power of low (LF) and high (HF) frequency bands were determined. Sympatho-vagal balance was obtained by LF/HF ratio. Spontaneous baroreflex sensitivity (BRS) was evaluated by calculation of α-index. MSNA was greater in patients with MetSyn + AMd compared with MetSyn and C. Patients with MetSyn + AMd showed higher LF and lower HF power compared with MetSyn and C. In addition, LF/HF balance was higher in MetSyn + AMd than in MetSyn and C groups. BRS was decreased in MetSyn + AMd compared with MetSyn and C groups. Anxiety and mood disturbance alter autonomic function in patients with MetSyn. This autonomic dysfunction may contribute to the increased cardiovascular risk observed in patients with mood alterations.
Costine, Beth A; Oberlander, Joseph G; Davis, Matthew C; Penatti, Carlos A A; Porter, Donna M; Leaton, Robert N; Henderson, Leslie P
Summary In the past several decades, the therapeutic use of anabolic androgenic steroids (AAS) has been overshadowed by illicit use of these drugs by elite athletes and a growing number of adolescents to enhance performance and body image. As with adults, AAS use by adolescents is associated with a range of behavioral effects, including increased anxiety and altered responses to stress. It has been suggested that adolescents, especially adolescent females, may be particularly susceptible to the effects of these steroids, but few experiments in animal models have been performed to test this assertion. Here we show that chronic exposure of adolescent female mice to a mixture of three commonly abused AAS (testosterone cypionate, nandrolone decanoate and methandrostenolone; 7.5 mg/kg/day for 5 days) significantly enhanced anxiety-like behavior as assessed by the acoustic startle response (ASR), but did not augment the fear-potentiated startle response (FPS) or alter sensorimotor gating as assessed by prepulse inhibition of the acoustic startle response (PPI). AAS treatment also significantly increased the levels of corticotropin releasing factor (CRF) mRNA and somal-associated CRF immunoreactivity in the central amygdala (CeA), as well as neuropil-associated immunoreactivity in the dorsal aspect of the anterolateral division of the bed nucleus of the stria terminalis (dBnST). AAS treatment did not alter CRF receptor 1 or 2 mRNA in either the CeA or the dBnST; CRF immunoreactivity in the ventral BNST, the paraventricular nucleus (PVN) or the median eminence (ME); or peripheral levels of corticosterone. These results suggest that chronic AAS treatment of adolescent female mice may enhance generalized anxiety, but not sensorimotor gating or learned fear, via a mechanism that involves increased CRF-mediated signaling from CeA neurons projecting to the dBnST. PMID:20537804
Costine, Beth A; Oberlander, Joseph G; Davis, Matthew C; Penatti, Carlos A A; Porter, Donna M; Leaton, Robert N; Henderson, Leslie P
In the past several decades, the therapeutic use of anabolic androgenic steroids (AAS) has been overshadowed by illicit use of these drugs by elite athletes and a growing number of adolescents to enhance performance and body image. As with adults, AAS use by adolescents is associated with a range of behavioral effects, including increased anxiety and altered responses to stress. It has been suggested that adolescents, especially adolescent females, may be particularly susceptible to the effects of these steroids, but few experiments in animal models have been performed to test this assertion. Here we show that chronic exposure of adolescent female mice to a mixture of three commonly abused AAS (testosterone cypionate, nandrolone decanoate and methandrostenolone; 7.5 mg/kg/day for 5 days) significantly enhanced anxiety-like behavior as assessed by the acoustic startle response (ASR), but did not augment the fear-potentiated startle response (FPS) or alter sensorimotor gating as assessed by prepulse inhibition of the acoustic startle response (PPI). AAS treatment also significantly increased the levels of corticotropin releasing factor (CRF) mRNA and somal-associated CRF immunoreactivity in the central nucleus of the amygdala (CeA), as well as neuropil-associated immunoreactivity in the dorsal aspect of the anterolateral division of the bed nucleus of the stria terminalis (dBnST). AAS treatment did not alter CRF receptor 1 or 2 mRNA in either the CeA or the dBnST; CRF immunoreactivity in the ventral BnST, the paraventricular nucleus (PVN) or the median eminence (ME); or peripheral levels of corticosterone. These results suggest that chronic AAS treatment of adolescent female mice may enhance generalized anxiety, but not sensorimotor gating or learned fear, via a mechanism that involves increased CRF-mediated signaling from CeA neurons projecting to the dBnST.
Esquivel, Bárbara Bárcena; Levin, Gloria; Rivarola, María Angélica; Suárez, Marta Magdalena
The present study investigated the effect of early maternal separation on anxiety and hypophyso-adrenal system activity to anterodorsal thalamic nuclei (ADTN) lesion in male rats as adults in order to compare this with previous results with female rats. During the first 3 weeks of life, male rats were isolated 4.5 hr daily and tested as adults. Thirty days after ADTN lesion we found that adrenocorticotropic hormone (ACTH) plasma levels were affected neither by maternal separation nor by ADTN lesion. Plasma corticosterone (CORT) concentration was increased with lesion of the ADTN in maternally separated rats. A significant increase in plasma catecholamine concentration was induced by early maternal separation. In ADTN-lesioned rats, plasma norepinephrine (NE) concentration was significantly lower than in the respective sham-lesioned groups. In terms of anxiety, there were no significant effects of early experience. However, the ADTN lesion tended to decrease anxiety-related behavior.
Pfeifer, Ronny; Hustedt, Michael; Wesling, Volker; Hurschler, Christoph; Olender, Gavin; Mach, Martin; Gösling, Thomas; Müller, Christian W
This article shows an approach to change the properties of an orthopaedic shape memory implant within biological tissue, using contactless induction heating. Due to inducing the one way-memory effect, triggered by the rise of temperature within the implant, the geometry and hence the mechanical properties of the implant itself, are altered. The power uptake of the implant, depending on the induction parameters as well as on its position within the induction coil, is shown. Thermographic measurements are carried out in order to determine the surface temperature distribution of the implant. In order to simulate biological tissue, the implant was embedded in agarose gel. Suitable heating parameters, in terms of a short heating process in combination with a reduced heat impact on the surrounding environment, were determined.
Komiyama, Takaaki; Sudo, Mizuki; Higaki, Yasuki; Kiyonaga, Akira; Tanaka, Hiroaki; Ando, Soichi
It has been suggested that acute exercise improves cognitive function. However, little is known about how exercise under hypoxia affects cognitive function. The purpose of this study was to determine if hypoxia alters working memory and executive function during prolonged exercise. Sixteen participants performed cognitive tasks at rest and during exercise under normoxia and hypoxia [fraction of inspired oxygen (FIO2)=0.15, corresponding to an altitude of approximately 2600 m]. The level of hypoxia was moderate. We used a combination of Spatial Delayed Response (Spatial DR) task and Go/No-Go (GNG) task, where spatial working memory and executive function are required. Working memory was assessed by the accuracy of the Spatial DR task, and executive function was assessed by the accuracy and reaction time in the GNG task. The participants cycled an ergometer for 30 min under normoxia and moderate hypoxia while keeping their heart rate (HR) at 140 beats/min. They performed the cognitive tasks 5 min and 23 min after their HR reached 140 beats/min. Moderate hypoxia did not alter the accuracy of the Spatial DR (P=0.38) and GNG tasks (P=0.14). In contrast, reaction time in the GNG task significantly decreased during exercise relative to rest under normoxia and moderate hypoxia (P=0.02). These results suggest that moderate hypoxia and resultant biological processes did not provide sufficient stress to impair working memory and executive function during prolonged exercise. The beneficial effects on speed of response appear to persist during prolonged exercise under moderate hypoxia.
Mattarella-Micke, Andrew; Mateo, Jill; Kozak, Megan N; Foster, Katherine; Beilock, Sian L
In the current study, we explored how a person's physiological arousal relates to their performance in a challenging math situation as a function of individual differences in working memory (WM) capacity and math-anxiety. Participants completed demanding math problems before and after which salivary cortisol, an index of arousal, was measured. The performance of lower WM individuals did not depend on cortisol concentration or math-anxiety. For higher WM individuals high in math-anxiety, the higher their concentration of salivary cortisol following the math task, the worse their performance. In contrast, for higher WM individuals lower in math-anxiety, the higher their salivary cortisol concentrations, the better their performance. For individuals who have the capacity to perform at a high-level (higher WMs), whether physiological arousal will lead an individual to choke or thrive depends on math-anxiety.
Vance, Alasdair; Ferrin, Maite; Winther, Jo; Gomez, Rapson
Spatial working memory (SWM) is known to be impaired in children with ADHD-CT, whether anxiety is present or not. Yet, it remains unclear whether anxiety disorders add to the SWM impairments evident in ADHD-CT and whether these findings extend into adolescents with ADHD-CT and anxiety. Further, it is not yet known whether children and adolescents with carefully defined anxiety disorders alone, demonstrate SWM deficits. This study explored the association of SWM and its strategy and spatial span components in carefully defined children and adolescents (age 6-16 years) with ADHD-CT alone (N = 163; 14 % female), ADHD-CT and anxiety (N = 243; 23 % female), anxiety disorders alone (N = 69; 25 % female) compared to age- and gender-matched healthy control participants (N = 116; 19 % female). The relationship between SWM and its strategy and span components and core ADHD-CT symptoms and anxiety symptoms were also examined. There was no evidence of an additive effect of ADHD and anxiety on SWM, strategy and spatial span deficits. But, anxiety disorders alone were associated with impaired SWM and span performance compared to healthy control participants. In contrast, strategy did not differ between children and adolescents with anxiety disorders alone and healthy control participants, suggesting that with anxiety span is the most affected component. Further, these findings were age-independent. This study concurs with and extends current influential models about the cognitive effects of anxiety on performance in the setting of ADHD-CT. Clinical implications and future research directions are discussed.
Qin, Shaozheng; Hermans, Erno J; van Marle, Hein J F; Fernández, Guillén
Exposure to an acute stressor can lead to unreliable remembrance of intrinsically neutral information, as exemplified by low reliability of eyewitness memories, which stands in contrast with enhanced memory for the stressful incident itself. Stress-sensitive neuromodulators (e.g., catecholamines) are believed to cause this low reliability by altering neurocognitive processes underlying memory formation. Using event-related functional magnetic resonance imaging, we investigated neural activity during memory formation in 44 young, healthy human participants while incidentally encoding emotionally neutral, complex scenes embedded in either a stressful or neutral context. We recorded event-related pupil dilation responses as an indirect index of phasic noradrenergic activity. Autonomic, endocrine, and psychological measures were acquired to validate stress manipulation. Acute stress during encoding led to a more liberal response bias (more hits and false alarms) when testing memory for the scenes 24 h later. The strength of this bias correlated negatively with pupil dilation responses and positively with stress-induced heart rate increases at encoding. Acute stress, moreover, reduced subsequent memory effects (SMEs; items later remembered vs forgotten) in hippocampus and midbrain, and in pupil dilation responses. The diminished SMEs indicate reduced selectivity and specificity in mnemonic processing during memory formation. This is in line with a model in which stress-induced catecholaminergic hyperactivation alters phasic neuromodulatory signaling in memory-related circuits, resulting in generalized (gist-based) processing at the cost of specificity. Thus, one may speculate that loss of specificity may yield less discrete memory representations at time of encoding, thereby causing a more liberal response bias when probing these memories.
Chris Ajonijebu, Duyilemi; Adeyemi Adeniyi, Philip; Oloruntoba Adekeye, Adeshina; Peter Olatunji, Babawale; Olakunle Ishola, Azeez; Michael Ogundele, Olalekan
In this study we evaluated the time dependence in cadmium-nicotine interaction and its effect on motor function, anxiety linked behavioural changes, serum electrolytes, and weight after acute and chronic treatment in adult male mice. Animals were separated randomly into four groups of n = 6 animals each. Treatment was done with nicotine, cadmium, or nicotine-cadmium for 21 days. A fourth group received normal saline for the same duration (control). Average weight was determined at 7-day interval for the acute (D1-D7) and chronic (D7-D21) treatment phases. Similarly, the behavioural tests for exploratory motor function (open field test) and anxiety were evaluated. Serum electrolytes were measured after the chronic phase. Nicotine, cadmium, and nicotine-cadmium treatments caused no significant change in body weight after the acute phase while cadmium-nicotine and cadmium caused a decline in weight after the chronic phase. This suggests the role of cadmium in the weight loss observed in tobacco smoke users. Both nicotine and cadmium raised serum Ca2+ concentration and had no significant effect on K+ ion when compared with the control. In addition, nicotine-cadmium treatment increased bioaccumulation of Cd2+ in the serum which corresponded to a decrease in body weight, motor function, and an increase in anxiety. PMID:26317007
Magano, Sara; Marrana, Francisco; Andrade, José P.
Abstract The model of accelerated senescence with the prolonged administration of d-galactose is used in anti-aging studies because it mimics several aging-associated alterations such as increase of oxidative stress and decline of cognition. However, there is no standardized protocol for this aging model, and recently some reports have questioned its effectiveness. To clarify this issue, we used a model of high-dose d-galactose on 1-month-old male Wistar rats and studied the hippocampus, one of the most affected brain regions. In one group (n = 10), d-galactose was daily administered intraperitoneally (300 mg/kg) during 8 weeks whereas age-matched controls (n = 10) were injected intraperitoneally with saline. A third group (n = 10) was treated with the same dose of d-galactose and with oral epigallocatechin-3-gallate (EGCG) (2 grams/L), a green tea catechin with anti-oxidant and neuroprotective properties. After treatments, animals were submitted to open-field, elevated plus-maze and Morris water maze tests, and neurogenesis in the dentate gyrus subgranular layer was quantified. There were no significant alterations when the three groups were compared in the number of doublecortin- and Ki-67–immunoreactive cells, and also on anxiety levels, spatial learning, and memory. Therefore, d-galactose was not effective in the induction of accelerated aging, and EGCG administered to d-galactose–treated animals did not improve behavior and had no effects on neurogenesis. We conclude that daily 300 mg/kg of d-galactose administered intraperitoneally may not be a suitable model for inducing age-related neurobehavioral alterations in young male Wistar rats. More studies are necessary to obtain a reliable and reproducible model of accelerated senescence in rodents using d-galactose. PMID:25936362
Cardoso, Armando; Magano, Sara; Marrana, Francisco; Andrade, José P
The model of accelerated senescence with the prolonged administration of d-galactose is used in anti-aging studies because it mimics several aging-associated alterations such as increase of oxidative stress and decline of cognition. However, there is no standardized protocol for this aging model, and recently some reports have questioned its effectiveness. To clarify this issue, we used a model of high-dose d-galactose on 1-month-old male Wistar rats and studied the hippocampus, one of the most affected brain regions. In one group (n = 10), d-galactose was daily administered intraperitoneally (300 mg/kg) during 8 weeks whereas age-matched controls (n = 10) were injected intraperitoneally with saline. A third group (n = 10) was treated with the same dose of d-galactose and with oral epigallocatechin-3-gallate (EGCG) (2 grams/L), a green tea catechin with anti-oxidant and neuroprotective properties. After treatments, animals were submitted to open-field, elevated plus-maze and Morris water maze tests, and neurogenesis in the dentate gyrus subgranular layer was quantified. There were no significant alterations when the three groups were compared in the number of doublecortin- and Ki-67-immunoreactive cells, and also on anxiety levels, spatial learning, and memory. Therefore, d-galactose was not effective in the induction of accelerated aging, and EGCG administered to d-galactose-treated animals did not improve behavior and had no effects on neurogenesis. We conclude that daily 300 mg/kg of d-galactose administered intraperitoneally may not be a suitable model for inducing age-related neurobehavioral alterations in young male Wistar rats. More studies are necessary to obtain a reliable and reproducible model of accelerated senescence in rodents using d-galactose.
Llorens-Martín, Maria; Blazquez-Llorca, Lidia; Benavides-Piccione, Ruth; Rabano, Alberto; Hernandez, Felix; Avila, Jesus; DeFelipe, Javier
A progressive loss of episodic memory is a well-known clinical symptom that characterizes Alzheimer's disease (AD). The beginning of this loss of memory has been associated with the very early, pathological accumulation of tau and neuronal degeneration observed in the entorhinal cortex (EC). Tau-related pathology is thought to then spread progressively to the hippocampal formation and other brain areas as the disease progresses. The major cortical afferent source of the hippocampus and dentate gyrus is the EC through the perforant pathway. At least two main circuits participate in the connection between EC and the hippocampus; one originating in layer II and the other in layer III of the EC giving rise to the classical trisynaptic (ECII → dentate gyrus → CA3 → CA1) and monosynaptic (ECIII → CA1) circuits. Thus, the study of the early pathological changes in these circuits is of great interest. In this review, we will discuss mainly the alterations of the granule cell neurons of the dentate gyrus and the atrophy of CA1 pyramidal neurons that occur in AD in relation to the possible differential alterations of these two main circuits.
Llorens-Martín, Maria; Blazquez-Llorca, Lidia; Benavides-Piccione, Ruth; Rabano, Alberto; Hernandez, Felix; Avila, Jesus; DeFelipe, Javier
A progressive loss of episodic memory is a well-known clinical symptom that characterizes Alzheimer’s disease (AD). The beginning of this loss of memory has been associated with the very early, pathological accumulation of tau and neuronal degeneration observed in the entorhinal cortex (EC). Tau-related pathology is thought to then spread progressively to the hippocampal formation and other brain areas as the disease progresses. The major cortical afferent source of the hippocampus and dentate gyrus is the EC through the perforant pathway. At least two main circuits participate in the connection between EC and the hippocampus; one originating in layer II and the other in layer III of the EC giving rise to the classical trisynaptic (ECII → dentate gyrus → CA3 → CA1) and monosynaptic (ECIII → CA1) circuits. Thus, the study of the early pathological changes in these circuits is of great interest. In this review, we will discuss mainly the alterations of the granule cell neurons of the dentate gyrus and the atrophy of CA1 pyramidal neurons that occur in AD in relation to the possible differential alterations of these two main circuits. PMID:24904307
Budzynska, Barbara; Boguszewska-Czubara, Anna; Kruk-Slomka, Marta; Skalicka-Wozniak, Krystyna; Michalak, Agnieszka; Musik, Irena; Biala, Grazyna; Glowniak, Kazimierz
The purpose of the reported experiments was to examine the effects of imperatorin [9-[(3-methylbut-2-en-1-yl)oxy]-7H-furo[3,2-g]chromen-7-one] on anxiety and memory-related responses induced by nicotine in mice and their relation to the level of nicotine-induced oxidative stress in brain as well as in the hippocampus and the prefrontal cortex. Male Swiss mice were tested for anxiety in the elevated plus maze test (EPM), and for cognition using passive avoidance (PA) procedures. Imperatorin, purified by high-speed counter-current chromatography from methanol extract of fruits of Angelica officinalis, acutely administered at the doses of 10 and 20mg/kg impaired the anxiogenic effect of nicotine (0.1mg/kg, s.c.). Furthermore, acute injections of subthreshold dose of imperatorin (1mg/kg, i.p.) improved processes of memory acquisition when co-administered with nicotine used at non-active dose of 0.05 mg/kg, s.c. Additionally, repeated administration of imperatorin (1mg/kg, i.p., twice daily, for 6 days) improved different stages of memory processes (both acquisition and consolidation) when injected in combination with non-active dose of nicotine (0.05 mg/kg, s.c.) in the PA task. Oxidative stress was assessed by determination of antioxidant enzymes (glutathione peroxidases (GPx), superoxide dismutase (SOD), glutathione reductase (GR)) activities as well as of malondialdehyde (MDA) concentration in the whole brain, the hippocampus and the prefrontal cortex after repeated administration of imperatorin (1mg/kg, 6 days) and single nicotine injection (0.05 mg/kgs.c.) on the seventh day. The results of our research suggest strong behavioural interaction between imperatorin and nicotine at the level of anxiety- and cognitive-like processes. Furthermore, imperatorin inhibited nicotine-induced changes in examined indicators of oxidative stress, especially in the hippocampus and the cortex.
Zoladz, Phillip R; Dailey, Alison M; Nagle, Hannah E; Fiely, Miranda K; Mosley, Brianne E; Brown, Callie M; Duffy, Tessa J; Scharf, Amanda R; Earley, McKenna B; Rorabaugh, Boyd R
FK506 binding protein 51 (FKBP5) is a co-chaperone of heat shock protein 90 and significantly influences glucocorticoid receptor sensitivity. Single nucleotide polymorphisms (SNPs) in the FKBP5 gene are associated with altered hypothalamus-pituitary-adrenal (HPA) axis function, changes in the structure and function of several cognitive brain areas, and increased susceptibility to post-traumatic stress disorder, major depression, bipolar disorder and suicidal events. The mechanisms underlying these associations are largely unknown, but it has been speculated that the influence of these SNPs on emotional memory systems may play a role. In the present study, 112 participants were exposed to the socially evaluated cold pressor test (stress) or control (no stress) conditions immediately prior to learning a list of 42 words. Participant memory was assessed immediately after learning (free recall) and 24 h later (free recall and recognition). Participants provided a saliva sample that enabled the genotyping of three FKBP5 polymorphisms: rs1360780, rs3800373 and rs9296158. Results showed that stress impaired immediate recall in risk allele carriers. More importantly, stress enhanced long-term recall and recognition memory in non-carriers of the risk alleles, effects that were completely absent in risk allele carriers. Follow-up analyses revealed that memory performance was correlated with salivary cortisol levels in non-carriers, but not in carriers. These findings suggest that FKBP5 risk allele carriers may possess a sensitized stress response system, perhaps specifically for stress-induced changes in corticosteroid levels, which might aid our understanding of how SNPs in the FKBP5 gene confer increased risk for stress-related psychological disorders and their related phenotypes.
Mayes, Susan Dickerson; Calhoun, Susan L.; Chase, Gary A.; Mink, Danielle M.; Stagg, Ryan E.
Objective: Wechsler Intelligence Scale for Children Freedom-from-Distractibility/Working Memory Index (FDI/WMI), Processing Speed Index (PSI), and Gordon Diagnostic System (GDS) scores in ADHD children were examined as a function of subtype and coexisting anxiety, depression, and oppositional-defiant disorder. Method: Participants were 587…
Albrecht, David; Lomoio, Selene; Haydon, Philip G.; Moss, Stephen J.; Tesco, Giuseppina
Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) is a monomeric clathrin adaptor that has been shown to regulate the trafficking of the Beta-site APP-cleaving enzyme (BACE1), which is required for production of the Alzheimer’s disease (AD)-associated amyloid βpeptide. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that depletion of GGA3 results in increased BACE1 levels and activity owing to impaired lysosomal trafficking and degradation. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. We report here that GGA3 deletion results in novelty-induced hyperactivity and decreased anxiety-like behaviors. Given the pivotal role of GABAergic transmission in the regulation of anxiety-like behaviors, we performed electrophysiological recordings in hippocampal slices and found increased phasic and decreased tonic inhibition in the dentate gyrus granule cells (DGGC). Moreover, we found that the number of inhibitory synapses is increased in the dentate gyrus of GGA3 null mice in further support of the electrophysiological data. Thus, the increased GABAergic transmission is a leading candidate mechanism underlying the reduced anxiety-like behaviors observed in GGA3 null mice. All together these findings suggest that GGA3 plays a key role in GABAergic transmission. Since BACE1 levels are elevated in the brain of GGA3 null mice, it is possible that at least some of these phenotypes are a consequence of increased processing of BACE1 substrates. PMID:27192432
Zhang, Wenping; Tian, Fengjie; Zheng, Jinping; Li, Senlin; Qiang, Mei
Background Recently, an increasing number of human and animal studies have reported that exposure to benzo(a)pyrene (BaP) induces neurological abnormalities and is also associated with adverse effects, such as tumor formation, immunosuppression, teratogenicity, and hormonal disorders. However, the exact mechanisms underlying BaP-induced impairment of neurological function remain unclear. The aim of this study was to examine the regulating mechanisms underlying the impact of chronic BaP exposure on neurobehavioral performance. Methods C57BL mice received either BaP in different doses (1.0, 2.5, 6.25 mg/kg) or olive oil twice a week for 90 days. Memory and emotional behaviors were evaluated using Y-maze and open-field tests, respectively. Furthermore, levels of mRNA expression were measured by using qPCR, and DNA methylation of NMDA receptor 2B subunit (NR2B) was examined using bisulfate pyrosequencing in the prefrontal cortex and hippocampus. Results Compared to controls, mice that received BaP (2.5, 6.25 mg/kg) showed deficits in short-term memory and an anxiety-like behavior. These behavioral alterations were associated with a down-regulation of the NR2B gene and a concomitant increase in the level of DNA methylation in the NR2B promoter in the two brain regions. Conclusions Chronic BaP exposure induces an increase in DNA methylation in the NR2B gene promoter and down-regulates NR2B expression, which may contribute to its neurotoxic effects on behavioral performance. The results suggest that NR2B vulnerability represents a target for environmental toxicants in the brain. PMID:26901155
Patki, Gaurav; Solanki, Naimesh; Atrooz, Fatin; Ansari, Amber; Allam, Farida; Jannise, Brittany; Maturi, Jaganmohan; Salim, Samina
Social defeat (SD) induced stress causes physiological and behavioral deficits in rodents, including depression and anxiety-like behaviors, as well as memory impairment. Anxiolytic and mood elevating effects of physical exercise are also known. However, rescue effect of physical exercise in social defeat-induced anxiety, depression or memory impairment has not been addressed. The role of epigenetic mechanisms that potentially contribute to these rescue or protective effects is also not known. The present study investigated the effect of moderate treadmill exercise on anxiety-like behavior and memory function in rats subjected to SD using a modified version of the resident-intruder model for social stress (defeat). Changes in histone acetylation and histone-modifying enzymes were examined in hippocampus, amygdala and frontal cortex which are considered critical for anxiety, depression and cognition. Sprague Dawley rats were randomly assigned in four groups; control, exercised, social defeat, social defeat and exercise. At the end of the SD or control exposure lasting 30 min daily for 7 days, one group of SD rats was subjected to treadmill exercise for 2 weeks, whereas the other SD group was handled without exercise. Anxiety-like behavior tests and radial arm water maze test suggested that moderate treadmill exercise rescued social defeat induced anxiety-like behavior and memory impairment. Moreover, exercise normalized SD-induced increase in oxidative stress, most likely by adjusting antioxidant response. Our data suggests involvement of epigenetic mechanisms including histone acetylation of H3 and modulation of methyl-CpG-binding in the hippocampus that might contribute to the rescue effects of exercise in SD-induced behavioral deficits in rats.
Puschban, Zoe; Sah, Anupam; Grutsch, Isabella; Singewald, Nicolas; Dechant, Georg
The presence of the p75 neurotrophin receptor (p75NTR) in adult basal forebrain cholinergic neurons, precursor cells in the subventricular cell layer and the subgranular cell layer of the hippocampus has been linked to alterations in learning as well as anxiety- and depression- related behaviors. In contrast to previous studies performed in a p75NTRexon III−/− model still expressing the short isoform of the p75NTR, we focused on locomotor and anxiety–associated behavior in p75NTRexon IV−/− mice lacking both p75NTR isoforms. Comparing p75NTRexon IV−/− and wildtype mice for both male and female animals showed an anxiolytic-like behavior as evidenced by increased central activities in the open field paradigm and flex field activity system as well as higher numbers of open arm entries in the elevated plus maze test in female p75NTR knockout mice. Morphometrical analyses of dorsal and ventral hippocampus revealed a reduction of width of the dentate gyrus and the granular cell layer in the dorsal but not ventral hippocampus in male and female p75NTRexon IV−/− mice. We conclude that germ-line deletion of p75NTR seems to differentially affect morphometry of dorsal and ventral dentate gyrus and that p75NTR may play a role in anxiety-like behavior, specifically in female mice. PMID:27313517
Scott, Julia A.; Goodrich-Hunsaker, Naomi; Kalish, Kristopher; Lee, Aaron; Hunsaker, Michael R.; Schumann, Cynthia M.; Carmichael, Owen T.; Simon, Tony J.
Background Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an elevated risk for schizophrenia, which increases with history of childhood anxiety. Altered hippocampal morphology is a common neuroanatomical feature of 22q11.2DS and idiopathic schizophrenia. Relating hippocampal structure in children with 22q11.2DS to anxiety and impaired cognitive ability could lead to hippocampus-based characterization of psychosis-proneness in this at-risk population. Methods We measured hippocampal volume using a semiautomated approach on MRIs collected from typically developing children and children with 22q11.2DS. We then analyzed hippocampal morphology with Localized Components Analysis. We tested the modulating roles of diagnostic group, hippocampal volume, sex and age on local hippocampal shape components. Lastly, volume and shape components were tested as covariates of IQ and anxiety. Results We included 48 typically developing children and 69 children with 22q11.2DS in our study. Hippocampal volume was reduced bilaterally in children with 22q11.2DS, and these children showed greater variation in the shape of the anterior hippocampus than typically developing children. Children with 22q11.2DS had greater inward deformation of the anterior hippocampus than typically developing children. Greater inward deformation of the anterior hippocampus was associated with greater severity of anxiety, specifically fear of physical injury, within the 22q11.2DS group. Limitations Shape alterations are not specific to hippocampal subfields. Conclusion Alterations in the structure of the anterior hippocampus likely affect function and may impact limbic circuitry. We suggest these alterations potentially contribute to anxiety symptoms in individuals with 22q11.2DS through modulatory pathways. Altered hippocampal morphology may be uniquely linked to anxiety risk factors for schizophrenia, which could be a powerful neuroanatomical marker of schizophrenia risk and hence protection
Dale, William; Hemmerich, Joshua; Meltzer, David
The Memorial Anxiety Scale for Prostate Cancer (MAX-PC) has been validated for assessing men with prostate cancer for cancer-specific anxiety. It was originally validated in a predominantly white population. The MAX-PC Prostate Cancer Anxiety Subscale (MAX-PC-PCAS) may be relevant for measuring cancer-specific anxiety in undiagnosed men at risk for prostate cancer. We assess the validity of the MAX-PC-PCAS at the time of prostate biopsy (n = 178). Questions assessed socio-demographic information, health status, patient-estimated risk of cancer, the Hospital Anxiety and Depression Scale--Anxiety Subscale (HADS-A), and the MAX-PC-PCAS. The patients' most recent PSA was recorded. Cronbach's alpha, inter-item correlations, and Pearson correlations with both the HADS-A and clinical variables were compared with the original validation sample. Our sample was younger (63.1 vs 71.1 years), had a larger fraction of African-Americans (43 vs 10%), and had higher PSAs. Cronbach's alpha was equivalent (0.91 vs 0.90), median inter-item correlation was equivalent (0.63 vs 0.61), and Pearson correlation with HADS-A was higher (0.71 vs 0.57). Anxiety levels were not correlated with PSA levels, and there were minor differences in the validation findings by race. The validity of the MAX-PC-PCAS extends to men without cancer undergoing biopsy and to African-Americans.
Bhattacharya, Subhrajit; Kimble, Whitney; Buabeid, Manal; Bhattacharya, Dwipayan; Bloemer, Jenna; Alhowail, Ahmad; Reed, Miranda; Dhanasekaran, Muralikrishnan; Escobar, Martha; Suppiramaniam, Vishnu
Retrieval of a memory appears to render it unstable until the memory is once again re-stabilized or reconsolidated. Although the occurrence and consequences of reconsolidation have received much attention in recent years, the specific mechanisms that underlie the process of reconsolidation have not been fully described. Here, we present the first electrophysiological model of the synaptic plasticity changes underlying the different stages of reconsolidation of a conditioned fear memory. In this model, retrieval of a fear memory results in immediate but transient alterations in synaptic plasticity, mediated by modified expression of the glutamate receptor subunits GluA1 and GluA2 in the hippocampus of rodents. Retrieval of a memory results in an immediate impairment in LTP, which is enhanced 6h following memory retrieval. Conversely, memory retrieval results in an immediate enhancement of LTD, which decreases with time. These changes in plasticity are accompanied by decreased expression of GluA2 receptor subunits. Recovery of LTP and LTD correlates with progressive overexpression of GluA2 receptor subunits. The contribution of the GluA2 receptor was confirmed by interfering with receptor expression at the postsynaptic sites. Blocking GluA2 endocytosis restored LTP and attenuated LTD during the initial portion of the reconsolidation period. These findings suggest that altered GluA2 receptor expression is one of the mechanisms that controls different forms of synaptic plasticity during reconsolidation.
Pellegrino, Rosa Maria; Boda, Enrica; Montarolo, Francesca; Boero, Martina; Mezzanotte, Mariarosa; Saglio, Giuseppe; Buffo, Annalisa; Roetto, Antonella
The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc response. Moreover, Tfr2-KO mice presented a selective overactivation of neurons in the limbic circuit and the emergence of an anxious-like behaviour. Furthermore, microglial cells showed a particular sensitivity to iron perturbation. We conclude that Tfr2 is a key regulator of brain iron homeostasis and propose a role for Tfr2 alpha in the regulation of anxiety circuits. PMID:27477597
Prager, Eric M.; Figueiredo, Taiza H.; Long, Robert P.; Aroniadou-Anderjaska, Vassiliki; Apland, James P.; Braga, Maria F.M.
Without timely pharmacological treatment, nerve agent exposure can cause a large number of casualties, as occurred in the recent sarin attack in Syria. Nerve agent-induced seizures are initiated due to inhibition of acetylcholinesterase, but they become quickly refractory to muscarinic antagonists, and their suppression by benzodiazepines can be only temporary. Therefore, novel treatments are necessary to stop seizures and prevent brain damage and the resulting long-term behavioral deficits. We have previously shown that LY293558, a GluK1/AMPA receptor antagonist, is a very effective anticonvulsant and neuroprotectant against nerve agent exposure. In the present study, we examined whether the protection against nerve agent-induced seizures and neuropathology conferred by LY293558 translates into protection against pathophysiological alterations in the basolateral amygdala (BLA) and the development of anxiety, which is the most prevalent behavioral deficit resulting from exposure. LY293558 (15 mg/kg) was administered to rats along with atropine and the oxime HI-6, at 20 min after exposure to soman (1.2 x LD50). At 24 h, 7 days, and 30 days after exposure, soman-exposed rats that did not receive LY293558 had reduced but prolonged evoked field potentials in the BLA, as well as increased paired-pulse ratio, suggesting neuronal damage and impaired synaptic inhibition. In contrast, soman-exposed rats that received LY293558 did not differ from controls in these parameters. Similarly, long-term potentiation of synaptic transmission was impaired at 7 days after exposure in the soman-exposed rats that did not receive anticonvulsant treatment, while this impairment was not present in the LY293558-treated rats. Anxiety-like behavior assessed by the open field and acoustic startle response tests was increased in the soman-exposed rats at 30 and 90 days after exposure, while soman-exposed rats treated with LY293558 did not differ from controls. Along with our previous findings
Southcombe, J. H.; Mounce, G.; McGee, K.; Elghajiji, A.; Brosens, J.; Quenby, S.; Child, T.; Granne, I.
When trying to conceive 1% of couples have recurrent miscarriages, defined as three or more consecutive pregnancy losses. This is not accounted for by the known incidence of chromosomal aneuploidy in miscarriage, and it has been suggested that there is an immunological aetiology. The endometrial mucosa is populated by a variety of immune cells which in addition to providing host pathogen immunity must facilitate pregnancy. Here we characterise the endometrial CD8-T cell population during the embryonic window of implantation and find that the majority of cells are tissue resident memory T cells with high levels of CD69 and CD103 expression, proteins that prevent cells egress. We demonstrate that unexplained recurrent miscarriage is associated with significantly decreased expression of the T-cell co-receptor CD8 and tissue residency marker CD69. These cells differ from those found in control women, with less expression of CD127 indicating a lack of homeostatic cell control through IL-7 signalling. Nevertheless this population is resident in the endometrium of women who have RM, more than three months after the last miscarriage, indicating that the memory CD8-T cell population is altered in RM patients. This is the first evidence of a differing pre-pregnancy phenotype in endometrial immune cells in RM. PMID:28112260
Southcombe, J H; Mounce, G; McGee, K; Elghajiji, A; Brosens, J; Quenby, S; Child, T; Granne, I
When trying to conceive 1% of couples have recurrent miscarriages, defined as three or more consecutive pregnancy losses. This is not accounted for by the known incidence of chromosomal aneuploidy in miscarriage, and it has been suggested that there is an immunological aetiology. The endometrial mucosa is populated by a variety of immune cells which in addition to providing host pathogen immunity must facilitate pregnancy. Here we characterise the endometrial CD8-T cell population during the embryonic window of implantation and find that the majority of cells are tissue resident memory T cells with high levels of CD69 and CD103 expression, proteins that prevent cells egress. We demonstrate that unexplained recurrent miscarriage is associated with significantly decreased expression of the T-cell co-receptor CD8 and tissue residency marker CD69. These cells differ from those found in control women, with less expression of CD127 indicating a lack of homeostatic cell control through IL-7 signalling. Nevertheless this population is resident in the endometrium of women who have RM, more than three months after the last miscarriage, indicating that the memory CD8-T cell population is altered in RM patients. This is the first evidence of a differing pre-pregnancy phenotype in endometrial immune cells in RM.
He, Hao; Sui, Jing; Yu, Qingbao; Turner, Jessica A; Ho, Beng-Choon; Sponheim, Scott R; Manoach, Dara S; Clark, Vincent P; Calhoun, Vince D
Impairment of working memory (WM) performance in schizophrenia patients (SZ) is well-established. Compared to healthy controls (HC), SZ patients show aberrant blood oxygen level dependent (BOLD) activations and disrupted functional connectivity during WM performance. In this study, we examined the small-world network metrics computed from functional magnetic resonance imaging (fMRI) data collected as 35 HC and 35 SZ performed a Sternberg Item Recognition Paradigm (SIRP) at three WM load levels. Functional connectivity networks were built by calculating the partial correlation on preprocessed time courses of BOLD signal between task-related brain regions of interest (ROIs) defined by group independent component analysis (ICA). The networks were then thresholded within the small-world regime, resulting in undirected binarized small-world networks at different working memory loads. Our results showed: 1) at the medium WM load level, the networks in SZ showed a lower clustering coefficient and less local efficiency compared with HC; 2) in SZ, most network measures altered significantly as the WM load level increased from low to medium and from medium to high, while the network metrics were relatively stable in HC at different WM loads; and 3) the altered structure at medium WM load in SZ was related to their performance during the task, with longer reaction time related to lower clustering coefficient and lower local efficiency. These findings suggest brain connectivity in patients with SZ was more diffuse and less strongly linked locally in functional network at intermediate level of WM when compared to HC. SZ show distinctly inefficient and variable network structures in response to WM load increase, comparing to stable highly clustered network topologies in HC.
Eden, Annuschka Salima; Zwitserlood, Pienie; Keuper, Katharina; Junghöfer, Markus; Laeger, Inga; Zwanzger, Peter; Dobel, Christian
The well-established memory bias for arousing-negative stimuli seems to be enhanced in high trait-anxious persons and persons suffering from anxiety disorders. We monitored the emergence and development of such a bias during and after learning, in high and low trait anxious participants. A word-learning paradigm was applied, consisting of spoken pseudowords paired either with arousing-negative or neutral pictures. Learning performance during training evidenced a short-lived advantage for arousing-negative associated words, which was not present at the end of training. Cued recall and valence ratings revealed a memory bias for pseudowords that had been paired with arousing-negative pictures, immediately after learning and two weeks later. This held even for items that were not explicitly remembered. High anxious individuals evidenced a stronger memory bias in the cued-recall test, and their ratings were also more negative overall compared to low anxious persons. Both effects were evident, even when explicit recall was controlled for. Regarding the memory bias in anxiety prone persons, explicit memory seems to play a more crucial role than implicit memory. The study stresses the need for several time points of bias measurement during the course of learning and retrieval, as well as the employment of different measures for learning success.
Papaleo, Francesco; Silverman, Jill L.; Aney, Jordan; Tian, Qingjun; Barkan, Charlotte L.; Chadman, Kathryn K.; Crawley, Jacqueline N.
BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher…
Weiss, Alison R.; Nadji, Ryhan; Bachevalier, Jocelyne
The lateral prefrontal cortex is known for its contribution to working memory (WM) processes in both humans and animals. Yet, recent studies indicate that the prefrontal cortex is part of a broader network of interconnected brain areas involved in WM. Within the medial temporal lobe (MTL) structures, the perirhinal cortex, which has extensive direct interactions with the lateral and orbital prefrontal cortex, is required to form active/flexible representations of familiar objects. However, its participation in WM processes has not be fully explored. The goal of this study was to assess the effects of neonatal perirhinal lesions on maintenance and monitoring WM processes. As adults, animals with neonatal perirhinal lesions and their matched controls were tested in three object-based (non-spatial) WM tasks that tapped different WM processing domains, e.g., maintenance only (Session-unique Delayed-nonmatching-to Sample, SU-DNMS), and maintenance and monitoring (Object-Self-Order, OBJ-SO; Serial Order Memory Task, SOMT). Neonatal perirhinal lesions transiently impaired the acquisition of SU-DNMS at a short (5 s) delay, but not when re-tested with a longer delay (30 s). The same neonatal lesions severely impacted acquisition of OBJ-SO task, and the impairment was characterized by a sharp increase in perseverative errors. By contrast, neonatal perirhinal lesion spared the ability to monitor the temporal order of items in WM as measured by the SOMT. Contrary to the SU-DNMS and OBJ-SO, which re-use the same stimuli across trials and thus produce proactive interference, the SOMT uses novel objects on each trial and is devoid of interference. Therefore, the impairment of monkeys with neonatal perirhinal lesions on SU-DNMS and OBJ-SO tasks is likely to be caused by an inability to solve working memory tasks with high proactive interference. The sparing of performance on the SOMT demonstrates that neonatal perirhinal lesions do not alter working memory processes per se but
Weiss, Alison R; Nadji, Ryhan; Bachevalier, Jocelyne
The lateral prefrontal cortex is known for its contribution to working memory (WM) processes in both humans and animals. Yet, recent studies indicate that the prefrontal cortex is part of a broader network of interconnected brain areas involved in WM. Within the medial temporal lobe (MTL) structures, the perirhinal cortex, which has extensive direct interactions with the lateral and orbital prefrontal cortex, is required to form active/flexible representations of familiar objects. However, its participation in WM processes has not be fully explored. The goal of this study was to assess the effects of neonatal perirhinal lesions on maintenance and monitoring WM processes. As adults, animals with neonatal perirhinal lesions and their matched controls were tested in three object-based (non-spatial) WM tasks that tapped different WM processing domains, e.g., maintenance only (Session-unique Delayed-nonmatching-to Sample, SU-DNMS), and maintenance and monitoring (Object-Self-Order, OBJ-SO; Serial Order Memory Task, SOMT). Neonatal perirhinal lesions transiently impaired the acquisition of SU-DNMS at a short (5 s) delay, but not when re-tested with a longer delay (30 s). The same neonatal lesions severely impacted acquisition of OBJ-SO task, and the impairment was characterized by a sharp increase in perseverative errors. By contrast, neonatal perirhinal lesion spared the ability to monitor the temporal order of items in WM as measured by the SOMT. Contrary to the SU-DNMS and OBJ-SO, which re-use the same stimuli across trials and thus produce proactive interference, the SOMT uses novel objects on each trial and is devoid of interference. Therefore, the impairment of monkeys with neonatal perirhinal lesions on SU-DNMS and OBJ-SO tasks is likely to be caused by an inability to solve working memory tasks with high proactive interference. The sparing of performance on the SOMT demonstrates that neonatal perirhinal lesions do not alter working memory processes per se but
Kawaguchi, Maiko; Irie, Kaoru; Morohoshi, Kaori; Watanabe, Gen; Taya, Kazuyoshi; Morita, Masatoshi; Kondo, Yasuhiko; Imai, Hideki; Himi, Toshiyuki
Isobutyl-paraben (IBP), one of the most widely used preservatives, exhibits estrogenic activity. In this study, we analyzed the effects of maternal IBP treatment on the emotional behavior and learning performance in mature offspring. Pregnant female Sprague-Dawley rats were treated with IBP via a subcutaneous Silastic capsule. Consequently, the offspring were exposed to IBP during gestation through the placentae, and before weaning through the milk. Male and female offspring were tested for emotional behavior in an open field and in an elevated plus maze at five and six weeks old, respectively. IBP-exposed male (but not female) rats spent less time in the open arms of the elevated plus maze. At 11 weeks old, all females were gonadectomized and treated chronically with 17beta-estradiol or cholesterol by Silastic capsules; all males were kept intact. They were tested for learning performance in a passive avoidance test and a Morris water maze. IBP exposure impaired the performance of males in the passive avoidance test. These findings suggest that male rats are more affected by early exposure to IBP than female rats. IBP affects their adult behavior including anxiety and learning abilities.
Giménez, Mónica; Pujol, Jesús; Ortiz, Hector; Soriano-Mas, Carles; López-Solà, Marina; Farré, Magí; Deus, Joan; Merlo-Pich, Emilio; Martín-Santos, Rocio
Although the fear of being scrutinized by others in a social context is a key symptom in social anxiety disorder (SAD), the neural processes underlying the perception of scrutiny have not previously been studied by functional magnetic resonance imaging (fMRI). We used fMRI to map brain activation during a perception-of-scrutiny task in 20 SAD patients and 20 controls. A multi-dimensional analytic approach was used. Scrutiny perception was mediated by activation of the medial frontal cortex, insula-operculum region and cerebellum, and the additional recruitment of visual areas and the thalamus in patients. Between-group comparison demonstrated significantly enhanced brain activation in patients in the primary visual cortex and cerebellum. Functional connectivity mapping demonstrated an abnormal connectivity between regions underlying general arousal and attention. SAD patients showed significantly greater task-induced functional connectivity in the thalamo-cortical and the fronto-striatal circuits. A statistically significant increase in task-induced functional connectivity between the anterior cingulate cortex and scrutiny-perception-related regions was observed in the SAD patients, suggesting the existence of enhanced behavior-inhibitory control. The presented data indicate that scrutiny perception in SAD enhances brain activity in arousal-attention systems, suggesting that fMRI may be a useful tool to explore such a behavioral dimension.
Loganathan, Sundareswaran; Rathinasamy, Sheeladevi
Background: Noise stress has different effects on memory and novelty and the link between them with an electroencephalogram (EEG) has not yet been reported. Objective: To find the effect of sub-acute noise stress on the memory and novelty along with EEG and neurotransmitter changes. Materials and Methods: Eight-arm maze (EAM) and Y-maze to analyze the memory and novelty by novel object test. Four groups of rats were used: Control, control treated with Scoparia dulcis extract, noise exposed, and noise exposed which received Scoparia extract. Results: The results showed no marked difference observed between control and control treated with Scoparia extract on EAM, Y-maze, novel object test, and EEG in both prefrontal and occipital region, however, noise stress exposed rats showed significant increase in the reference memory and working memory error in EAM and latency delay, triad errors in Y-maze, and prefrontal and occipital EEG frequency rate with the corresponding increase in plasma corticosterone and epinephrine, and significant reduction in the novelty test, and significant reduction in the novelty test, amplitude of prefrontal, occipital EEG, and acetylcholine. Conclusion: These noise stress induced changes in EAM, Y-maze, novel object test, and neurotransmitters were significantly prevented when treated with Scoparia extract and these changes may be due to the normalizing action of Scoparia extract on the brain, which altered due to noise stress. SUMMARY Noise stress exposure causes EEG, behavior, and neurotransmitter alteration in the frontoparietal and occipital regions mainly involved in planning and recognition memoryOnly the noise stress exposed animals showed the significant alteration in the EEG, behavior, and neurotransmittersHowever, these noise stress induced changes in EEG behavior and neurotransmitters were significantly prevented when treated with Scoparia extractThese changes may be due to the normalizing action of Scoparia dulcis (adoptogen) on
Pillay, Neville; Rimbach, Rebecca; Rymer, Tasmin
Dietary protein deficiency influences the behavioural phenotypes of mammals. We studied whether protein deficiency during gestation and/or post-weaning heightened anxiety, reduced memory recall and influenced competitive ability in the African striped mouse Rhabdomys dilectus chakae. Mice were subjected to five protein diet treatments, which they received continuously, or were raised on one diet to weaning and switched to an alternate diet post-weaning (Day 16): 1) HP-HP: high protein (24%); first letter pair indicates maternal diet and the second pair indicates offspring diet post-weaning; 2) BP-BP: baseline protein (19%); 3) LP-LP: low protein (10%); 4) HP-LP: switched from high to low protein diet; and 5) LP-HP: switched from low protein to high protein diet. From Day 70, when mice were sexually mature, 20 individuals (10 males, 10 females) per treatment were subjected to three successive experiments, in which we tested their anxiety responses in: 1) an open field arena (time spent in the centre of the open field); 2) novel object recognition (time spent exploring a novel object); and 3) social interactions (excluding BP-BP) in age-matched same-sex dyadic encounters (aggressive, amicable and avoidance behaviours). LP-LP and LP-HP treatment mice spent the least amount of time in the centre of the open field, did not demonstrate object preference compared to the other treatments, and were the most aggressive in dyadic encounters. Our study shows that the systemic effects of protein-deficient diets during early life shapes the behavioural phenotype in R. d. chakae, possibly through early organisation of neuro-biological pathways or competition among littermates.
Tse, Chi-Shing; Pu, Xiaoping
Despite being viewed as a better way to enhance learning than repeated study, it has not been clear whether repeated testing is equally effective for students with a wide range of cognitive abilities. The current study examined whether test-enhanced learning would be equally beneficial to participants with varied working-memory capacity (WMC) and trait test anxiety (TA). Chinese-English bilingual undergraduates in Hong Kong were recruited as participants. They acquired Swahili-English word pairs (half via repeated study and half via repeated testing) and performed a delayed cued-recall test for all pairs about one week after the acquisition phase. Their WMC and TA were estimated by Unsworth, Heitz, Schrock, and Engle's (2005) operation-span task and the Chinese version of Spielberger's (1980) Test Anxiety Inventory, respectively. We replicated the typical testing effect: Participants performed better for pairs in the repeated-testing condition than those in the repeated-study condition. Regression analyses showed that, (a) relative to other participants, those with lower WMC and higher TA made more intralist intrusion errors (i.e., recalling a wrong English translation to a Swahili word cue) during the acquisition phase, and (b) the testing effect was negatively correlated with TA for participants with lower WMC, but was not correlated with TA for participants with higher WMC. This demonstrates a boundary condition for the use of test-enhanced learning. Implications of these findings for theories of the testing effect (e.g., Pyc & Rawson's, 2010, mediator-effectiveness hypothesis) and their application in classroom settings are discussed.
Swanson, Thomas; Enos, Jennifer K.; Bailey, Aileen M.; Kolb, Bryan; Frost, Douglas O.
Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug treatment. Most antipsychotic drugs are potent antagonists or partial agonists of dopamine D2 receptors; atypical antipsychotic drugs also antagonize type 2A serotonin receptors. Dopamine and serotonin regulate many neurodevelopmental processes. Thus, early life antipsychotic drug treatment can, potentially, perturb these processes, causing long-term behavioral- and neurobiological impairments. Here, we treated adolescent, male rats with olanzapine on post-natal days 28–49. As adults, they exhibited impaired working memory, but normal spatial memory, as compared to vehicle-treated control rats. They also showed a deficit in extinction of fear conditioning. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, parietal cortex, nucleus accumbens core and dentate gyrus, adolescent olanzapine treatment altered the developmental dynamics and mature values of dendritic spine density in a region-specific manner. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, D1 binding was reduced and binding of GABAA receptors with open Cl− channels was increased. In medial prefrontal cortex, D2 binding was also increased. The persistence of these changes underscores the importance of improved understanding of the enduring sequelae of pediatric APD treatment as a basis for weighing the benefits and risks of adolescent antipsychotic drug therapy, especially prophylactic treatment in high risk, asymptomatic patients. The long-term changes in neurotransmitter receptor binding and neural circuitry induced by adolescent APD treatment may also cause enduring changes in behavioral- and neurobiological responses to
Fernández, Esteban R.; Olivera, Gabriela C.; Quebrada Palacio, Luz P.; González, Mariela N.; Hernandez-Vasquez, Yolanda; Sirena, Natalia María; Morán, María L.; Ledesma Patiño, Oscar S.; Postan, Miriam
Numerous abnormalities of the peripheral blood T cell compartment have been reported in human chronic Trypanosoma cruzi infection and related to prolonged antigenic stimulation by persisting parasites. Herein, we measured circulating lymphocytes of various phenotypes based on the differential expression of CD19, CD4, CD27, CD10, IgD, IgM, IgG and CD138 in a total of 48 T. cruzi-infected individuals and 24 healthy controls. Infected individuals had decreased frequencies of CD19+CD27+ cells, which positively correlated with the frequencies of CD4+CD27+ cells. The contraction of CD19+CD27+ cells was comprised of IgG+IgD-, IgM+IgD- and isotype switched IgM-IgD- memory B cells, CD19+CD10+CD27+ B cell precursors and terminally differentiated CD19+CD27+CD138+ plasma cells. Conversely, infected individuals had increased proportions of CD19+IgG+CD27-IgD- memory and CD19+IgM+CD27-IgD+ transitional/naïve B cells. These observations prompted us to assess soluble CD27, a molecule generated by the cleavage of membrane-bound CD27 and used to monitor systemic immune activation. Elevated levels of serum soluble CD27 were observed in infected individuals with Chagas cardiomyopathy, indicating its potentiality as an immunological marker for disease progression in endemic areas. In conclusion, our results demonstrate that chronic T. cruzi infection alters the distribution of various peripheral blood B cell subsets, probably related to the CD4+ T cell deregulation process provoked by the parasite in humans. PMID:25111833
DeVito, Loren M.; Balu, Darrick T.; Kanter, Benjamin R.; Lykken, Christine; Basu, Alo C.; Coyle, Joseph T.; Eichenbaum, Howard
There is substantial evidence implicating N-methyl-d-aspartate receptors (NMDARs) in memory and cognition. It has also been suggested that NMDAR hypofunction might underlie the cognitive deficits observed in schizophrenia since morphological changes, including alterations in the dendritic architecture of pyramidal neurons in the prefrontal cortex (PFC), have been reported in the schizophrenic brain post mortem. Here, we used a genetic model of NMDAR hypofunction, a serine racemase knockout (SR−/−) mouse in which the first coding exon of the mouse serine racemase gene has been deleted, to explore the role of d-serine in regulating cognitive functions as well as dendritic architecture. SR −/− mice exhibited a significantly disrupted representation of the order of events in distinct experiences as revealed by object recognition and odor sequence tests; however, SR −/− animals were unimpaired in the detection of novel objects and in spatial displacement, and showed intact relational memory in a test of transitive inference. In addition, SR −/− mice exhibited normal sociability and preference for social novelty. Neurons in the medial PFC of SR−/− mice displayed reductions in the complexity, total length, and spine density of apical dendrites. These findings demonstrate that d-serine is important for specific aspects of cognition, as well as in regulating dendritic morphology of pyramidal neurons in the mPFC. Moreover, they suggest that NMDAR hypofunction might, in part, be responsible for the cognitive deficits and synaptic changes associated with schizophrenia, and highlight this signaling pathway as a potential target for therapeutic intervention. PMID:21029376
Venero, César; Guadaño-Ferraz, Ana; Herrero, Ana Isabel; Nordström, Kristina; Manzano, Jimena; de Escobar, Gabriella Moreale; Bernal, Juan; Vennström, Björn
The transcriptional properties of unliganded thyroid hormone receptors are thought to cause the misdevelopment during hypothyroidism of several functions essential for adult life. To specifically determine the role of unliganded thyroid hormone receptor α1 (TRα1) in neuronal tissues, we introduced a mutation into the mouse TRα1 gene that lowers affinity to thyroid hormone (TH) 10-fold. The resulting heterozygous mice exhibit several distinct neurological abnormalities: extreme anxiety, reduced recognition memory, and locomotor dysfunction. The anxiety and memory deficiencies were relieved by treatment with high levels of TH in adulthood, an effect that correlated with a normalization of GABAergic inhibitory interneurons in the hippocampal CA1 region. In contrast, a post-natal TH treatment was necessary and sufficient for ameliorating the adult locomotor dysfunction. Here, the hormone treatment normalized the otherwise delayed cerebellar development. The data thus identify two novel and distinct functions of an unliganded TRα1 during development and adulthood, respectively. PMID:16131613
... it has to decide what is worth remembering. Memory is the process of storing and then remembering this information. There are different types of memory. Short-term memory stores information for a few ...
Sbihi, Zineb; Dossier, Antoine; Boutboul, David; Galicier, Lionel; Parizot, Christophe; Emarre, Amandine; Hoareau, Bénédicte; Dupin, Nicolas; Marcelin, Anne-Geneviève; Oudin, Anne; Fieschi, Claire; Agbalika, Félix; Autran, Brigitte; Oksenhendler, Eric; Carcelain, Guislaine
Human herpesvirus 8 (HHV-8) is the causative agent of Kaposi sarcoma (KS) and multicentric Castleman disease (MCD), a life-threatening, virally induced B-cell lymphoproliferative disorder. HHV-8 is a B-lymphotropic γ-herpesvirus closely related to the Epstein-Barr virus (EBV). Invariant natural killer T (iNKT) cells are innate-like T cells that play a role in antiviral immunity, specifically in controlling viral replication in EBV-infected B cells. Decline of iNKT cells is associated with age or HIV infection, both situations associated with HHV-8-related diseases. We analyzed iNKT cells in both blood (n = 26) and spleen (n = 9) samples from 32 patients with HHV-8 MCD and compared them with patients with KS (n = 24) and healthy donors (n = 29). We determined that both circulating and splenic iNKT cell frequencies were markedly decreased in patients with HHV-8 MCD and were undetectable in 6 of them. Moreover, iNKT cells from patients with HHV-8 MCD displayed a proliferative defect after stimulation with α-galactosylceramide. These iNKT cell alterations were associated with an imbalance in B-cell subsets, including a significant decrease in memory B cells, particularly of marginal zone (MZ) B cells. Coculture experiments revealed that the decrease in iNKT cells contributed to the alterations in the B-cell subset distribution. These observations contribute to a better understanding of the complex interactions between HHV-8 and immune cells that cause HHV-8-related MCD.
Sawyer, Nikki T; Papale, Ligia A; Eliason, Jessica; Neigh, Gretchen N; Escayg, Andrew
Stress is known to trigger seizures in patients with epilepsy, highlighting the physiological stress response as a possible therapeutic target for epilepsy treatment. Nevertheless, little is currently known about how a genetic predisposition to epilepsy interacts with the stress response to influence seizure outcome. To address this question, we examined the effect of acute stress on seizure outcome in mice with mutations in the voltage-gated sodium channel (VGSC) gene Scn8a. Scn8a mutants display spontaneous spike-wave discharges (SWDs) characteristic of absence epilepsy. We saw that the baseline frequency of SWDs in Scn8a mutants correlates closely with the diurnal activity of the hypothalamic-pituitary-adrenal (HPA) axis, with a peak in seizure activity occurring at around the same time as the peak in corticosterone (1700h–1900h). A 20-minute acute restraint stress administered in the morning increases the frequency of spontaneous SWDs immediately following the stressor. Seizure frequency then returns to baseline levels within three hours after stressor exposure, but the subsequent evening peak in seizure frequency is delayed and broadened, changes that persist into the next evening and are accompanied by long-lasting changes in HPA axis activity. Scn8a mutants also show increased anxiety-like behavior in mildly stressful situations. A 20-minute acute restraint stress can also increase the severity and duration of chemically induced seizures in Scn8a mutants, changes that differ from wild-type littermates. Overall, our data show that a voltage-gated sodium channel mutation can alter the behavioral response to stress and can interact with the stress response to alter seizure outcome. PMID:24138934
Guan, Zhuo; Buhl, Lauren K.; Quinn, William G.; Littleton, J. Troy
Genetic studies in "Drosophila" have revealed two separable long-term memory pathways defined as anesthesia-resistant memory (ARM) and long-lasting long-term memory (LLTM). ARM is disrupted in "radish" ("rsh") mutants, whereas LLTM requires CREB-dependent protein synthesis. Although the downstream effectors of ARM and LLTM are distinct, pathways…
Shiflett, M W; Gavin, M; Tran, T S
Semaphorins have an important role in synapse refinement in the mammalian nervous system. The class 3 semaphorin-3F (Sema3F) acting through neuropilin 2/plexin-A3 (Nrp2/PlexA3) holoreceptor complex signals in vivo to restrain apical dendritic spine morphogenesis of cortical pyramidal neurons and hippocampal neurons during postnatal development and mediates excitatory synaptic transmission. Semaphorin signaling has been implicated in the etiology of a number of neurodevelopmental disorders; however, the effects on behavior and mental function of dysregulated Sema3F-Nrp2 signaling have not been fully addressed. The present study is the first behavioral investigation of mice harboring a mutation of the nrp2 gene. Given that loss of Nrp2 signaling alters cortical and hippocampal synaptic organization, we investigated performance of nrp2-deficient mice on learning and sensorimotor function that are known to depend on cortical and hippocampal circuitry. When compared with age-matched controls, nrp2 null mice showed striking impairments in object recognition memory and preference for social novelty. In addition, nrp2−/− mice displayed impaired motor function in the rotarod test and in observations of grooming behavior. Exploration of novel olfactory sensory stimuli and nociception were unaffected by the loss of Nrp2. Overall, loss of Nrp2 may induce aberrant processing within hippocampal and corticostriatal networks that may contribute to neurodevelopmental disease mechanisms. PMID:25734514
Asth, Laila; Lobão-Soares, Bruno; André, Eunice; Soares, Vanessa de Paula; Gavioli, Elaine Cristina
The elevated T-maze (ETM) is an apparatus derived from the elevated plus-maze test, which is used to evaluate anxiety. Because anxiety is a biasing factor in models of memory, this study proposed the ETM as a task for the simultaneous assessment of memory and anxiety in mice. The ETM consists of one enclosed and two open arms. The procedure is based on the avoidance of open spaces learned during training session, in which mice were exposed to the enclosed arm as many times as needed to stay 300s. In the test session, memory is assessed by re-exposing the mouse to the enclosed arm and the latency to enter an open arm was recorded. The anxiolytic diazepam (DZP; 1 or 2mg/kg) and the amnestic biperiden (BPR; 0.5, 1 or 3mg/kg) were injected at three distinct times: pre-training, post-training, and pre-test. Pre-training administration of BPR 1 and DZP 2 increased the number of trials needed to reach the avoidance criterion, suggesting a passive avoidance learning impairment. However, BPR induced hyperlocomotion, which could bias the interpretation of any BPR-induced effects during the training session. Pre-training injection of BPR did not affect the spontaneous increase in the latency to enter an open arm between trials, while DZP reduced latencies in the first three trials suggesting anxiolysis. In the test session, pre-training injection of BPR 1 and DZP 2 reduced latencies to enter an open arm, indicating memory impairment. Post-training and pre-test injection of DZP or BPR did not affect memory. In conclusion, the proposed ETM task is practical for the detection of the anxiolytic and amnesic effects of drugs.
Fraga, Mabel Carneiro; de Moura, Egberto Gaspar; da Silva Lima, Natália; Lisboa, Patrícia C; de Oliveira, Elaine; Silva, Juliana Oliveira; Claudio-Neto, Sylvio; Filgueiras, Cláudio C; Abreu-Villaça, Yael; Manhães, Alex C
The most frequently used animal models of early weaning (EW) in rodents, maternal deprivation and pharmacological inhibition of lactation, present confounding factors, such as high stress or drug side effects, that can mask or interact with the effects of milk deprivation per se. Given these limitations, the development of new models of EW may provide useful information regarding the impact of a shortened period of breastfeeding on the endocrine and nervous systems, both during development and at adulthood. Using a model of EW in which lactating Wistar rat dams are wrapped with a bandage to block access to milk during the last three days of lactation, we have recently shown that the adult offspring presented higher body mass, hyperphagia, hyperleptinemia, leptin as well as insulin resistance, and higher adrenal catecholamine content at adulthood. Here, we used this EW model, which involves no pharmacological treatment or maternal separation, to analyze anxiety-like, novelty-seeking and memory/learning behavioral traits in the adult male offspring. To that end, animals were tested in the elevated plus maze, in the hole board arena and in the radial arm water maze. Except for an increased number of rearing events (a measure of vertical activity), no other behavioral differences were observed between EW and control animals. The contrasting behavioral results between the three EW models may be associated with differences in HPA axis function in the offspring at weaning, since it has been observed that bandaging does not affect corticosteronemia while maternal separation and pharmacological EW increase it.
Turner, Cortney A; Clinton, Sarah M; Thompson, Robert C; Watson, Stanley J; Akil, Huda
Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety- and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders.
Discusses current research (including that involving amnesiacs and snails) into the nature of the memory process, differentiating between and providing examples of "fact" memory and "skill" memory. Suggests that three brain parts (thalamus, fornix, mammilary body) are involved in the memory process. (JN)
Nelson, Jason M.; Lindstrom, Will; Foels, Patricia A.
Test anxiety and its correlates were examined with college students with and without specific reading disability (RD; n = 50 in each group). Results indicated that college students with RD reported higher test anxiety than did those without RD, and the magnitude of these differences was in the medium range on two test anxiety scales. Relative to…
Callaerts-Vegh, Zsuzsanna; Beckers, Tom; Ball, Simon M; Baeyens, Frank; Callaerts, Patrick F; Cryan, John F; Molnar, Elek; D'Hooge, Rudi
Metabotropic glutamate receptor 7 (mGluR7), a receptor with a distinct brain distribution and a putative role in anxiety, emotional responding, and spatial working memory, could be an interesting therapeutic target for fear and anxiety disorders. mGluR7-deficient (mGluR7-/-) mice showed essentially normal performance in tests for neuromotor and exploratory activity and passive avoidance learning but prominent anxiolytic behavior in two anxiety tests. They showed a delayed learning curve during the acquisition of the hidden-platform water maze, and three interspersed probe trials indicated that mGluR7-/- mice were slower to acquire spatial information. Working memory in the water maze task and the radial arm maze was impaired in mGluR7-/- mice compared with mGluR7+/+. mGluR7-/- mice also displayed a higher resistance to extinction of fear-elicited response suppression in a conditioned emotional response protocol. In a non-fear-based water maze protocol, mGluR7-/- mice displayed similar delayed extinction. These observed behavioral changes are probably not attributable to changes in AMPA or NMDA receptor function because expression levels of AMPA and NMDA receptors were unaltered. Extinction of conditioned fear is an active and context-dependent form of inhibitory learning and an experimental model for therapeutic fear reduction. It appears to depend on glutamatergic and higher-level brain functions similar to those involved in spatial working memory but functionally dissociated from those that mediate constitutional responses in anxiety tests.
Wu, Pei-Jung; Liu, Hsin-Yu; Huang, Tzyy-Nan; Hsueh, Yi-Ping
Inflammasomes are the protein assemblies that consist of inflammasome sensors, adaptor apoptosis-associated speck-like proteins containing a CARD (ASC) and inflammasome caspase. Inflammasomes sense multiple danger signals via various inflammasome sensors and consequently use caspase to trigger proteolytic processing and secretion of IL-1β cytokines. Recent studies have suggested that neurons use their own innate immune system to detect danger signals and regulate neuronal morphology. Here, we investigate whether inflammasomes, the critical components of innate immunity, participate in regulation of neuronal morphology and function. Among various sensors, Absent in melanoma 2 (Aim2) expression in neurons is most prominent. Adding synthetic double-stranded DNA (dsDNA) to cultured neurons induces IL-1β secretion in an AIM2-dependent manner and consequently downregulates dendritic growth but enhances axon extension. The results of Aim2 knockout and knockdown show that AIM2 acts cell-autonomously to regulate neuronal morphology. Behavioral analyses further reveal that Aim2−/− mice exhibit lower locomotor activity, increased anxious behaviors and reduced auditory fear memory. In conclusion, our study suggests that AIM2 inflammasomes regulate neuronal morphology and influence mouse behaviors. PMID:27561456
Weinberg, Seth H.
Excitable cells and cell membranes are often modeled by the simple yet elegant parallel resistor-capacitor circuit. However, studies have shown that the passive properties of membranes may be more appropriately modeled with a non-ideal capacitor, in which the current-voltage relationship is given by a fractional-order derivative. Fractional-order membrane potential dynamics introduce capacitive memory effects, i.e., dynamics are influenced by a weighted sum of the membrane potential prior history. However, it is not clear to what extent fractional-order dynamics may alter the properties of active excitable cells. In this study, we investigate the spiking properties of the neuronal membrane patch, nerve axon, and neural networks described by the fractional-order Hodgkin-Huxley neuron model. We find that in the membrane patch model, as fractional-order decreases, i.e., a greater influence of membrane potential memory, peak sodium and potassium currents are altered, and spike frequency and amplitude are generally reduced. In the nerve axon, the velocity of spike propagation increases as fractional-order decreases, while in a neural network, electrical activity is more likely to cease for smaller fractional-order. Importantly, we demonstrate that the modulation of the peak ionic currents that occurs for reduced fractional-order alone fails to reproduce many of the key alterations in spiking properties, suggesting that membrane capacitive memory and fractional-order membrane potential dynamics are important and necessary to reproduce neuronal electrical activity. PMID:25970534
Weinberg, Seth H
Excitable cells and cell membranes are often modeled by the simple yet elegant parallel resistor-capacitor circuit. However, studies have shown that the passive properties of membranes may be more appropriately modeled with a non-ideal capacitor, in which the current-voltage relationship is given by a fractional-order derivative. Fractional-order membrane potential dynamics introduce capacitive memory effects, i.e., dynamics are influenced by a weighted sum of the membrane potential prior history. However, it is not clear to what extent fractional-order dynamics may alter the properties of active excitable cells. In this study, we investigate the spiking properties of the neuronal membrane patch, nerve axon, and neural networks described by the fractional-order Hodgkin-Huxley neuron model. We find that in the membrane patch model, as fractional-order decreases, i.e., a greater influence of membrane potential memory, peak sodium and potassium currents are altered, and spike frequency and amplitude are generally reduced. In the nerve axon, the velocity of spike propagation increases as fractional-order decreases, while in a neural network, electrical activity is more likely to cease for smaller fractional-order. Importantly, we demonstrate that the modulation of the peak ionic currents that occurs for reduced fractional-order alone fails to reproduce many of the key alterations in spiking properties, suggesting that membrane capacitive memory and fractional-order membrane potential dynamics are important and necessary to reproduce neuronal electrical activity.
Li, Xia; Risbrough, Victoria B; Cates-Gatto, Chelsea; Kaczanowska, Katarzyna; Finn, M G; Roberts, Amanda J; Markou, Athina
γ-Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of drug addiction, pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar therapeutic effects as agonists with superior side-effect profiles. The present study behaviorally characterized N-([1R,2R,4S]-bicyclo[2.2.1]hept-2-yl)-2-methyl-5-(4-[trifluoromethyl]phenyl)-4-pyrimidinamine (BHF177), a GABAB receptor PAM, in mouse models of anxiety-like behavior, learning and memory. In addition, the effects of BHF177 were compared with the agonist baclofen. Unlike the anxiolytic chlordiazepoxide, baclofen (0.5, 1.5, and 2.5 mg/kg, intraperitoneally) and BHF177 (10, 20, and 40 mg/kg, orally) had no effect on anxiety-like behavior in the elevated plus maze, light/dark box, or Vogel conflict test. Baclofen increased punished drinking in the Vogel conflict test, but this effect may be attributable to the analgesic actions of baclofen. At the highest dose tested (2.5 mg/kg), baclofen-treated mice exhibited sedation-like effects (i.e., reduced locomotor activity) across many of the tests, whereas BHF177-treated mice exhibited no sedation-like effects. BHF177 exhibited pro-convulsion properties only in mice, but not in rats, indicating that this effect may be species-specific. At doses that were not sedative or pro-convulsant, baclofen and BHF177 had no selective effects on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory in the Barnes maze. These data suggest that BHF177 has little sedative activity, no anxiolytic-like profile, and minimal impairment of learning and memory in mice.
Kutiyanawalla, Ammar; Promsote, Wanwisa; Terry, Alvin; Pillai, Anilkumar
Brain-derived neurotrophic factor (BDNF) signalling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signalling have been implicated in the pathophysiology of schizophrenia and as a result, they are a potential therapeutic target. Interestingly, heterozygous reeler mice (HRM) have decreased GAD67 expression in the frontal cortex and hippocampus and they exhibit many behavioural and neurochemical abnormalities similar to schizophrenia. In this study, we evaluated the potential of cysteamine, a neuroprotective compound to improve the deficits in GAD67 expression and cognitive function in HRM. We found that cysteamine administration (150 mg/kg.d, through drinking water) for 30 d significantly ameliorated the decreases in GAD67, mature BDNF and full-length TrkB protein levels found in frontal cortex and hippocampus of HRM. A significant attenuation of the increased levels of truncated BDNF in frontal cortex and hippocampus, as well as truncated TrkB in frontal cortex of HRM was also observed following cysteamine treatment. In behavioural studies, HRM were impaired in a Y-maze spatial recognition memory task, but not in a spontaneous alternation task or a sensorimotor, prepulse inhibition (PPI) procedure. Cysteamine improved Y-maze spatial recognition in HRM to the level of wide-type controls and it improved PPI in both wild-type and HRM. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in GAD67 expression suggesting that TrkB signalling plays an important role in GAD67 regulation by cysteamine.
Custodio, Nilton; Lira, David; Herrera-Perez, Eder; Nuñez del Prado, Liza; Parodi, José; Guevara-Silva, Erik; Castro-Suarez, Sheila; Montesinos, Rosa; Cortijo, Patricia
Background/Aims Dementia is a worldwide public health problem and there are several diagnostic tools for its assessment. The aim of this study was to evaluate the performance of the Memory Alteration Test (M@T) to discriminate between patients with early Alzheimer's disease (AD), patients with amnestic mild cognitive impairment (a-MCI), and subjects with a cognitively healthy status (CHS). Methods The discriminative validity was assessed in a sample of 90 patients with AD, 45 patients with a-MCI, and 180 subjects with CHS. Clinical, functional, and cognitive studies were independently performed in a blinded fashion and the gold standard diagnosis was established by consensus on the basis of these results. The test performance was assessed by means of a receiver operating characteristic curve analysis as area under the curve (AUC). Results M@T mean scores were 17.7 (SD = 5.7) in AD, 30.8 (SD = 2.3) in a-MCI, and 44.5 (SD = 3.1) in CHS. A cutoff score of 37 points had a sensitivity of 98.3% and a specificity of 97.8% to differentiate a-MCI from CHS (AUC = 0.999). A cutoff score of 27 points had a sensitivity of 100% and a specificity of 98.9% to differentiate mild AD from a-MCI and from CHS (AUC = 1.000). Conclusions The M@T had a high performance in the discrimination between early AD, a-MCI and CHS. PMID:25298775
Favaro, Vanessa Manchim; Yonamine, Maurício; Soares, Juliana Carlota Kramer; Oliveira, Maria Gabriela Menezes
Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.
Favaro, Vanessa Manchim; Yonamine, Maurício; Soares, Juliana Carlota Kramer; Oliveira, Maria Gabriela Menezes
Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes. PMID:26716991
de Andrade, J S; Céspedes, I C; Abrão, R O; Dos Santos, T B; Diniz, L; Britto, L R G; Spadari-Bratfisch, R C; Ortolani, D; Melo-Thomas, L; da Silva, R C B; Viana, M B
Previous results show that elevated T-maze (ETM) avoidance responses are facilitated by acute restraint. Escape, on the other hand, was unaltered. To examine if the magnitude of the stressor is an important factor influencing these results, we investigated the effects of unpredictable chronic mild stress (UCMS) on ETM avoidance and escape measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to map areas activated by stress exposure in response to ETM avoidance and escape performance. Additionally, the effects of the UCMS protocol on the number of cells expressing the marker of migrating neuroblasts doublecortin (DCX) in the hippocampus were investigated. Corticosterone serum levels were also measured. Results showed that UCMS facilitates ETM avoidance, not altering escape. In unstressed animals, avoidance performance increases Fos-ir in the cingulate cortex, hippocampus (dentate gyrus) and basomedial amygdala, and escape increases Fos-ir in the dorsolateral periaqueductal gray and locus ceruleus. In stressed animals submitted to ETM avoidance, increases in Fos-ir were observed in the cingulate cortex, ventrolateral septum, hippocampus, hypothalamus, amygdala, dorsal and median raphe nuclei. In stressed animals submitted to ETM escape, increases in Fos-ir were observed in the cingulate cortex, periaqueductal gray and locus ceruleus. Also, UCMS exposure decreased the number of DCX-positive cells in the dorsal and ventral hippocampus and increased corticosterone serum levels. These data suggest that the anxiogenic effects of UCMS are related to the activation of specific neurobiological circuits that modulate anxiety and confirm that this stress protocol activates the hypothalamus-pituitary-adrenal axis and decreases hippocampal adult neurogenesis.
Patki, Gaurav; Li, Lumeng; Allam, Farida; Solanki, Naimesh; Dao, An T; Alkadhi, Karim; Salim, Samina
Post-traumatic stress disorder (PTSD) is a condition which can develop from exposure to a severe traumatic event such as those occurring during wars or natural disasters. Benzodiazepines and selective serotonin reuptake inhibitors (SSRIs) are considered the gold standard for PTSD treatment, but their side effects pose a serious problem. While regular physical exercise is regarded as a mood elevator and known to enhance cognitive function, its direct role in rescuing core symptoms of PTSD including anxiety and depression-like behaviors and cognitive impairment is unclear. In the present study using the single-prolonged stress (SPS) rat model of PTSD (2h restrain, 20 min forced swimming, 15 min rest, and 1-2 min diethyl ether exposure), we examined the beneficial effect of moderate treadmill exercise on SPS-induced behavioral deficits including anxiety and depression-like behaviors and memory impairment. Male Wistar rats were randomly assigned into four groups: control (sedentary), exercised, SPS (no exercise), or SPS-exercised. Rats were exercised on a rodent treadmill for 14 consecutive days. Rats in all groups were tested for anxiety-like behaviors using open field (OF), light-dark and elevated-plus maze tests. All rats were tested for short-term and long-term memory in the radial arm water maze test. Rats were then sacrificed, blood was collected (for corticosterone levels), and individual organs (spleen, adrenals, and thymus) harvested. Results suggest that moderate physical exercise ameliorates SPS-induced behavioral deficits in rats.
Onakomaiya, Marie M; Porter, Donna M; Oberlander, Joseph G; Henderson, Leslie P
Anabolic androgenic steroids (AAS) are taken by both sexes to enhance athletic performance and body image, nearly always in conjunction with an exercise regime. Although taken to improve physical attributes, chronic AAS use can promote negative behavior, including anxiety. Few studies have directly compared the impact of AAS use in males versus females or assessed the interaction of exercise and AAS. We show that AAS increase anxiety-like behaviors in female but not male mice and that voluntary exercise accentuates these sex-specific differences. We also show that levels of the anxiogenic peptide corticotrophin releasing factor (CRF) are significantly greater in males, but that AAS selectively increase CRF levels in females, thus abrogating this sex-specific difference. Exercise did not ameliorate AAS-induced anxiety or alter CRF levels in females. Exercise was anxiolytic in males, but this behavioral outcome did not correlate with CRF levels. Brain-derived neurotrophic factor (BDNF) has also been implicated in the expression of anxiety. As with CRF, levels of hippocampal BDNF mRNA were significantly greater in males than females. AAS and exercise were without effect on BDNF mRNA in females. In males, anxiolytic effects of exercise correlated with increased BDNF mRNA, however AAS-induced changes in BDNF mRNA and anxiety did not. In sum, we find that AAS elicit sex-specific differences in anxiety and that voluntary exercise accentuates these differences. In addition, our data suggest that these behavioral outcomes may reflect convergent actions of AAS and exercise on a sexually differentiated CRF signaling system within the extended amygdala.
Conrad, Kelly L; Louderback, Katherine M; Gessner, Caitlin P; Winder, Danny G
In vulnerable individuals, exposure to stressors can result in chronic disorders such as generalized anxiety disorder (GAD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). The extended amygdala is critically implicated in mediating acute and chronic stress responsivity and anxiety-like behaviors. The bed nucleus of the stria terminalis (BNST), a subregion of the extended amygdala, serves as a relay of corticolimbic information to the paraventricular nucleus of the hypothalamus (PVN) to directly influence the stress response. To investigate the influence of the corticosteroid milieu and housing conditions on BNST function, adult C57Bl/6J were either acutely or chronically administered corticosterone (CORT, 25mg/kg in sesame oil) or vehicle (sesame oil) or were group housed or socially isolated for 1 day (acute) or 6-8 weeks (chronic). To ascertain whether these stressors could influence anxiety-like behavior, studies were performed using the novel open-field (NOF) and the elevated zero maze (EZM) tests. To investigate potential associated changes in plasticity, alterations in BNST function were assessed using ex vivo extracellular field potential recordings in the (dorsal-lateral) dlBNST and a high frequency stimulus protocol to induce long-term potentiation (LTP). Our results suggest that chronic CORT injections and chronic social isolation housing conditions lead to an increase in anxiety-like behavior on the EZM and NOF. Chronically stressed mice also displayed a parallel blunting of LTP in the dlBNST. Conversely, acute social isolation housing had no effect on anxiety-like behavior but still resulted in a blunting of LTP in the dlBNST. Collectively, our results suggest acute and chronic stressors can have a distinct profile on plasticity in the BNST that is not uniformly associated with an increase in anxiety-like behavior.
Onakomaiya, Marie M.; Porter, Donna M.; Oberlander, Joseph G.; Henderson, Leslie P.
Anabolic androgenic steroids (AAS) are taken by both sexes to enhance athletic performance and body image, nearly always in conjunction with an exercise regime. Although taken to improve physical attributes, chronic AAS use can promote negative behavior, including anxiety. Few studies have directly compared the impact of AAS use in males versus females or assessed the interaction of exercise and AAS. We show that AAS increase anxiety-like behaviors in female but not male mice and that voluntary exercise accentuates these sex-specific differences. We also show that levels of the anxiogenic peptide corticotrophin releasing factor (CRF) are significantly greater in males, but that AAS selectively increase CRF levels in females, thus abrogating this sex-specific difference. Exercise did not ameliorate AAS-induced anxiety or alter CRF levels in females. Exercise was anxiolytic in males, but this behavioral outcome did not correlate with CRF levels. Brain-derived neurotrophic factor (BDNF) has also been implicated in the expression of anxiety. As with CRF, levels of hippocampal BDNF mRNA were significantly greater in males than females. AAS and exercise were without effect on BDNF mRNA in females. In males, anxiolytic effects of exercise correlated with increased BDNF mRNA, however AAS-induced changes in BDNF mRNA and anxiety did not. In sum, we find that AAS elicit sex-specific differences in anxiety and that voluntary exercise accentuates these differences. In addition, our data suggest that these behavioral outcomes may reflect convergent actions of AAS and exercise on a sexually differentiated CRF signaling system within the extended amygdala. PMID:24768711
Starns, Jeffrey J.; Ksander, John C.
Increasing the number of study trials creates a crossover pattern in source memory zROC slopes; that is, the slope is either below or above 1 depending on which source receives stronger learning. This pattern can be produced if additional learning affects memory processes such as the relative contribution of recollection and familiarity to source…
Güler, O Evren; Hostinar, Camelia E; Frenn, Kristin A; Nelson, Charles A; Gunnar, Megan R; Thomas, Kathleen M
Associations between early deprivation and memory functioning were examined in 9- to 11-year-old children. Children who had experienced prolonged institutional care prior to adoption were compared to children who were adopted early from foster care and children reared in birth families. Measures included the Paired Associates Learning task from the Cambridge Neuropsychological Test and Automated Battery (CANTAB) and a continuous recognition memory task during which ERPs were also recorded. Children who experienced prolonged institutionalization showed deficits in both behavioral memory measures as well as an attenuated P300 parietal memory effect. Results implicate memory function as one of the domains that may be negatively influenced by early deprivation in the form of institutional care.
Doesburg, Sam M; Ribary, Urs; Herdman, Anthony T; Miller, Steven P; Poskitt, Kenneth J; Moiseev, Alexander; Whitfield, Michael F; Synnes, Anne; Grunau, Ruth E
Children born very preterm, even when intelligence is broadly normal, often experience selective difficulties in executive function and visual-spatial processing. Development of structural cortical connectivity is known to be altered in this group, and functional magnetic resonance imaging (fMRI) evidence indicates that very preterm children recruit different patterns of functional connectivity between cortical regions during cognition. Synchronization of neural oscillations across brain areas has been proposed as a mechanism for dynamically assigning functional coupling to support perceptual and cognitive processing, but little is known about what role oscillatory synchronization may play in the altered neurocognitive development of very preterm children. To investigate this, we recorded magnetoencephalographic (MEG) activity while 7–8 year old children born very preterm and age matched full-term controls performed a visual short-term memory task. Very preterm children exhibited reduced long-range synchronization in the alpha-band during visual short-term memory retention, indicating that cortical alpha rhythms may play a critical role in altered patterns functional connectivity expressed by this population during cognitive and perceptual processing. Long-range alpha-band synchronization was also correlated with task performance and visual-perceptual ability within the very preterm group, indicating that altered alpha-oscillatory mechanisms mediating transient functional integration between cortical regions may be relevant to selective problems in neurocognitive development in this vulnerable population at school age. PMID:20974268
Teixeira, A M; Pase, C S; Boufleur, N; Roversi, K; Barcelos, R C S; Benvegnú, D M; Segat, H J; Dias, V T; Reckziegel, P; Trevizol, F; Dolci, G S; Carvalho, N R; Soares, F A A; Rocha, J B T; Emanuelli, T; Bürger, M E
Here we evaluated the influence of physical exercise on behavior parameters and enzymatic status of rats supplemented with different dietary fatty acids (FA). Male Wistar rats fed diets enriched with soybean oil (SO), lard (L), or hydrogenated vegetable fat (HVF) for 48 weeks were submitted to swimming (30 min/d, five times per week) for 90 days. Dietary FA per se did not cause anxiety-like symptoms in the animals, but after physical exercise, SO group showed a better behavioral performance than L and the HVF groups in elevated plus maze (EPM). In Barnes maze, HVF group showed impaired memory acquisition as compared to L group, and exercise reversed this effect. SO-fed rats showed an improvement in memory acquisition after 1 day of training, whereas lard caused an improvement of memory only from day 4. HVF-fed rats showed no improvement of memory acquisition, but this effect was reversed by exercise in all training days. A lower activity of the Na(+)K(+)-ATPase in brain cortex of rats fed lard and HVF was observed, and this effect was maintained after exercise. Similarly, the HVF diet was related to lower activity of hippocampal Na(+)K(+)-ATPase, and exercise reduced activity of this enzyme in the SO and L groups. Our findings show influences of dietary FA on memory acquisition, whereas regular exercise improved this function and was beneficial on anxiety-like symptoms. As FA are present in neuronal membrane phospholipids and play a critical role in brain function, our results suggest that low incorporation of trans FA in neuronal membranes may act on cortical and hippocampal Na(+)K(+)-ATPase activity, but this change appears to be unrelated to the behavioral parameters primarily harmed by consumption of trans and less so by saturated FA, which were reversed by exercise.
Du, Ming-Ying; Liao, Wei; Huang, Xiao-Qi; Li, Fei; Kuang, Wei-Hong; Li, Jing; Chen, Hua-Fu; Kendrick, Keith Maurice; Gong, Qi-Yong
Although acute impact of traumatic experiences on brain function in disaster survivors is similar to that observed in post-traumatic stress disorders (PTSD), little is known about the long-term impact of this experience. We have used structural and functional magnetic resonance imaging to investigate resting-state functional connectivity and gray and white matter (WM) changes occurring in the brains of healthy Wenchuan earthquake survivors both 3 weeks and 2 years after the disaster. Results show that while functional connectivity changes 3 weeks after the disaster involved both frontal–limbic–striatal and default-mode networks (DMN), at the 2-year follow-up only changes in the latter persisted, despite complete recovery from high initial levels of anxiety. No gray or WM volume changes were found at either time point. Taken together, our findings provide important new evidence that while altered functional connectivity in the frontal–limbic–striatal network may underlie the post-trauma anxiety experienced by survivors, parallel changes in the DMN persist despite the apparent absence of anxiety symptoms. This suggests that long-term changes occur in neural networks involved in core aspects of self-processing, cognitive and emotional functioning in disaster survivors which are independent of anxiety symptoms and which may also confer increased risk of subsequent development of PTSD. PMID:25862672
Fortress, Ashley M.; Kim, Jaekyoon; Poole, Rachel L.; Gould, Thomas J.; Frick, Karyn M.
Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17ß-estradiol…
Scherr, Jessica F.; Hahn, Laura J.; Hooper, Stephen R.; Hatton, Deborah; Roberts, Jane E.
The present study examines verbal working memory over time in boys with fragile X syndrome (FXS) compared to nonverbal mental-age (NVMA) matched, typically developing (TD) boys. Concomitantly, the relationship between cortisol—a physiological marker for stress—and verbal working memory performance over time is examined to understand the role of physiological mechanisms in cognitive development in FXS. Participants were assessed between one and three times over a 2-year time frame using two verbal working memory tests that differ in complexity: memory for words and auditory working memory with salivary cortisol collected at the beginning and end of each assessment. Multilevel modeling results indicate specific deficits over time on the memory for words task in boys with FXS compared to TD controls that is exacerbated by elevated baseline cortisol. Similar increasing rates of growth over time were observed for boys with FXS and TD controls on the more complex auditory working memory task, but only boys with FXS displayed an association of increased baseline cortisol and lower performance. This study highlights the benefit of investigations of how dynamic biological and cognitive factors interact and influence cognitive development over time. PMID:26760450
Morgan, Celia J. A.; Dodds, Chris M.; Furby, Hannah; Pepper, Fiona; Fam, Johnson; Freeman, Tom P.; Hughes, Emer; Doeller, Christian; King, John; Howes, Oliver; Stone, James M.
Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 poly-drug controls, matched for IQ, age, years in education. We used fMRI utilizing an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus, and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls. Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users. PMID:25538631
Schneider, Sophia; Brassen, Stefanie
Brooding rumination is considered a central aspect of depression in midlife. As older people tend to review their past, rumination tendency might be particularly crucial in late life since it might hinder older adults to adequately evaluate previous events. We scanned 22 non-depressed older adults with varying degrees of brooding tendency with functional magnetic resonance imaging (MRI) while they performed the construction and elaboration of autobiographical memories. Behavioral findings demonstrate that brooders reported lower mood states, needed more time for memory construction and rated their memories as less detailed and less positive. On the neural level, brooding tendency was related to increased amygdala activation during the search for specific memories and reduced engagement of cortical networks during elaboration. Moreover, coupling patterns of the subgenual cingulate cortex with the hippocampus (HC) and the amygdala predicted details and less positive valence of memories in brooders. Our findings support the hypothesis that ruminative thinking interferes with the search for specific memories while facilitating the uncontrolled retrieval of negatively biased self-schemes. The observed neurobehavioral dysfunctions might put older people with brooding tendency at high risk for becoming depressed when reviewing their past. Training of autobiographical memory ability might therefore be a promising approach to increase resilience against depression in late-life. PMID:27695414
Duval, Elizabeth R; Garfinkel, Sarah N; Swain, James E; Evans, Gary W; Blackburn, Erika K; Angstadt, Mike; Sripada, Chandra S; Liberzon, Israel
Childhood poverty is a risk factor for poorer cognitive performance during childhood and adulthood. While evidence linking childhood poverty and memory deficits in adulthood has been accumulating, underlying neural mechanisms are unknown. To investigate neurobiological links between childhood poverty and adult memory performance, we used functional magnetic resonance imaging (fMRI) during a visuospatial memory task in healthy young adults with varying income levels during childhood. Participants were assessed at age 9 and followed through young adulthood to assess income and related factors. During adulthood, participants completed a visuospatial memory task while undergoing MRI scanning. Patterns of neural activation, as well as memory recognition for items, were assessed to examine links between brain function and memory performance as it relates to childhood income. Our findings revealed associations between item recognition, childhood income level, and hippocampal activation. Specifically, the association between hippocampal activation and recognition accuracy varied as a function of childhood poverty, with positive associations at higher income levels, and negative associations at lower income levels. These prospective findings confirm previous retrospective results detailing deleterious effects of childhood poverty on adult memory performance. In addition, for the first time, we identify novel neurophysiological correlates of these deficits localized to hippocampus activation.
Vanderheyden, William M.; George, Sophie A.; Urpa, Lea; Kehoe, Michaela; Liberzon, Israel; Poe, Gina R.
Sleep abnormalities such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of post-traumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating these sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stress exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops in rats. SPS resulted in acutely increased REM sleep, transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. We also report reductions in theta (4–10 Hz) and sigma (10–15 Hz) band power during transition to REM sleep which also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID:26019008
Albores-Garcia, Damaris; Hernandez, Alberto J.; Loera, Miriam J.
Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined. PMID:26885512
Albores-Garcia, Damaris; Acosta-Saavedra, Leonor C; Hernandez, Alberto J; Loera, Miriam J; Calderón-Aranda, Emma S
Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined.
Camera, Daria; Coleman, Harold A; Parkington, Helena C; Jenkins, Trisha A; Pow, David V; Boase, Natasha; Kumar, Sharad; Poronnik, Philip
The consolidation of short-term memory into long-term memory involves changing protein level and activity for the synaptic plasticity required for long-term potentiation (LTP). AMPA receptor trafficking is a key determinant of LTP and recently ubiquitination by Nedd4 has been shown to play an important role via direct action on the GluA1 subunit, although the physiological relevance of these findings are yet to be determined. We therefore investigated learning and memory in Nedd4(+/-) mice that have a 50% reduction in levels of Nedd4. These mice showed decreased long-term spatial memory as evidenced by significant increases in the time taken to learn the location of and subsequently find a platform in the Morris water maze. In contrast, there were no significant differences between Nedd4(+/+) and Nedd4(+/-) mice in terms of short-term spatial memory in a Y-maze test. Nedd4(+/-) mice also displayed a significant reduction in post-synaptic LTP measured in hippocampal brain slices. Immunofluorescence of Nedd4 in the hippocampus confirmed its expression in hippocampal neurons of the CA1 region. These findings indicate that reducing Nedd4 protein by 50% significantly impairs LTP and long-term memory thereby demonstrating an important role for Nedd4 in these processes.
Jang, Saebyeol; Dilger, Ryan N.; Johnson, Rodney W.
A dysregulated overexpression of inflammatory mediators by microglia may facilitate cognitive aging and neurodegeneration. Considerable evidence suggests the flavonoid luteolin has antiinflammatory effects, but its ability to inhibit microglia, reduce inflammatory mediators, and improve hippocampal-dependent learning and memory in aged mice is unknown. In initial studies, pretreatment of BV-2 microglia with luteolin inhibited the induction of inflammatory genes and the release of inflammatory mediators after lipopolysaccharide (LPS) stimulation. Supernatants from LPS-stimulated microglia caused discernible death in Neuro.2a cells. However, treating microglia with luteolin prior to LPS reduced neuronal cell death caused by conditioned supernatants, indicating luteolin was neuroprotective. In subsequent studies, adult (3–6 mo) and aged (22–24 mo) mice were fed control or luteolin (20 mg/d)-supplemented diet for 4 wk and spatial working memory was assessed as were several inflammatory markers in the hippocampus. Aged mice fed control diet exhibited deficits in spatial working memory and expression of inflammatory markers in the hippocampus indicative of increased microglial cell activity. Luteolin consumption improved spatial working memory and restored expression of inflammatory markers in the hippocampus compared with that of young adults. Luteolin did not affect either spatial working memory or inflammatory markers in young adults. Taken together, the current findings suggest dietary luteolin enhanced spatial working memory by mitigating microglial-associated inflammation in the hippocampus. Therefore, luteolin consumption may be beneficial in preventing or treating conditions involving increased microglial cell activity and inflammation. PMID:20685893
Pascuan, C G; Di Rosso, M E; Pivoz-Avedikian, J E; Wald, M R; Zorrilla Zubilete, M A; Genaro, A M
Much evidence has suggested that early life adversity can have a lasting effect on behavior. The aim of this study was to explore the impact of prenatal exposure to stress on cognition in adult life and how it impacts chronic stress situations. In addition, we investigated the participation of glucocorticoids, neurotrophins and cytokines in prenatal stress effects. For this purpose, pregnant mice were placed in a cylindrical restraint tube for 2h daily during the last week of pregnancy. Control pregnant females were left undisturbed during their entire pregnancy period. Object-in-place task results showed that adult female mice exposed to prenatal stress exhibited an impairment in spatial memory. However, in the alternation test this memory deficit was only found in prenatally stressed mice submitted to chronic stress. This alteration occurred in parallel with a decrease in BDNF, an increase in glucocorticoid receptors and an alteration of Th1/Th2 in the hippocampus. Interestingly, these changes were observed in peripheral lymph nodes as well. However, none of the mentioned changes were observed in adult male mice. These results indicate that lymphoid cells could be good candidates as peripheral markers of susceptibility to behavioral alterations associated with prenatal exposure to stress.
Maurice, Tangui; Duclot, Florian; Meunier, Johann; Naert, Gaëlle; Givalois, Laurent; Meffre, Julie; Célérier, Aurélie; Jacquet, Chantal; Copois, Virginie; Mechti, Nadir; Ozato, Keiko; Gongora, Céline
Chromatin remodeling by posttranslational modification of histones plays an important role in brain plasticity, including memory, response to stress and depression. The importance of H3/4 histones acetylation by CREB-binding protein (CBP) or related histone acetyltransferase, including p300, was specifically demonstrated using knockout (KO) mouse models. The physiological role of a related protein that also acts as a transcriptional coactivator with intrinsic histone acetylase activity, the p300/CBP-associated factor (PCAF), is poorly documented. We analyzed the behavioral phenotype of homozygous male and female PCAF KO mice and report a marked impact of PCAF deletion on memory processes and stress response. PCAF KO animals showed short-term memory deficits at 2 months of age, measured using spontaneous alternation, object recognition, or acquisition of a daily changing platform position in the water maze. Acquisition of a fixed platform location was delayed, but preserved, and no passive avoidance deficit was noted. No gender-related difference was observed. These deficits were associated with hippocampal alterations in pyramidal cell layer organization, basal levels of Fos immunoreactivity, and MAP kinase activation. PCAF KO mice also showed an exaggerated response to acute stress, forced swimming, and conditioned fear, associated with increased plasma corticosterone levels. Moreover, learning and memory impairments worsened at 6 and 12 months of age, when animals failed to acquire the fixed platform location in the water maze and showed passive avoidance deficits. These observations demonstrate that PCAF histone acetylase is involved lifelong in the chromatin remodeling necessary for memory formation and response to stress.
Nissen, Christoph; Power, Ann E; Nofzinger, Eric A; Feige, Bernd; Voderholzer, Ulrich; Kloepfer, Corinna; Waldheim, Bernhard; Radosa, Marc-Philipp; Berger, Mathias; Riemann, Dieter
Preclinical studies have implicated cholinergic neurotransmission, specifically M1 muscarinic acetylcholine receptor (mAChR) activation, in sleep-associated memory consolidation. In the present study, we investigated the effects of administering the direct M1 mAChR agonist RS-86 on pre-post sleep memory consolidation. Twenty healthy human participants were tested in a declarative word-list task and a procedural mirror-tracing task. RS-86 significantly reduced rapid eye movement (REM) sleep latency and slow wave sleep (SWS) duration in comparison with placebo. Presleep acquisition and postsleep recall rates were within the expected ranges. However, recall rates in both tasks were almost identical for the RS-86 and placebo conditions. These results indicate that selective M1 mAChR activation in healthy humans has no clinically relevant effect on pre-post sleep consolidation of declarative or procedural memories at a dose that reduces REM sleep latency and SWS duration.
Guler, O. Evren; Hostinar, Camelia E.; Frenn, Kristin A.; Nelson, Charles A.; Gunnar, Megan R.; Thomas, Kathleen M.
Associations between early deprivation and memory functioning were examined in 9- to 11-year-old children. Children who had experienced prolonged institutional care prior to adoption were compared to children who were adopted early from foster care and children reared in birth families. Measures included the Paired Associates Learning task from…
Bombardier, Andreanne; Beauchemin, Maude; Gosselin, Nadia; Poirier, Judes; De Beaumont, Louis
While most studies have been interested in the distinct, predisposing roles of the common BDNF Val66Met variant and extraversion personality traits on episodic memory, very few studies have looked at the synergistic effects of genetic and personality factors to account for cognitive variance. This is surprising considering recent reports challenging the long-held belief that the BDNFMet variant negatively impacts cognitive function. A total of 75 young healthy adults (26 of them carried at least one copy of the BDNFMet allele) took part in this study consisting of genetic profiling from saliva, personality assessment using the Revised NEO Personality Inventory (NEO PI-R) and a short battery of neuropsychological tests. An ANOVA revealed that BDNFMet carriers were significantly less extraverted than BDNFVal carriers (F1,73 = 9.54; p < 0.01; ηp2 = 0.126). Moreover, extraversion was found to significantly moderate the relationship between the BDNF genotype and episodic memory performance (p = 0.03). Subsequent correlational analyses yielded a strong and significant correlation (r = 0.542; p < 0.005) between introversion and delayed episodic memory specific to BDNFMet individuals. The present study suggests that introversion and the BDNFMet variant synergistically interact to reduce episodic memory performance in healthy, young adults. These findings reaffirm that a more accurate explanation of cognitive variance can be achieved by looking at the synergistic effects of genotype and phenotype factors. PMID:27845759
Gabriele, Amanda; Setlow, Barry; Packard, Mark G.
Rats were trained to run a straight-alley maze for an oral cocaine or sucrose vehicle solution reward, followed by either response or latent extinction training procedures that engage neuroanatomically dissociable "habit" and "cognitive" memory systems, respectively. In the response extinction condition, rats performed a runway approach response…
Kurhe, Yeshwant; Mahesh, Radhakrishnan
In our earlier study we reported the antidepressant activity of ondansetron in obese mice. The present study investigates the effect of ondansetron on depression and anxiety associated with obesity in experimental mice with biochemical evidences. Male Swiss albino mice were fed with high fat diet (HFD) for 14weeks to induce obesity. Then the subsequent treatment with ondansetron (0.5 and 1mg/kg, p.o.), classical antidepressant escitalopram (ESC) (10mg/kg, p.o.) and vehicle (distilled water 10ml/kg, p.o.) was given once daily for 28days. Behavioral assay for depression including sucrose preference test, forced swim test (FST) and anxiety such as light dark test (LDT) and hole board test (HBT) were performed in obese mice. Furthermore, in biochemical estimations oral glucose tolerance test (OGTT), plasma leptin, insulin, corticosterone, brain oxidative stress marker malonaldehyde (MDA), antioxidant reduced glutathione (GSH) and serotonin assays were performed. Results indicated that HFD fed obese mice showed severe depressive and anxiety-like behaviors. Chronic treatment with ondansetron inhibited the co-morbid depression and anxiety in obese mice by increasing sucrose consumption in sucrose preference test and reducing the immobility time in FST, increasing time and transitions of light chamber in LDT, improving head dip and crossing scores in HBT compared to HFD control mice. Ondansetron in obese mice inhibited glucose sensitivity in OGTT, improved plasma leptin and insulin sensitivity, reversed hypothalamic pituitary adrenal (HPA) axis hyperactivity by reducing the corticosterone concentration, restored brain pro-oxidant/anti-oxidant balance by inhibiting MDA and elevating GSH concentrations and facilitated serotonergic neurotransmission. In conclusion, ondansetron reversed the co-morbid depression and anxiety associated with obesity in experimental mice by attenuating the behavioral and biochemical abnormalities.
Zhao, Xiaohu; Xi, Qian; Li, Chunbo; He, Hongjian
Objective The prior functional MRI studies have demonstrated significantly abnormal activity in the bilateral superior temporal gyrus (STG) of anxiety patients. The purpose of the current investigation was to determine whether the abnormal activity in these regions was related to a loss of functional connectivity between these regions. Materials and Methods Ten healthy controls and 10 anxiety patients underwent noninvasive fMRI while actively listening to emotionally neutral words alternated by silence (Task 1) or threat-related words (Task 2). The participants were instructed to silently make a judgment of each word's valence (i.e., unpleasant, pleasant, or neutral). A coherence analysis was applied to the functional MRI data to examine the functional connectivity between the left and the right STG, which was selected as the primary region of interest on the basis of our prior results. Results The data demonstrated that the anxiety patients exhibited significantly increased activation in the bilateral STG than the normal controls. The functional connectivity analysis indicated that the patient group showed significantly decreased degree of connectivity between the bilateral STG during processing Task 2 compared to Task 1 (t = 2.588, p = 0.029). In addition, a significantly decreased connectivity was also observed in the patient group compared to the control group during processing Task 2 (t = 2.810, p = 0.012). Conclusion Anxiety patients may exhibit increased activity of the STG but decreased functional connectivity between the left and right STG, which may reflect the underlying neural abnormality of anxiety disorder, and this will provide new insights into this disease. PMID:25053913
Hill, Rachel A; Klug, Maren; Kiss Von Soly, Szerenke; Binder, Michele D; Hannan, Anthony J; van den Buuse, Maarten
Post-mortem studies have demonstrated reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of schizophrenia and major depression patients. The "two hit" hypothesis proposes that two or more major disruptions at specific time points during development are involved in the pathophysiology of these mental illnesses. However, the role of BDNF in these "two hit" effects is unclear. Our aim was to behaviorally characterize a "two hit" rat model of developmental stress accompanied by an in-depth assessment of BDNF expression and signalling. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. In adulthood, models of cognitive and negative symptoms of mental illness were analyzed. The hippocampus was then dissected into dorsal (DHP) and ventral (VHP) regions and analyzed by qPCR for exon-specific BDNF gene expression or by Western blot for BDNF protein expression and downstream signaling. Male "two hit" rats showed marked disruptions in short-term spatial memory (Y-maze) which were absent in females. However, female "two hit" rats showed signs of anhedonia (sucrose preference test), which were absent in males. Novel object recognition and anxiety (elevated plus maze) were unchanged by either of the two "hits". In the DHP, MS caused a male-specific increase in BDNF Exons I, II, IV, VII, and IX mRNA but a decrease in mature BDNF and phosphorylated TrkB (pTrkB) protein expression in adulthood. In the VHP, BDNF transcript expression was unchanged; however, in female rats only, MS significantly decreased mature BDNF and pTrkB protein expression in adulthood. These data demonstrate that MS causes region-specific and sex-specific long-term effects on BDNF expression and signaling and, importantly, mRNA expression does not always infer protein expression. Alterations to BDNF signaling may mediate the sex-specific effects of developmental stress on anhedonic behaviors.
Underwood, Erica L.; Thompson, Lucien T.
While high-fat diets are associated with rising incidence of obesity/type-2 diabetes and can induce metabolic and cognitive deficits, sex-dependent comparisons are rarely systematically made. Effects of exclusive consumption of a high-fat diet (HFD) on systemic metabolism and on behavioral measures of hippocampal-dependent memory were compared in young male and female LE rats. Littermates were fed from weaning either a HFD or a control diet (CD) for 12 wk prior to testing. Sex-different effects of the HFD were observed in classic metabolic signs associated with type-2 diabetes. Males fed the HFD became obese, and had elevated fasted blood glucose levels, elevated corticosterone, and impaired glucose-tolerance, while females on the HFD exhibited only elevated corticosterone. Regardless of peripheral metabolism alteration, rats of both sexes fed the HFD were equally impaired in a spatial object recognition memory task associated with impaired hippocampal function. While the metabolic changes reported here have been characterized previously in males, the set of diet-induced effects observed here in females are novel. Impaired memory can have significant cognitive consequences, over the short-term and over the lifespan. A significant need exists for comparative research into sex-dependent differences underlying obesity and metabolic syndromes relating systemic, cognitive, and neural plasticity mechanisms. PMID:26819773
Hermans, Erno J; Battaglia, Francesco P; Atsak, Piray; de Voogd, Lycia D; Fernández, Guillén; Roozendaal, Benno
The amygdala has long been known to play a key role in supporting memory for emotionally arousing experiences. For example, classical fear conditioning depends on neural plasticity within this anterior medial temporal lobe region. Beneficial effects of emotional arousal on memory, however, are not restricted to simple associative learning. Our recollection of emotional experiences often includes rich representations of, e.g., spatiotemporal context, visceral states, and stimulus-response associations. Critically, such memory features are known to bear heavily on regions elsewhere in the brain. These observations led to the modulation account of amygdala function, which postulates that amygdala activation enhances memory consolidation by facilitating neural plasticity and information storage processes in its target regions. Rodent work in past decades has identified the most important brain regions and neurochemical processes involved in these modulatory actions, and neuropsychological and neuroimaging work in humans has produced a large body of convergent data. Importantly, recent methodological developments make it increasingly realistic to monitor neural interactions underlying such modulatory effects as they unfold. For instance, functional connectivity network modeling in humans has demonstrated how information exchanges between the amygdala and specific target regions occur within the context of large-scale neural network interactions. Furthermore, electrophysiological and optogenetic techniques in rodents are beginning to make it possible to quantify and even manipulate such interactions with millisecond precision. In this paper we will discuss that these developments will likely lead to an updated view of the amygdala as a critical nexus within large-scale networks supporting different aspects of memory processing for emotionally arousing experiences.
Au Duong, My-Van; Audoin, Bertrand; Boulanouar, Kader; Ibarrola, Daniella; Malikova, Irina; Confort-Gouny, Sylrane; Celsis, Pierre; Pelletier, Jean; Cozzone, Patrick J; Ranjeva, Jean-Philippe
Functional magnetic resonance imaging (fMRI) using paced auditory serial addition test (PASAT) as paradigm was used to study the functional connectivity in 18 patients at the very early stage of multiple sclerosis (MS) compared with 18 controls, to determine the existence of circuitry disturbance inside the working memory network and its relationship with white matter abnormalities assessed by conventional MRI and magnetization transfer ratio (MTR) imaging. The left BA 45/46 was selected as the seed region to compute correlation maps with other brain regions. After obtaining the correlation map for each subject, between-group comparisons were performed using random effect procedure. Compared with controls, patients did not show any greater functional connectivity between left BA 45/46 and other regions during PASAT. In contrast, decrease in functional connectivity was observed in patients between left BA 45/46 and left BA 9, right BA 3, and the anterior cingulate cortex (BA 24). In patients, no correlations were found between altered functional connectivity and clinical data. However, functional connectivity observed between left BA 45/46 and BA 24 in patients was correlated with the MTR of normal appearing white matter, and with brain T(2) lesion load. Altered functional connectivity is present inside the working memory network of patients at the very early stage of MS and is related to the extent of diffuse white matter changes.
Hitchcock, Caitlin; Werner-Seidler, Aliza; Blackwell, Simon E; Dalgleish, Tim
We review evidence for training programmes that manipulate autobiographical processing in order to treat mood, anxiety, and stress-related disorders, using the GRADE criteria to judge evidence quality. We also position the current status of this research within the UK Medical Research Council's (2000, 2008) framework for the development of novel interventions. A literature search according to PRISMA guidelines identified 15 studies that compared an autobiographical episodic memory-based training (AET) programme to a control condition, in samples with a clinician-derived diagnosis. Identified AET programmes included Memory Specificity Training (Raes, Williams, & Hermans, 2009), concreteness training (Watkins, Baeyens, & Read, 2009), Competitive Memory Training (Korrelboom, van der Weele, Gjaltema, & Hoogstraten, 2009), imagery-based training of future autobiographical episodes (Blackwell & Holmes, 2010), and life review/reminiscence therapy (Arean et al., 1993). Cohen's d was calculated for between-group differences in symptom change from pre- to post-intervention and to follow-up. We also completed meta-analyses for programmes evaluated across multiple studies, and for the overall effect of AET as a treatment approach. Results demonstrated promising evidence for AET in the treatment of depression (d=0.32), however effect sizes varied substantially (from -0.18 to 1.91) across the different training protocols. Currently, research on AET for the treatment of anxiety and stress-related disorders is not yet at a stage to draw firm conclusions regarding efficacy as there were only a very small number of studies which met inclusion criteria. AET offers a potential avenue through which low-intensity treatment for affective disturbance might be offered.
Tarr, Andrew J; Galley, Jeffrey D; Fisher, Sydney E; Chichlowski, Maciej; Berg, Brian M; Bailey, Michael T
There are extensive bidirectional interactions between the gut microbiota and the central nervous system (CNS), and studies demonstrate that stressor exposure significantly alters gut microbiota community structure. We tested whether oligosaccharides naturally found in high levels in human milk, which have been reported to impact brain development and enhance the growth of beneficial commensal microbes, would prevent stressor-induced alterations in gut microbial community composition and attenuate stressor-induced anxiety-like behavior. Mice were fed standard laboratory diet, or laboratory diet containing the human milk oligosaccharides 3'Sialyllactose (3'SL) or 6'Sialyllactose (6'SL) for 2 weeks prior to being exposed to either a social disruption stressor or a non-stressed control condition. Stressor exposure significantly changed the structure of the colonic mucosa-associated microbiota in control mice, as indicated by changes in beta diversity. The stressor resulted in anxiety-like behavior in both the light/dark preference and open field tests in control mice. This effect was associated with a reduction in immature neurons in the dentate gyrus as indicated by doublecortin (DCX) immunostaining. These effects were not evident in mice fed milk oligosaccharides; stressor exposure did not significantly change microbial community structure in mice fed 3'SL or 6'SL. In addition, 3'SL and 6'SL helped maintain normal behavior on tests of anxiety-like behavior and normal numbers of DCX+ immature neurons. These studies indicate that milk oligosaccharides support normal microbial communities and behavioral responses during stressor exposure, potentially through effects on the gut microbiota-brain axis.
Garg, Ruchika; Kumar, Anil
Sleep is an essential physiological process for maintaining physical, mental, and emotional health. Sleep deprivation and associated disorders like depression and anxiety are one of the major problems now-days. The present study was designed to explore the neuroprotecitve effect of citalopram and desipramine on 72 hr sleep deprivation-induced behavioral alterations and oxidative damage in mice. Various behavioral tests (plus maze, zero maze, mirror chamber, actophotometer), body weight followed by oxidative parameters (malondialdehyde level, glutathione, catalase, nitrite and protein) were assessed. Treatment with citalopram (5 and 10 mg/kg, ip) and desipramine (10 and 20 mg/kg, ip) for 5 days significantly improved locomotor activity, anti-anxiety like behavior in all paradigms tasks (mirror chamber, plus maze, zero maze) as compared to control (72 hr sleep-deprived). Biochemically, citalopram and desipramine treatment significantly restored depleted reduced glutathione, catalase activity, attenuated raised lipid peroxidation and nitrite level as compared to control (72 hr sleep-deprived) animals. Results of present study suggest that citalopram (5 and 10mg/kg, ip) and desipramine (10 and 20 mg/kg, ip) have neuroprotective effect against sleep deprivation-induced behavior alteration and oxidative damage in mice.
Le, Thang M; Borghi, John A; Kujawa, Autumn J; Klein, Daniel N; Leung, Hoi-Chung
The present study examined the impacts of major depressive disorder (MDD) on visual and prefrontal cortical activity as well as their connectivity during visual working memory updating and related them to the core clinical features of the disorder. Impairment in working memory updating is typically associated with the retention of irrelevant negative information which can lead to persistent depressive mood and abnormal affect. However, performance deficits have been observed in MDD on tasks involving little or no demand on emotion processing, suggesting dysfunctions may also occur at the more basic level of information processing. Yet, it is unclear how various regions in the visual working memory circuit contribute to behavioral changes in MDD. We acquired functional magnetic resonance imaging data from 18 unmedicated participants with MDD and 21 age-matched healthy controls (CTL) while they performed a visual delayed recognition task with neutral faces and scenes as task stimuli. Selective working memory updating was manipulated by inserting a cue in the delay period to indicate which one or both of the two memorized stimuli (a face and a scene) would remain relevant for the recognition test. Our results revealed several key findings. Relative to the CTL group, the MDD group showed weaker postcue activations in visual association areas during selective maintenance of face and scene working memory. Across the MDD subjects, greater rumination and depressive symptoms were associated with more persistent activation and connectivity related to no-longer-relevant task information. Classification of postcue spatial activation patterns of the scene-related areas was also less consistent in the MDD subjects compared to the healthy controls. Such abnormalities appeared to result from a lack of updating effects in postcue functional connectivity between prefrontal and scene-related areas in the MDD group. In sum, disrupted working memory updating in MDD was revealed by
Verbitsky, Miguel; Yonan, Amanda L.; Malleret, Gael; Kandel, Eric R.; Gilliam, T. Conrad; Pavlidis, Paul
We have carried out a global survey of age-related changes in mRNA levels in the 57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged…
Lucas, Heather D.; Paller, Ken A.
The mechanisms that give rise to familiarity memory have received intense research interest. One current topic of debate concerns the extent to which familiarity is driven by the same fluency sources that give rise to certain implicit memory phenomena. Familiarity may be tied to conceptual fluency, given that familiarity and conceptual implicit memory can exhibit similar neurocognitive properties. However, familiarity can also be driven by perceptual factors, and its neural basis under these circumstances has received less attention. Here we recorded brain potentials during recognition testing using a procedure that has previously been shown to encourage a reliance on letter information when assessing familiarity for words. Studied and unstudied words were derived either from two separate letter pools or a single letter pool (“letter-segregated” and “normal” conditions, respectively) in a within-subjects contrast. As predicted, recognition accuracy was higher in the letter-segregated relative to the normal condition. Electrophysiological analyses revealed parietal old-new effects from 500–700 ms in both conditions. In addition, a topographically dissociable occipital old-new effect from 300–700 ms was present in the letter-segregated condition only. In a second experiment, we found that similar occipital brain potentials were associated with confident false recognition of words that shared letters with studied words but were not themselves studied. These findings indicate that familiarity is a multiply determined phenomenon, and that the stimulus dimensions on which familiarity is based can moderate its neural correlates. Conceptual and perceptual contributions to familiarity vary across testing circumstances, and both must be accounted for in theories of recognition memory and its neural basis. PMID:23871869
Cheng, Bochao; Huang, Xiaoqi; Li, Shiguang; Hu, Xinyu; Luo, Ya; Wang, Xiuli; Yang, Xun; Qiu, Changjian; Yang, Yanchun; Zhang, Wei; Bi, Feng; Roberts, Neil; Gong, Qiyong
Post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and social anxiety disorder (SAD) all bear the core symptom of anxiety and are separately classified in the new DSM-5 system. The aim of the present study is to obtain evidence for neuroanatomical difference for these disorders. We applied voxel-based morphometry (VBM) with Diffeomorphic Anatomical Registration Through Exponentiated Lie to compare gray matter volume (GMV) in magnetic resonance images obtained for 30 patients with PTSD, 29 patients with OCD, 20 patients with SAD, and 30 healthy controls. GMV across all four groups differed in left hypothalamus and left inferior parietal lobule and post hoc analyses revealed that this difference is primarily due to reduced GMV in the PTSD group relative to the other groups. Further analysis revealed that the PTSD group also showed reduced GMV in frontal lobe, temporal lobe, and cerebellum compared to the OCD group, and reduced GMV in frontal lobes bilaterally compared to SAD group. A significant negative correlation with anxiety symptoms is observed for GMV in left hypothalamus in three disorder groups. We have thus found evidence for brain structure differences that in future could provide biomarkers to potentially support classification of these disorders using MRI.
Kastenberger, Iris; Schwarzer, Christoph
The putative estrogen receptor GPER1 (the former orphan receptor GPR30) is discussed to be involved in emotional and cognitive functions and stress control. We recently described the induction of anxiety-like effects by the GPER1 agonist G-1 upon systemic injection into mice. To contribute to a better understanding of the role of GPER1 in anxiety and stress, we investigated germ-line GPER1 deficient mice. Our experiments revealed marked differences between the sexes. A mild but consistent phenotype of increased exploratory drive was observed in the home cage, the elevated plus maze and the light-dark choice test in male GPER1 KO mice. In contrast, female GPER1-KO mice displayed a less pronounced phenotype in these tests. Estrous-stage dependent mild anxiolytic-like effects were observed solely in the open field test. Notably, we observed a strong shift in acute stress coping behavior in the tail suspension test and basal corticosterone levels in different phases of the estrous cycle in female GPER1-KO mice. Our data, in line with previous reports, suggest that GPER1 is involved in anxiety and stress control. Surprisingly, its effects appear to be stronger in male than female mice.
Cheng, Bochao; Huang, Xiaoqi; Li, Shiguang; Hu, Xinyu; Luo, Ya; Wang, Xiuli; Yang, Xun; Qiu, Changjian; Yang, Yanchun; Zhang, Wei; Bi, Feng; Roberts, Neil; Gong, Qiyong
Post-traumatic stress disorder (PTSD), obsessive–compulsive disorder (OCD), and social anxiety disorder (SAD) all bear the core symptom of anxiety and are separately classified in the new DSM-5 system. The aim of the present study is to obtain evidence for neuroanatomical difference for these disorders. We applied voxel-based morphometry (VBM) with Diffeomorphic Anatomical Registration Through Exponentiated Lie to compare gray matter volume (GMV) in magnetic resonance images obtained for 30 patients with PTSD, 29 patients with OCD, 20 patients with SAD, and 30 healthy controls. GMV across all four groups differed in left hypothalamus and left inferior parietal lobule and post hoc analyses revealed that this difference is primarily due to reduced GMV in the PTSD group relative to the other groups. Further analysis revealed that the PTSD group also showed reduced GMV in frontal lobe, temporal lobe, and cerebellum compared to the OCD group, and reduced GMV in frontal lobes bilaterally compared to SAD group. A significant negative correlation with anxiety symptoms is observed for GMV in left hypothalamus in three disorder groups. We have thus found evidence for brain structure differences that in future could provide biomarkers to potentially support classification of these disorders using MRI. PMID:26347628
Kastenberger, Iris; Schwarzer, Christoph
The putative estrogen receptor GPER1 (the former orphan receptor GPR30) is discussed to be involved in emotional and cognitive functions and stress control. We recently described the induction of anxiety-like effects by the GPER1 agonist G-1 upon systemic injection into mice. To contribute to a better understanding of the role of GPER1 in anxiety and stress, we investigated germ-line GPER1 deficient mice. Our experiments revealed marked differences between the sexes. A mild but consistent phenotype of increased exploratory drive was observed in the home cage, the elevated plus maze and the light–dark choice test in male GPER1 KO mice. In contrast, female GPER1-KO mice displayed a less pronounced phenotype in these tests. Estrous-stage dependent mild anxiolytic-like effects were observed solely in the open field test. Notably, we observed a strong shift in acute stress coping behavior in the tail suspension test and basal corticosterone levels in different phases of the estrous cycle in female GPER1-KO mice. Our data, in line with previous reports, suggest that GPER1 is involved in anxiety and stress control. Surprisingly, its effects appear to be stronger in male than female mice. PMID:25236887
Narwade, Santosh C.; Mallick, Birendra N.; Deobagkar, Deepti D.
Sleep disorders are associated with cognitive impairment. Selective rapid eye movement sleep (REMS) deprivation (REMSD) alters several physiological processes and behaviors. By employing NGS platform we carried out transcriptomic analysis in brain samples of control rats and those exposed to REMSD. The expression of genes involved in chromatin assembly, methylation, learning, memory, regulation of synaptic transmission, neuronal plasticity and neurohypophysial hormone synthesis were altered. Increased transcription of BMP4, DBH and ATP1B2 genes after REMSD supports our earlier findings and hypothesis. Alteration in the transcripts encoding histone subtypes and important players in chromatin remodeling was observed. The mRNAs which transcribe neurotransmitters such as OXT, AVP, PMCH and LNPEP and two small non-coding RNAs, namely RMRP and BC1 were down regulated. At least some of these changes are likely to regulate REMS and may participate in the consequences of REMS loss. Thus, the findings of this study have identified key epigenetic regulators and neuronal plasticity genes associated to REMS and its loss. This analysis provides a background and opens up avenues for unraveling their specific roles in the complex behavioral network particularly in relation to sustained REMS-loss associated changes. PMID:28367113
Jung, Yong Woo; Kim, Hyun Gyung; Perry, Curtis J; Kaech, Susan M
C-C receptor 7 (CCR7) is important to allow T cells and dendritic cells to migrate toward CCL19- and CCL21-producing cells in the T-cell zone of the spleen and lymph nodes. The role of this chemokine receptor in regulating the homeostasis of effector and memory T cells during acute viral infection is poorly defined, however. In this study, we show that CCR7 expression alters memory CD8 T-cell homeostasis following lymphocytic choriomeningitis virus infection. Greater numbers of CCR7-deficient memory T cells were formed and maintained compared with CCR7-sufficient memory T cells, especially in the lung and bone marrow. The CCR7-deficient memory T cells also displayed enhanced rates of homeostatic turnover, which may stem from increased exposure to IL-15 as a consequence of reduced exposure to IL-7, because removal of IL-15, but not of IL-7, normalized the numbers of CCR7-sufficient and CCR7-deficient memory CD8 T cells. This result suggests that IL-15 is the predominant cytokine supporting augmentation of the CCR7(-/-) memory CD8 T-cell pool. Taken together, these data suggest that CCR7 biases memory CD8 T cells toward IL-7-dependent niches over IL-15-dependent niches, which provides insight into the homeostatic regulation of different memory T-cell subsets.
Hansen, Katelin F.; Sakamoto, Kensuke; Aten, Sydney; Snider, Kaitlin H.; Loeser, Jacob; Hesse, Andrea M.; Page, Chloe E.; Pelz, Carl; Arthur, J. Simon C.; Impey, Soren
miR-132 and miR-212 are structurally related microRNAs that have been found to exert powerful modulatory effects within the central nervous system (CNS). Notably, these microRNAs are tandomly processed from the same noncoding transcript, and share a common seed sequence: thus it has been difficult to assess the distinct contribution of each microRNA to gene expression within the CNS. Here, we employed a combination of conditional knockout and transgenic mouse models to examine the contribution of the miR-132/-212 gene locus to learning and memory, and then to assess the distinct effects that each microRNA has on hippocampal gene expression. Using a conditional deletion approach, we show that miR-132/-212 double-knockout mice exhibit significant cognitive deficits in spatial memory, recognition memory, and in tests of novel object recognition. Next, we utilized transgenic miR-132 and miR-212 overexpression mouse lines and the miR-132/-212 double-knockout line to explore the distinct effects of these two miRNAs on the transcriptional profile of the hippocampus. Illumina sequencing revealed that miR-132/-212 deletion increased the expression of 1138 genes; Venn analysis showed that 96 of these genes were also downregulated in mice overexpressing miR-132. Of the 58 genes that were decreased in animals overexpressing miR-212, only four of them were also increased in the knockout line. Functional gene ontology analysis of downregulated genes revealed significant enrichment of genes related to synaptic transmission, neuronal proliferation, and morphogenesis, processes known for their roles in learning, and memory formation. These data, coupled with previous studies, firmly establish a role for the miR-132/-212 gene locus as a key regulator of cognitive capacity. Further, although miR-132 and miR-212 share a seed sequence, these data indicate that these miRNAs do not exhibit strongly overlapping mRNA targeting profiles, thus indicating that these two genes may function in
McCormick, Cheryl M; Thomas, Catherine M; Sheridan, Cheryl S; Nixon, Feather; Flynn, Jennifer A; Mathews, Iva Z
The ongoing development of the hippocampus in adolescence may be vulnerable to stressors. The effects of social instability stress (SS) in adolescence (daily 1 h isolation and change of cage partner postnatal days 30-45) on cell proliferation in the dentate gyrus (DG) in adolescence (on days 33 and 46, experiment 1) and in adulthood (experiment 2) was examined in Long Evans male rats and compared to nonstressed controls (CTL). Additionally, in experiment 2, a separate group of SS and CTL rats was tested on either a spatial (hippocampal-dependent) or nonspatial (nonhippocampal dependent) version of an object memory test and also were used to investigate hippocampal expression of markers of synaptic plasticity. No memory impairment was evident until the SS rats were adults, and the impairment was only on the spatial test. SS rats initially (postnatal day 33) had increased cell proliferation based on counts of Ki67 immunoreactive (ir) cells and greater survival of immature neurons based on counts of doublecortin ir cells on day 46 and in adulthood, irrespective of behavioral testing. Counts of microglia in the DG did not differ by stress group, but behavioral testing was associated with reduced microglia counts compared to nontested rats. As adults, SS and CTL rats did not differ in hippocampal expression of synaptophysin, but compared to CTL rats, SS rats had higher expression of basal calcium/calmodulin-dependent kinase II (CamKII), and lower expression of the phosphorylated CamKII subunit threonine 286, signaling molecules related to synaptic plasticity. The results are contrasted with those from previous reports of chronic stress in adult rats, and we conclude that adolescent stress alters the ongoing development of the hippocampus leading to impaired spatial memory in adulthood, highlighting the heightened vulnerability to stressors in adolescence.
Winkle, Cortney C.; Olsen, Reid H. J.; Kim, Hyojin; Moy, Sheryl S.
During hippocampal development, newly born neurons migrate to appropriate destinations, extend axons, and ramify dendritic arbors to establish functional circuitry. These developmental stages are recapitulated in the dentate gyrus of the adult hippocampus, where neurons are continuously generated and subsequently incorporate into existing, local circuitry. Here we demonstrate that the E3 ubiquitin ligase TRIM9 regulates these developmental stages in embryonic and adult-born mouse hippocampal neurons in vitro and in vivo. Embryonic hippocampal and adult-born dentate granule neurons lacking Trim9 exhibit several morphological defects, including excessive dendritic arborization. Although gross anatomy of the hippocampus was not detectably altered by Trim9 deletion, a significant number of Trim9−/− adult-born dentate neurons localized inappropriately. These morphological and localization defects of hippocampal neurons in Trim9−/− mice were associated with extreme deficits in spatial learning and memory, suggesting that TRIM9-directed neuronal morphogenesis may be involved in hippocampal-dependent behaviors. SIGNIFICANCE STATEMENT Appropriate generation and incorporation of adult-born neurons in the dentate gyrus are critical for spatial learning and memory and other hippocampal functions. Here we identify the brain-enriched E3 ubiquitin ligase TRIM9 as a novel regulator of embryonic and adult hippocampal neuron shape acquisition and hippocampal-dependent behaviors. Genetic deletion of Trim9 elevated dendritic arborization of hippocampal neurons in vitro and in vivo. Adult-born dentate granule cells lacking Trim9 similarly exhibited excessive dendritic arborization and mislocalization of cell bodies in vivo. These cellular defects were associated with severe deficits in spatial learning and memory. PMID:27147649
McDonald, Robert J; Zelinski, Erin L; Keeley, Robin J; Sutherland, Dylan; Fehr, Leah; Hong, Nancy S
Humans exposed to shiftwork conditions have been reported to have increased susceptibility to various health problems including various forms of dementia, cancer, heart disease, and metabolic disorders related to obesity. The present experiments assessed the effects of circadian disruption on learning and memory function and various food related processes including diet consumption rates, food metabolism, and changes in body weight. These experiments utilized a novel variant of the conditioned place preference task (CPP) that is normally used to assess Pavlovian associative learning and memory processes produced via repeated context-reward pairings. For the present experiments, the standard CPP paradigm was modified in that both contexts were paired with food, but the dietary constituents of the food were different. In particular, we were interested in whether rats could differentiate between two types of carbohydrates, simple (dextrose) and complex (starch). Consumption rates for each type of carbohydrate were measured throughout training. A test of context preference without the food present was also conducted. At the end of behavioral testing, a fasting glucose test and a glucose challenge test were administered. Chronic photoperiod shifting resulted in impaired context learning and memory processes thought to be mediated by a neural circuit centered on the hippocampus. The results also showed that preferences for the different carbohydrate diets were altered in rats experiencing photoperiod shifting in that they maintained an initial preference for the simple carbohydrate throughout training. Lastly, photoperiod shifting resulted in changes in fasting blood glucose levels and elicited weight gain. These results show that chronic photoperiod shifting, which likely resulted in circadian dysfunction, impairs multiple functions of the brain and/or body in the same individual.
Brand, Judith, Ed.
This theme issue of the journal "Exploring" covers the topic of "memories" and describes an exhibition at San Francisco's Exploratorium that ran from May 22, 1998 through January 1999 and that contained over 40 hands-on exhibits, demonstrations, artworks, images, sounds, smells, and tastes that demonstrated and depicted the biological,…
Stratton, Matthew S; Staros, Michelle; Budefeld, Tomaz; Searcy, Brian T; Nash, Connor; Eitel, Chad; Carbone, David; Handa, Robert J; Majdic, Gregor; Tobet, Stuart A
Neurons of the paraventricular nucleus of the hypothalamus (PVN) regulate the hypothalamic- pituitary-adrenal (HPA) axis and the autonomic nervous system. Females lacking functional GABA(B) receptors because of a genetic disruption of the R1 subunit have altered cellular characteristics in and around the PVN at birth. The genetic disruption precluded appropriate assessments of physiology or behavior in adulthood. The current study was conducted to test the long term impact of a temporally restricting pharmacological blockade of the GABA(B) receptor to a 7-day critical period (E11-E17) during embryonic development. Experiments tested the role of GABA(B) receptor signaling in fetal development of the PVN and later adult capacities for adult stress related behaviors and physiology. In organotypic slices containing fetal PVN, there was a female specific, 52% increase in cell movement speeds with GABA(B) receptor antagonist treatment that was consistent with a sex-dependent lateral displacement of cells in vivo following 7 days of fetal exposure to GABA(B) receptor antagonist. Anxiety-like and depression-like behaviors, open-field activity, and HPA mediated responses to restraint stress were measured in adult offspring of mothers treated with GABA(B) receptor antagonist. Embryonic exposure to GABA(B) receptor antagonist resulted in reduced HPA axis activation following restraint stress and reduced depression-like behaviors. There was also increased anxiety-like behavior selectively in females and hyperactivity in males. A sex dependent response to disruptions of GABA(B) receptor signaling was identified for PVN formation and key aspects of physiology and behavior. These changes correspond to sex specific prevalence in similar human disorders, namely anxiety disorders and hyperactivity.
Stratton, Matthew S.; Staros, Michelle; Budefeld, Tomaz; Searcy, Brian T.; Nash, Connor; Eitel, Chad; Carbone, David; Handa, Robert J.; Majdic, Gregor; Tobet, Stuart A.
Neurons of the paraventricular nucleus of the hypothalamus (PVN) regulate the hypothalamic- pituitary-adrenal (HPA) axis and the autonomic nervous system. Females lacking functional GABAB receptors because of a genetic disruption of the R1 subunit have altered cellular characteristics in and around the PVN at birth. The genetic disruption precluded appropriate assessments of physiology or behavior in adulthood. The current study was conducted to test the long term impact of a temporally restricting pharmacological blockade of the GABAB receptor to a 7-day critical period (E11–E17) during embryonic development. Experiments tested the role of GABAB receptor signaling in fetal development of the PVN and later adult capacities for adult stress related behaviors and physiology. In organotypic slices containing fetal PVN, there was a female specific, 52% increase in cell movement speeds with GABAB receptor antagonist treatment that was consistent with a sex-dependent lateral displacement of cells in vivo following 7 days of fetal exposure to GABAB receptor antagonist. Anxiety-like and depression-like behaviors, open-field activity, and HPA mediated responses to restraint stress were measured in adult offspring of mothers treated with GABAB receptor antagonist. Embryonic exposure to GABAB receptor antagonist resulted in reduced HPA axis activation following restraint stress and reduced depression-like behaviors. There was also increased anxiety-like behavior selectively in females and hyperactivity in males. A sex dependent response to disruptions of GABAB receptor signaling was identified for PVN formation and key aspects of physiology and behavior. These changes correspond to sex specific prevalence in similar human disorders, namely anxiety disorders and hyperactivity. PMID:25162235
Fraga, Mabel C; Moura, Egberto G; Silva, Juliana Oliveira; Bonomo, Isabela Teixeira; Filgueiras, Cláudio C; Abreu-Villaça, Yael; Passos, Magna C F; Lisboa, Patrícia C; Manhães, Alex C
Maternal hypoprolactinemia at the end of lactation in rats reduces milk production and is associated with offspring's malnutrition. Since malnutrition during development is also known to have long lasting effects on cognition and emotion, in the present study we tested the hypothesis that maternal hypoprolactinemia, induced by bromocriptine treatment, at the end of the lactating period affects memory/learning, novelty-seeking and anxiety-like behaviors in adult male Wistar rats using, respectively, the radial arm water maze (RAWM), the hole board (HB) arena and the elevated plus-maze (EPM). We also analyzed serum corticosterone and thyroid hormone levels at postnatal day (PN) 21. Lactating dams were treated with bromocriptine (BRO, 1mg twice a day, inhibiting prolactin) or saline from PN19 to 21 (the last 3 days of lactation). BRO offspring had hypercorticosteronemia and hypothyroidism at PN21. In the RAWM, reductions in latency observed in CON rats were initially more accentuated than in BRO ones. By the end of the testing period, latencies became similar between groups. No difference was observed between groups regarding the number of nose-pokes in the HB. In the EPM, BRO rats stayed less time in and had fewer entries into the open-arms than CON ones. This pattern of results indicates that maternal bromocriptine treatment at the end of the lactating period results in poorer memory/learning performance and in higher levels of anxiety-like behavior in the adult offspring, demonstrating that even a relatively short period of malnutrition during development can have long lasting detrimental effects regarding cognition and emotion.
Lach, Gilliard; de Lima, Thereza Christina Monteiro
Neuropeptide Y (NPY) is the most abundant peptide in the central nervous system (CNS) and is densely localized in the brain regions involved in stress, memory, fear and anxiety. Although previous research supports a role for NPY in the mediation of rodent and human emotional behavior, there is currently a lack of information on the effects of low doses of NPY that could have a potential therapeutic advantage, minimizing side-effects such as cognition impairment or sedation. Herein, we assessed the effects of intracerebroventricular (i.c.v.) administration of low doses of NPY, and of the Y1-agonist Leu31Pro34-NPY (LP-NPY) on contextual fear conditioning (CFC), as they have no effect on unconditioned anxiety-like, locomotor activity and non-emotional memory. NPY (3 pmol) and LP-NPY (1 pmol) inhibited freezing behavior when administered in the acquisition or consolidation stages, indicating a reduction of fear. When injected in the extinction phase, only NPY inhibited freezing behavior on CFC. Pre-treatment with the Y1-antagonist BIBO3304 before NPY and LP-NPY was able to prevent the inhibition of fear responses induced by both NPY agonists. Taken together, our results demonstrate robust fear-inhibiting effects of i.c.v. injection of NPY on contextual fear conditioning in rats, a response that is mediated, at least in part, by the Y1 receptor. Moreover, these treatments were unable to change locomotor activity or to show an anxiolytic-like effect, as evaluated in an open-field and an elevated plus-maze. This specific fear reduction effect may underlie resilience systems in the CNS and has potential therapeutic relevance in PTSD.
Zoladz, Phillip R; Fleshner, Monika; Diamond, David M
Individuals exposed to life-threatening trauma are at risk for developing post-traumatic stress disorder (PTSD), a debilitating condition that involves persistent anxiety, intrusive memories and several physiological disturbances. Current pharmacotherapies for PTSD manage only a subset of these symptoms and typically have adverse side effects which limit their overall effectiveness. We evaluated the effectiveness of three different pharmacological agents to ameliorate a broad range of PTSD-like symptoms in our established predator-based animal model of PTSD. Adult male Sprague-Dawley rats were given 1-h cat exposures on two occasions that were separated by 10 days, in conjunction with chronic social instability. Beginning 24 h after the first cat exposure, rats received daily injections of amitriptyline, clonidine, tianeptine or vehicle. Three weeks after the second cat exposure, all rats underwent a battery of behavioral and physiological tests. The vehicle-treated, psychosocially stressed rats demonstrated a robust fear memory for the two cat exposures, as well as increased anxiety expressed on the elevated plus maze, an exaggerated startle response, elevated heart rate and blood pressure, reduced growth rate and increased adrenal gland weight, relative to the vehicle-treated, non-stressed (control) rats. Neither amitriptyline nor clonidine was effective at blocking the entire cluster of stress-induced sequelae, and each agent produced adverse side effects in control subjects. Only the antidepressant tianeptine completely blocked the effects of psychosocial stress on all of the physiological and behavioral measures that were examined. These findings illustrate the differential effectiveness of these three treatments to block components of PTSD-like symptoms in rats, and in particular, reveal the profile of tianeptine as the most effective of all three agents.
Liao, Wei; Qiu, Changjian; Gentili, Claudio; Walter, Martin; Pan, Zhengyong; Ding, Jurong; Zhang, Wei; Gong, Qiyong; Chen, Huafu
The amygdala is often found to be abnormally recruited in social anxiety disorder (SAD) patients. The question whether amygdala activation is primarily abnormal and affects other brain systems or whether it responds "normally" to an abnormal pattern of information conveyed by other brain structures remained unanswered. To address this question, we investigated a network of effective connectivity associated with the amygdala using Granger causality analysis on resting-state functional MRI data of 22 SAD patients and 21 healthy controls (HC). Implications of abnormal effective connectivity and clinical severity were investigated using the Liebowitz Social Anxiety Scale (LSAS). Decreased influence from inferior temporal gyrus (ITG) to amygdala was found in SAD, while bidirectional influences between amygdala and visual cortices were increased compared to HCs. Clinical relevance of decreased effective connectivity from ITG to amygdala was suggested by a negative correlation of LSAS avoidance scores and the value of Granger causality. Our study is the first to reveal a network of abnormal effective connectivity of core structures in SAD. This is in support of a disregulation in predescribed modules involved in affect control. The amygdala is placed in a central position of dysfunction characterized both by decreased regulatory influence of orbitofrontal cortex and increased crosstalk with visual cortex. The model which is proposed based on our results lends neurobiological support towards cognitive models considering disinhibition and an attentional bias towards negative stimuli as a core feature of the disorder.
Beccano-Kelly, Dayne A; Volta, Mattia; Munsie, Lise N; Paschall, Sarah A; Tatarnikov, Igor; Co, Kimberley; Chou, Patrick; Cao, Li-Ping; Bergeron, Sabrina; Mitchell, Emma; Han, Heather; Melrose, Heather L; Tapia, Lucia; Raymond, Lynn A; Farrer, Matthew J; Milnerwood, Austen J
Mutations in leucine-rich repeat kinase 2 (Lrrk2) are the most common genetic cause of Parkinson's disease (PD), a neurodegenerative disorder affecting 1-2% of those >65 years old. The neurophysiology of LRRK2 remains largely elusive, although protein loss suggests a role in glutamatergic synapse transmission and overexpression studies show altered dopamine release in aged mice. We show that glutamate transmission is unaltered onto striatal projection neurons (SPNs) of adult LRRK2 knockout mice and that adult animals exhibit no detectable cognitive or motor deficits. Basal synaptic transmission is also unaltered in SPNs of LRRK2 overexpressing mice, but they do exhibit clear alterations to D2-receptor-mediated short-term synaptic plasticity, behavioral hypoactivity and impaired recognition memory. These phenomena are associated with decreased striatal dopamine tone and abnormal dopamine- and cAMP-regulated phosphoprotein 32 kDa signal integration. The data suggest that LRRK2 acts at the nexus of dopamine and glutamate signaling in the adult striatum, where it regulates dopamine levels, presynaptic glutamate release via D2-dependent synaptic plasticity and dopamine-receptor signal transduction.
Onaolapo, Olakunle James; Aremu, Olaleye Samuel; Onaolapo, Adejoke Yetunde
The present study investigated changes in behaviour associated with oral monosodium glutamate (a flavouring agent), using the open field, elevated plus maze and conditioned place preference (CPP) paradigms, respectively. Mice were assigned to two groups for CPP [monosodium glutamate (MSG)-naïve (n = 40) and MSG-pretreated (n = 40)] and two groups for open field (OF) and elevated plus maze (EPM) tests [n = 40 each], respectively. Animals in respective groups were then divided into four subgroups (n = 10) (vehicle or MSG (80, 160 and 320 mg/kg)). MSG-naïve mice were observed in the CPP box in three phases (pre-conditioning, conditioning and post-conditioning). Mice were conditioned to MSG or an equivalent volume of saline. The MSG pretreatment group received vehicle or respective doses of MSG daily for 21 days, prior to conditioning. Mice in the OF or EPM groups received vehicle or doses of MSG (orally) for 21 days, at 10 ml/kg. Open field or EPM behaviours were assessed on days 1 and 21. At the end of the experiments, mice in the OF groups were sacrificed and brain homogenates used to assay glutamate and glutamine. Results showed that administration of MSG was associated with a decrease in rearing, dose-related mixed horizontal locomotor, grooming and anxiety-related response and an increase in brain glutamate/glutamine levels. Following exposure to the CPP paradigm, MSG-naïve and MSG-pretreated mice both showed 'drug-paired' chamber preference. The study concluded that MSG (at the administered doses) was associated with changes in open field activities, anxiety-related behaviours and brain glutamate/glutamine levels; its ingestion also probably leads to a stimulation of the brain reward system.
Hoeller, Alexandre Ademar; Duzzioni, Marcelo; Duarte, Filipe Silveira; Leme, Leandro Rinaldi; Costa, Ana Paula Ramos; Santos, Evelyn Cristina da Silva; de Pieri, Claudini Honório; dos Santos, Alessandra Antunes; Naime, Aline Aita; Farina, Marcelo; de Lima, Thereza Christina Monteiro
The cholinergic system is implicated in emotional regulation. The injection of non-convulsant doses of the muscarinic receptor agonist pilocarpine (PILO) induces long-lasting anxiogenic responses in rats evaluated at different time-points (24h to 3 months). To investigate the underlying mechanisms, rats treated with PILO (150mg/kg) were injected 24h or 1 month later with an anxiolytic (diazepam, 1mg/kg, DZP) or anxiogenic (pentylenetetrazole, 15mg/kg, PTZ) drug and evaluated in the elevated plus-maze (EPM). Prefrontal cortex (PFC) and hippocampal (HIP) electroencephalographic recordings and acetylcolinesterase (AChE) activity were also analyzed after PILO treatment. Anxiogenic responses observed in the EPM 24h or 1 month after PILO treatment (e.g., decreased time spent and number of entries into the open arms of the maze) were blocked by DZP but not affected by PTZ. No epileptiform events were registered in the HIP or PFC at 24h or 1 month after PILO injection, but enhanced theta activity was observed in the HIP. DZP decreased hippocampal theta of PILO-treated rats in contrast with PTZ, which increased this parameter in saline- and PILO-treated rats. The HIP and PFC AChE activity did not change after PILO treatment. Our findings demonstrate that the long-term effects on the emotionality of rats induced by PILO are associated with electrophysiological changes in the HIP and sensitive to pharmacological manipulation of the GABAergic system. The present work may support this new research model of long-lasting anxiety, while also highlighting the muscarinic system as a potential target involved in anxiety disorders.
Darcet, Flavie; Gardier, Alain M; David, Denis J; Guilloux, Jean-Philippe
Cognitive disturbances are often reported as serious invalidating symptoms in patients suffering from major depression disorders (MDD) and are not fully corrected by classical monoaminergic antidepressant drugs. If the role of 5-HT4 receptor agonists as cognitive enhancers is well established in naïve animals or in animal models of cognitive impairment, their cognitive effects in the context of stress need to be examined. Using a mouse model of anxiety/depression (CORT model), we reported that a chronic 5-HT4 agonist treatment (RS67333, 1.5mg/kg/day) restored chronic corticosterone-induced cognitive deficits, including episodic-like, associative and spatial learning and memory impairments. On the contrary, a chronic monoaminergic antidepressant drug treatment with fluoxetine (18mg/kg/day) only partially restored spatial learning and memory deficits and had no effect in the associative/contextual task. These results suggest differential mechanisms underlying cognitive effects of these drugs. Finally, the present study highlights 5-HT4 receptor stimulation as a promising therapeutic mechanism to alleviate cognitive symptoms related to MDD.
Ribeiro, Leandro Rodrigo; Della-Pace, Iuri Domingues; de Oliveira Ferreira, Ana Paula; Funck, Vinícius Rafael; Pinton, Simone; Bobinski, Franciane; de Oliveira, Clarissa Vasconcelos; da Silva Fiorin, Fernando; Duarte, Marta Maria Medeiros Frescura; Furian, Ana Flávia; Oliveira, Mauro Schneider; Nogueira, Cristina Wayne; Dos Santos, Adair Roberto Soares; Royes, Luiz Fernando Freire; Fighera, Michele Rechia
The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67 μmol/g as a function of animal age). In the following days (29th-31st) animal behavior was assessed in the object exploration test and elevated plus maze. It was performed differential cell and the number of neutrophils counting and interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels in the blood, as well as levels of IL-1β, TNF-α, inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in the cerebral cortex were measured. Behavioral tests showed that animals injected chronically with MMA have a reduction in the recognition index (R.I.) when the objects were arranged in a new configuration space, but do not exhibit anxiety-like behaviors. The blood of MMA-treated animals showed a decrease in the number of polymorphonuclear and neutrophils, and an increase in mononuclear and other cell types, as well as an increase of IL-1β and TNF-α levels. Concomitantly, MMA increased levels of IL-1β, TNF-α, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the
Mathew, Roy J.
Anxiety disorders are some of the commonest psychiatric disorders and anxiety commonly co-exists with other psychiatric conditions. Anxiety can also be a normal emotion. Thus, study of the neurobiological effects of anxiety is of considerable significance. In the normal brain, cerebral blood flow (CBF) and metabolism (CMR) serve as indices of brain function. CBF/CMR research is expected to provide new insight into alterations in brain function in anxiety disorders and other psychiatric disorders. Possible associations between stress I anxiety I panic and cerebral ischemia I stroke give additional significance to the effects of anxiety on CBF. With the advent of non-invasive techniques, study of CBF/CMR in anxiety disorders became easier. A large numbers of research reports are available on the effects of stress, anxiety and panic on CBF/CMR in normals and anxiety disorder patients. This article reviews the available human research on this topic. PMID:21743685
Xu, Xinyu; Zhang, Qian; Tian, Xin; Wang, Guolin
Sevoflurane has been found to increase apoptosis and pathologic markers associated with Alzheimer disease, provoking concern over their potential contribution to postoperative cognitive dysfunction. This study aimed to determine the effects of sevoflurane on contextual fear memory of aged rats and to characterize local population connectivity of local field potentials (LFPs) in medial prefrontal cortex (mPFC) of aged rats during contextual fear memory. Eighteen-month-old male SD rats were implanted with one multichannel electrode array in mPFC. The aged rats were divided into control group, sevoflurane group (1 MAC sevoflurane for 2 h) and surgical group with 1.0 MAC sevoflurane for 2 h. We then assessed the effect of the anesthesia on contextual fear memory, and alterations in the local population connectivity of mPFC LFP networks by partial directed coherence (PDC). Surgery impaired contextual fear memory and reduced local population connectivity of mPFC LFP networks in aged rats at day 1 after the surgery and anesthesia. 1 MAC Sevoflurane anesthesia induced neither contextual fear memory impairment nor alterations in local population connectivity of mPFC LFP networks in aged rats when tested 1, 7, 15 and 30 days after exposure (P > 0.05). PDC values of theta band mPFC LFPs became strongly increased during contextual fear memory at 1, 7, 15, and 30 days after anesthesia. Our results suggest that 1 MAC sevoflurane anesthesia does not induce contextual fear memory impairment in aged rats and suggest that the increased local population connectivity in theta bands LFPs of mPFC plays a role in contextual fear memory.
Brent, Benjamin K.; Rosso, Isabelle M.; Thermenos, Heidi W.; Holt, Daphne J.; Faraone, Stephen V.; Makris, Nikos; Tsuang, Ming T.; Seidman, Larry J.
Background Structural alterations of the lateral temporal cortex (LTC) in association with memory impairments have been reported in schizophrenia. This study investigated whether alterations of LTC structure were linked with impaired facial and/or verbal memory in young first-degree relatives of people with schizophrenia and, thus, may be indicators of vulnerability to the illness. Methods Subjects included 27 non-psychotic, first-degree relatives of schizophrenia patients, and 48 healthy controls, between the ages of 13 and 28. Participants underwent high-resolution magnetic resonance imaging (MRI) at 1.5 Tesla. The LTC was parcellated into superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, and temporal pole. Total cerebral and LTC volumes were measured using semi-automated morphometry. The Wechsler Memory Scale – Third Edition and the Children’s Memory Scale – Third Edition assessed facial and verbal memory. General linear models tested for associations among LTC subregion volumes, familial risk and memory. Results Compared with controls, relatives had significantly smaller bilateral middle temporal gyri. Moreover, right middle temporal gyral volume showed a significant positive association with delayed facial memory in relatives. Conclusion These results support the hypothesis that smaller middle temporal gyri are related to the genetic liability to schizophrenia and may be linked with reduced facial memory in persons at genetic risk for the illness. The findings add to the growing evidence that children at risk for schizophrenia on the basis of positive family history have cortical and subcortical structural brain abnormalities well before psychotic illness occurs. PMID:26621001
Sanefuji, Masafumi; Yamashita, Hiroshi; Torisu, Hiroyuki; Takada, Yui; Imanaga, Hisako; Matsunaga, Mayumi; Ishizaki, Yoshito; Sakai, Yasunari; Yoshida, Keiko; Hara, Toshiro
Strategy in short-term memory for serially presented pictures shifts gradually from a non-phonological to a phonological method as memory ability increases during typical childhood development. However, little is known about the development of this strategic change in children with attention-deficit/hyperactivity disorder (ADHD). To understand the neural basis of ADHD, we investigated short-term memory strategies using near-infrared spectroscopy. ADHD children aged from 6 to 12 years and age- and sex-matched control children were assessed in this study. Regional activity was monitored in the left ventrolateral prefrontal cortex to assess strategies used during short-term memory for visual or phonological objects. We examined the hypothesis that the strategic methods used would be correlated with memory ability. Higher memory ability and the phonological strategy were significantly correlated in the control group but not in the ADHD group. Intriguingly, ADHD children receiving methylphenidate treatment exhibited increased use of phonological strategy compared with those without. In conclusion, we found evidence of an altered strategy in short-term memory in ADHD children. The modulatory effect of methylphenidate indicates its therapeutic efficacy.
Moon, Chung-Man; Jeong, Gwang-Woo
Generalized anxiety disorder (GAD) is characterized by emotional dysregulation and cognitive deficit in conjunction with brain morphometric and metabolic alterations. This study assessed the combined neural morphological deficits and metabolic abnormality in patients with GAD. Thirteen patients with GAD and 13 healthy controls matched for age, sex, and education level underwent high-resolution T1-weighted MRI and proton magnetic resonance spectroscopy ((1)H-MRS) at 3Tesla. In this study, the combination of voxel-based morphometry (VBM) and (1)H-MRS was used to assess the brain morphometric and metabolic alterations in GAD. The patients showed significantly reduced white matter (WM) volumes in the midbrain (MB), precentral gyrus (PrG), dorsolateral prefrontal cortex (DLPFC) and anterior limb of the internal capsule (ALIC) compared to the controls. In MRS study, the choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) ratios in the DLPFC were significantly lower in the patients. Particularly, the WM volume variation of the DLPFC was positively correlated with both of the Cho/Cr and Cho/NAA ratios in patients with GAD. This study provides an evidence for the association between the morphometric deficit and metabolic changes in GAD. This finding would be helpful to understand the neural dysfunction and pathogenesis in connection with cognitive impairments in GAD.
Short, A K; Fennell, K A; Perreau, V M; Fox, A; O'Bryan, M K; Kim, J H; Bredy, T W; Pang, T Y; Hannan, A J
Recent studies have suggested that physiological and behavioral traits may be transgenerationally inherited through the paternal lineage, possibly via non-genomic signals derived from the sperm. To investigate how paternal stress might influence offspring behavioral phenotypes, a model of hypothalamic–pituitary–adrenal (HPA) axis dysregulation was used. Male breeders were administered water supplemented with corticosterone (CORT) for 4 weeks before mating with untreated female mice. Female, but not male, F1 offspring of CORT-treated fathers displayed altered fear extinction at 2 weeks of age. Only male F1 offspring exhibited altered patterns of ultrasonic vocalization at postnatal day 3 and, as adults, showed decreased time in open on the elevated-plus maze and time in light on the light–dark apparatus, suggesting a hyperanxiety-like behavioral phenotype due to paternal CORT treatment. Interestingly, expression of the paternally imprinted gene Igf2 was increased in the hippocampus of F1 male offspring but downregulated in female offspring. Male and female F2 offspring displayed increased time spent in the open arm of the elevated-plus maze, suggesting lower levels of anxiety compared with control animals. Only male F2 offspring showed increased immobility time on the forced-swim test and increased latency to feed on the novelty-supressed feeding test, suggesting a depression-like phenotype in these animals. Collectively, these data provide evidence that paternal CORT treatment alters anxiety and depression-related behaviors across multiple generations. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf. Sustained elevation of glucocorticoids is therefore involved in the transmission of
Zhu, Hongru; Qiu, Changjian; Meng, Yajing; Yuan, Minlan; Zhang, Yan; Ren, Zhengjia; Li, Yuchen; Huang, Xiaoqi; Gong, Qiyong; Lui, Su; Zhang, Wei
Recent studies involving connectome analysis including graph theory have yielded potential biomarkers for mental disorders. In this study, we aimed to investigate the differences of resting-state network between patients with social anxiety disorder (SAD) and healthy controls (HCs), as well as to distinguish between individual subjects using topological properties. In total, 42 SAD patients and the same number of HCs underwent resting functional MRI, and the topological organization of the whole-brain functional network was calculated using graph theory. Compared with the controls, the patients showed a decrease in 49 positive connections. In the topological analysis, the patients showed an increase in the area under the curve (AUC) of the global shortest path length of the network (Lp) and a decrease in the AUC of the global clustering coefficient of the network (Cp). Furthermore, the AUCs of Lp and Cp were used to effectively discriminate the individual SAD patients from the HCs with high accuracy. This study revealed that the neural networks of the SAD patients showed changes in topological characteristics, and these changes were prominent not only in both groups but also at the individual level. This study provides a new perspective for the identification of patients with SAD. PMID:28266518
Salvan, Piergiorgio; Froudist Walsh, Seán; Allin, Matthew P G; Walshe, Muriel; Murray, Robin M; Bhattacharyya, Sagnik; McGuire, Philip K; Williams, Steven C R; Nosarti, Chiara
thalamic/hippocampal region that was differently activated during the recall condition, with the hippocampal fornix, inferior longitudinal fasciculus and inferior fronto-occipital fasciculus particularly affected. Young adults who were born very preterm display a strikingly different pattern of activation during the process of learning in key structures of the learning and memory network, including anterior cingulate and caudate body during encoding and thalamus/parahippocampal gyrus during cued recall. Altered activation in thalamus/parahippocampal gyrus may be explained by reduced connections between these areas and the hippocampus, which may be a direct consequence of neonatal hypoxic/ischemic injury. These results could reflect the effect of adaptive plastic processes associated with high-order cognitive functions, at least when the cognitive load remains relatively low, as ex-preterm young adults displayed unimpaired performance in completing the verbal paired associate learning task.
Schweitzer, Julie B; Riggins, Tracy; Liang, Xia; Gallen, Courtney; Kurup, Pradeep K; Ross, Thomas J; Black, Maureen M; Nair, Prasanna; Salmeron, Betty Jo
The persistence of effects of prenatal drug exposure (PDE) on brain functioning during adolescence is poorly understood. We explored neural activation to a visuospatial working memory (VSWM) versus a control task using functional magnetic resonance imaging (fMRI) in adolescents with PDE and a community comparison group (CC) of non-exposed adolescents. We applied graph theory metrics to resting state data using a network of nodes derived from the VSWM task activation map to further explore connectivity underlying WM functioning. Participants (ages 12-15 years) included 47 adolescents (27 PDE and 20 CC). All analyses controlled for potentially confounding differences in birth characteristics and postnatal environment. Significant group by task differences in brain activation emerged in the left middle frontal gyrus (BA 6) with the CC group, but not the PDE group, activating this region during VSWM. The PDE group deactivated the culmen, whereas the CC group activated it during the VSWM task. The CC group demonstrated a significant relation between reaction time and culmen activation, not present in the PDE group. The network analysis underlying VSWM performance showed that PDE group had lower global efficiency than the CC group and a trend level reduction in local efficiency. The network node corresponding to the BA 6 group by task interaction showed reduced nodal efficiency and fewer direct connections to other nodes in the network. These results suggest that adolescence reveals altered neural functioning related to response planning that may reflect less efficient network functioning in youth with PDE.
Beaumier, Coreen M; Mathew, Anuja; Bashyam, Hema S; Rothman, Alan L
Dengue virus is the causative agent of dengue fever and the more-severe dengue hemorrhagic fever (DHF). Human studies suggest that the increased risk of DHF during secondary infection is due to immunopathology partially mediated by cross-reactive memory T cells from the primary infection. To model T cell responses to sequential infections, we immunized mice with different sequences of dengue virus serotypes and measured the frequency of peptide-specific T cells after infection. The acute response after heterologous secondary infections was enhanced compared with the acute or memory response after primary infection. Also, the hierarchy of epitope-specific responses was influenced by the specific sequence of infection. Adoptive-transfer experiments showed that memory T cells responded preferentially to the secondary infection. These findings demonstrate that cross-reactive T cells from a primary infection alter the immune response during a heterologous secondary infection.
Bellés, Montserrat; Heredia, Luis; Serra, Noemí; Domingo, José L; Linares, Victoria
Radiation therapy is a major cause of long-term complications observed in survivors of pediatric brain tumors. However, the effects of low-doses of ionizing radiation (IR) to the brain are less studied. On the other hand, tobacco is one of the most heavily abused drugs in the world. Tobacco is not only a health concern for adults. It has also shown to exert deleterious effects on fetuses, newborns, children and adolescents. Exposure to nicotine (Nic) from smoking may potentiate the toxic effects induced by IR on brain development. In this study, we evaluated in mice the cognitive effects of concomitant exposure to low doses of internal radiation ((137)Cs) and Nic during neonatal brain development. On postnatal day 10 (PND10), two groups of C57BL/6J mice were subcutaneously exposed to 137-Cesium ((137)Cs) (4000 and 8000 Bq/kg) and/or Nic (100 μg/ml). At the age of two months, neurobehavior of mice was assessed. Results showed that exposure to IR-alone or in combination with Nic-increased the anxiety-like of the animals without changing the activity levels. Moreover, exposure to IR impaired learning and spatial memory. However, Nic administration was able to reverse this effect, but only at the low dose of (137)Cs.
Hüttenrauch, Melanie; Salinas, Gabriela; Wirths, Oliver
There is ample evidence that physical activity exerts positive effects on a variety of brain functions by facilitating neuroprotective processes and influencing neuroplasticity. Accordingly, numerous studies have shown that continuous exercise can successfully diminish or prevent the pathology of neurodegenerative diseases such as Alzheimer’s disease in transgenic mouse models. However, the long-term effect of physical activity on brain health of aging wild-type (WT) mice has not yet been studied in detail. Here, we show that prolonged physical and cognitive stimulation, mediated by an enriched environment (EE) paradigm for a duration of 11 months, leads to reduced anxiety and improved spatial reference memory in C57BL6 WT mice. While the number of CA1 pyramidal neurons remained unchanged between standard housed (SH) and EE mice, the number of dentate gyrus (DG) neurons, as well as the CA1 and DG volume were significantly increased in EE mice. A whole-brain deep sequencing transcriptome analysis, carried out to better understand the molecular mechanisms underlying the observed effects, revealed an up-regulation of a variety of genes upon EE, mainly associated with synaptic plasticity and transcription regulation. The present findings corroborate the impact of continuous physical activity as a potential prospective route in the prevention of age-related cognitive decline and neurodegenerative disorders. PMID:27536216
Law, Janice W S; Lee, Alan Y W; Sun, Mu; Nikonenko, Alexander G; Chung, Sookja K; Dityatev, Alexander; Schachner, Melitta; Morellini, Fabio
L1, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation and axon outgrowth and guidance. Mutations in the human and mouse L1 gene result in similarly severe neurological abnormalities. To dissociate the functional roles of L1 in the adult brain from developmental abnormalities, we have generated a mutant in which the L1 gene is inactivated by cre-recombinase under the control of the calcium/calmodulin-dependent kinase II promoter. This mutant (L1fy+) did not show the overt morphological and behavioral abnormalities observed previously in constitutive L1-deficient (L1-/-) mice; however, there was an increase in basal excitatory synaptic transmission that was not apparent in L1-/- mice. Similar to L1-/- mice, no defects in short- and long-term potentiation in the CA1 region of the hippocampus were observed. Interestingly, L1fy+ mice showed decreased anxiety in the open field and elevated plus-maze, contrary to L1-/- mice, and altered place learning in the water maze, similar to L1-/- mice. Thus, mice conditionally deficient in L1 expression in the adult brain share some abnormalities, but also display different ones, as compared with L1-/- mice, highlighting the role of L1 in the regulation of synaptic transmission and behavior in adulthood.
Kim, Soyoung; Stephenson, Mary C; Morris, Peter G; Jackson, Stephen R
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that alters cortical excitability in a polarity specific manner and has been shown to influence learning and memory. tDCS may have both on-line and after-effects on learning and memory, and the latter are thought to be based upon tDCS-induced alterations in neurochemistry and synaptic function. We used ultra-high-field (7 T) magnetic resonance spectroscopy (MRS), together with a robotic force adaptation and de-adaptation task, to investigate whether tDCS-induced alterations in GABA and Glutamate within motor cortex predict motor learning and memory. Note that adaptation to a robot-induced force field has long been considered to be a form of model-based learning that is closely associated with the computation and 'supervised' learning of internal 'forward' models within the cerebellum. Importantly, previous studies have shown that on-line tDCS to the cerebellum, but not to motor cortex, enhances model-based motor learning. Here we demonstrate that anodal tDCS delivered to the hand area of the left primary motor cortex induces a significant reduction in GABA concentration. This effect was specific to GABA, localised to the left motor cortex, and was polarity specific insofar as it was not observed following either cathodal or sham stimulation. Importantly, we show that the magnitude of tDCS-induced alterations in GABA concentration within motor cortex predicts individual differences in both motor learning and motor memory on the robotic force adaptation and de-adaptation task.
Featherstone, Robert E; Burton, Christie L; Coppa-Hopman, Romina; Rizos, Zoë; Sinyard, Judy; Kapur, Shitij; Fletcher, Paul J
Schizophrenia is associated with increased rates of substance abuse that are thought to be the result of changes in cortical and mesolimbic dopamine activity. Previous work has shown that gestational methylazoxymethanol acetate (MAM) treatment induces increased mesolimbic dopamine activity when given around the time of embryonic day 17 (ED17), suggesting that MAM treatment may model some aspects of schizophrenia. Given that increased dopaminergic activity facilitates aspects of drug self-administration and reinstatement of drug seeking, the current experiments sought to assess cocaine self-administration in MAM treated animals. Experiment 1 examined the acquisition of cocaine self-administration in ED17 MAM and saline treated rats using a sub-threshold dose of cocaine. In experiment 2 ED17 MAM and saline treated animals were trained to self-administer cocaine and were then assessed under varying doses of cocaine (dose-response), followed by extinction and drug-induced reinstatement of responding. A subset of these animals was trained on a win-shift radial maze task, designed to detect impairments in hippocampal-dependent memory. In experiment 3, MAM and saline treated animals were assessed on a progressive ratio schedule of cocaine delivery. Finally, in experiment 4 MAM and saline treated animals were assessed on cocaine-induced locomotor activity across a range of doses of cocaine. MAM treatment disrupted performance of the win-shift task but did not alter cocaine self-administration or cocaine-induced locomotion. Implications of these results for the MAM model of schizophrenia are discussed.
Šlamberová, R; Vrajová, M; Schutová, B; Mertlová, M; Macúchová, E; Nohejlová, K; Hrubá, L; Puskarčíková, J; Bubeníková-Valešová, V; Yamamotová, A
Since close relationship was shown between drug addiction and memory formation, the aim of the present study was to investigate the effects of interaction between prenatal methamphetamine (MA) exposure and MA treatment in adulthood on spatial and non-spatial memory and on the structure of the N-methyl-D-aspartate (NMDA) receptors in the hippocampus. Adult male rats prenatally exposed to MA (5 mg/kg) or saline were tested in adulthood. Non-spatial memory was examined in the Object Recognition Test (ORT) and spatial memory in the Object Location Test (OLT) and in the Memory Retention Test (MRT) conducted in the Morris Water Maze (MWM), respectively. Based on the type of the memory test animals were injected either acutely (ORT, OLT) or long-term (MWM) with MA (1 mg/kg). After each testing, animals were sacrificed and brains were removed. The hippocampus was then examined in Western Blot analysis for occurrence of different NMDA receptors' subtypes. Our results demonstrated that prenatal MA exposure affects the development of the NMDA receptors in the hippocampus that might correspond with improvement of spatial memory tested in adulthood in the MWM. On the other hand, the effect of prenatal MA exposure on non-spatial memory examined in the ORT was the opposite. In addition, we showed that the effect of MA administration in adulthood on NMDA receptors is influenced by prenatal MA exposure, which seems to correlate with the spatial memory examined in the OLT.
Fortress, Ashley M; Kim, Jaekyoon; Poole, Rachel L; Gould, Thomas J; Frick, Karyn M
Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17β-estradiol (E2) to enhance object recognition memory consolidation requires histone H3 acetylation in the dorsal hippocampus. However, the extent to which histone acetylation is regulated by E2 in middle-aged females is unknown. The mnemonic benefits of E2 in aging females appear to be greatest in middle age, and so pinpointing the molecular mechanisms through which E2 enhances memory at this age could lead to the development of safer and more effective treatments for maintaining memory function without the side effects of current therapies. Here, we show that dorsal hippocampal infusion of E2 rapidly enhanced object recognition and spatial memory, and increased histone H3 acetylation in the dorsal hippocampus, while also significantly reducing levels of histone deacetylase (HDAC2 and HDAC3) proteins. E2 specifically increased histone H3 acetylation at Bdnf promoters pII and pIV in the dorsal hippocampus of both young and middle-aged mice, despite age-related decreases in pI and pIV acetylation. Furthermore, levels of mature BDNF and pro-BDNF proteins in the dorsal hippocampus were increased by E2 in middle-aged females. Together, these data suggest that the middle-aged female dorsal hippocampus remains epigenetically responsive to E2, and that E2 may enhance memory in middle-aged females via epigenetic regulation of Bdnf.
Faucher, Pierre; Mons, Nicole; Micheau, Jacques; Louis, Caroline; Beracochea, Daniel J.
Increasing evidence suggests that abnormal brain accumulation of soluble rather than aggregated amyloid-β1–42 oligomers (Aβo(1–42)) plays a causal role in Alzheimer’s disease (AD). However, as yet, animal’s models of AD based on oligomeric amyloid-β1–42 injections in the brain have not investigated their long-lasting impacts on molecular and cognitive functions. In addition, the injections have been most often performed in ventricles, but not in the hippocampus, in spite of the fact that the hippocampus is importantly involved in memory processes and is strongly and precociously affected during the early stages of AD. Thus, in the present study, we investigated the long-lasting impacts of intra-hippocampal injections of oligomeric forms of Aβo(1–42) on working and spatial memory and on the related activation of ERK1/2. Indeed, the extracellular signal-regulated kinase (ERK) which is involved in memory function had been found to be activated by amyloid peptides. We found that repeated bilateral injections (1injection/day over 4 successive days) of oligomeric forms of Aβo(1–42) into the dorsal hippocampus lead to long-lasting impairments in two working memory tasks, these deficits being observed 7 days after the last injection, while spatial memory remained unaffected. Moreover, the working memory deficits were correlated with sustained impairments of ERK1/2 activation in the medial prefrontal cortex (mPFC) and the septum, two brain areas tightly connected with the hippocampus and involved in working memory. Thus, our study is first to evidence that sub-chronic injections of oligomeric forms of Aβo(1–42) into the dorsal hippocampus produces the main sign of cognitive impairments corresponding to the early stages of AD, via long-lasting alterations of an ERK/MAPK pathway in an interconnected brain networks. PMID:26793098
Bi, Ai-Ling; Wang, Yue; Li, Bo-Qin; Wang, Qian-Qian; Ma, Ling; Yu, Hui; Zhao, Ling; Chen, Zhe-Yu
Actin rearrangement plays an essential role in learning and memory; however, the spatial and temporal regulation of actin dynamics in different phases of associative memory has not been fully understood. Here, using the conditioned taste aversion (CTA) paradigm, we investigated the region-specific involvement of actin rearrangement-related…
Sanderson, David J.; Sprengel, Rolf; Seeburg, Peter H.; Bannerman, David M.
Deletion of the GluA1 AMPA receptor subunit selectively impairs short-term memory for spatial locations. We further investigated this deficit by examining memory for discrete nonspatial visual stimuli in an operant chamber. Unconditioned suppression of magazine responding to visual stimuli was measured in wild-type and GluA1 knockout mice.…
Ethinyl estradiol and levonorgestrel alter cognition and anxiety in rats concurrent with a decrease in tyrosine hydroxylase expression in the locus coeruleus and brain-derived neurotrophic factor expression in the hippocampus.
Simone, Jean; Bogue, Elizabeth A; Bhatti, Dionnet L; Day, Laura E; Farr, Nathan A; Grossman, Anna M; Holmes, Philip V
In the United States, more than ten million women use contraceptive hormones. Ethinyl estradiol and levonorgestrel have been mainstay contraceptive hormones for the last four decades. Surprisingly, there is scant information regarding their action on the central nervous system and behavior. Intact female rats received three weeks of subcutaneous ethinyl estradiol (10 or 30μg/rat/day), levonorgestrel (20 or 60μg/rat/day), a combination of both (10/20μg/rat/day and 30/60μg/rat/day), or vehicle. Subsequently, the rats were tested in three versions of the novel object recognition test to assess learning and memory, and a battery of tests for anxiety-like behavior. Serum estradiol and ovarian weights were measured. All treatment groups exhibited low endogenous 17β-estradiol levels at the time of testing. Dose-dependent effects of drug treatment manifested in both cognitive and anxiety tests. All low dose drugs decreased anxiety-like behavior and impaired performance on novel object recognition. In contrast, the high dose ethinyl estradiol increased anxiety-like behavior and improved performance in cognitive testing. In the cell molecular analyses, low doses of all drugs induced a decrease in tyrosine hydroxylase mRNA and protein in the locus coeruleus. At the same time, low doses of ethinyl estradiol and ethinyl estradiol/levonorgestrel increased galanin protein in this structure. Consistent with the findings above, the low dose treatments of ethinyl estradiol and combination ethinyl estradiol/levonorgestrel reduced brain-derived neurotrophic factor mRNA in the hippocampus. These effects of ethinyl estradiol 10μg alone and in combination with levonorgestrel 20μg suggest a diminution of norepinephrine input into the hippocampus resulting in a decline in learning and memory.
Guha, Suman K; Tillu, Rucha; Sood, Ankit; Patgaonkar, Mandar; Nanavaty, Ishira N; Sengupta, Arjun; Sharma, Shobhona; Vaidya, Vidita A; Pathak, Sulabha
Cerebral malaria is associated with cerebrovascular damage and neurological sequelae. However, the neurological consequences of uncomplicated malaria, the most prevalent form of the disease, remain uninvestigated. Here, using a mild malaria model, we show that a single Plasmodium chabaudi adami infection in adult mice induces neuroinflammation, neurogenic, and behavioral changes in the absence of a blood-brain barrier breach. Using cytokine arrays we show that the infection induces differential serum and brain cytokine profiles, both at peak parasitemia and 15days post-parasite clearance. At the peak of infection, along with the serum, the brain also exhibited a definitive pro-inflammatory cytokine profile, and gene expression analysis revealed that pro-inflammatory cytokines were also produced locally in the hippocampus, an adult neurogenic niche. Hippocampal microglia numbers were enhanced, and we noted a shift to an activated profile at this time point, accompanied by a striking redistribution of the microglia to the subgranular zone adjacent to hippocampal neuronal progenitors. In the hippocampus, a distinct decline in progenitor turnover and survival was observed at peak parasitemia, accompanied by a shift from neuronal to glial fate specification. Studies in transgenic Nestin-GFP reporter mice demonstrated a decline in the Nestin-GFP(+)/GFAP(+) quiescent neural stem cell pool at peak parasitemia. Although these cellular changes reverted to normal 15days post-parasite clearance, specific brain cytokines continued to exhibit dysregulation. Behavioral analysis revealed selective deficits in social and anxiety-like behaviors, with no change observed in locomotor, cognitive, and depression-like behaviors, with a return to baseline at recovery. Collectively, these findings indicate that even a single episode of mild malaria results in alterations of the brain cytokine profile, causes specific behavioral dysfunction, is accompanied by hippocampal microglial
Chengyang, Li; Daqing, Huang; Jianlin, Qi; Haisheng, Chang; Qingqing, Meng; Jin, Wang; Jiajia, Liu; Enmao, Ye; Yongcong, Shao; Xi, Zhang
Acute sleep restriction heavily influences cognitive function, affecting executive processes such as attention, response inhibition, and memory. Previous neuroimaging studies have suggested a link between hippocampal activity and short-term memory function. However, the specific contribution of the hippocampus to the decline of short-term memory following sleep restriction has yet to be established. In the current study, we utilized resting-state functional magnetic resonance imaging (fMRI) to examine the association between hippocampal functional connectivity (FC) and the decline of short-term memory following total sleep deprivation (TSD). Twenty healthy adult males aged 20.9 ± 2.3 years (age range, 18-24 years) were enrolled in a within-subject crossover study. Short-term memory and FC were assessed using a Delay-matching short-term memory test and a resting-state fMRI scan before and after TSD. Seed-based correlation analysis was performed using fMRI data for the left and right hippocampus to identify differences in hippocampal FC following TSD. Subjects demonstrated reduced alertness and a decline in short-term memory performance following TSD. Moreover, fMRI analysis identified reduced hippocampal FC with the superior frontal gyrus (SFG), temporal regions, and supplementary motor area. In addition, an increase in FC between the hippocampus and bilateral thalamus was observed, the extent of which correlated with short-term memory performance following TSD. Our findings indicate that the disruption of hippocampal-cortical connectivity is linked to the decline in short-term memory observed after acute sleep restriction. Such results provide further evidence that support the cognitive impairment model of sleep deprivation.
Cuellar-Herrera, Manola; Velasco, Ana Luisa; Velasco, Francisco; Trejo, David; Alonso-Vanegas, Mario; Nuche-Bricaire, Avril; Vázquez-Barrón, Daruni; Guevara-Guzmán, Rosalinda; Rocha, Luisa
The 5-hydroxytryptamine-1A (5-HT1A) receptors are known to be involved in the inhibition of seizures in epilepsy. Moreover, studies propose a role for the 5-HT1A receptor in memory function; it is believed that the higher density of this receptor in the hippocampus plays an important role in its regulation. Positron emission tomography (PET) studies in patients with mesial temporal lobe epilepsy (mTLE) have demonstrated that a decrease in 5-HT1A receptor binding in temporal regions may play a role in memory impairment. The evidences lead us to speculate whether this decrease in receptor binding is associated with a reduced receptor number or if the functionality of the 5-HT1A receptor-induced G-protein activation and/or the second messenger cascade is modified. The purpose of the present study is to determine 5-HT1A receptor-induced G-protein functional activation by 8-OH-DPAT-stimulated [(35)S]GTPγS binding assay in hippocampal tissue of surgical patients with mTLE. We correlate functional activity with epilepsy history and neuropsychological assessment of memory. We found that maximum functional activation stimulation values (Emax) of [(35)S]GTPγS binding were significantly increased in mTLE group when compared to autopsy samples. Furthermore, significant correlations were found: (1) positive coefficients between the Emax with the age of patient and frequency of seizures; (2) negative coefficients between the Emax and working memory, immediate recall and delayed recall memory tasks. Our data suggest that the epileptic hippocampus of patients with mTLE presents an increase in 5-HT1A receptor-induced G-protein functional activation, and that this altered activity is related to age and seizure frequency, as well as to memory consolidation deficit.
Varani, Andrés P; Pedrón, Valeria T; Bettler, Bernhard; Balerio, Graciela N
Previous studies from our laboratory showed that anxiety-related responses induced by nicotine (NIC), measured by the elevated plus maze, were abolished by 2-OH-saclofen (GABAB receptor antagonist) (1 mg/kg; ip) or the lack of GABAB receptors (GABAB1 knockout mice). Based on these behavioral data, the aims of the present study were: 1) to evaluate the possible neurochemical changes (dopamine, DA, serotonin, 5-HT, 3,4-dihydroxyphenylacetic acid, DOPAC, 5-hydroxyindoleacetic acid, 5-HIAA and noradrenaline, NA) and the c-Fos expression induced by the anxiolytic (0.05 mg/kg) or anxiogenic (0.8 mg/kg) doses of NIC in the dorsal raphe (DRN) and lateral septal (LSN) nucleus; 2) to study the possible involvement of GABAB receptors on the neurochemical alterations and c-Fos expression induced by NIC (0.05 and 0.8 mg/kg), using both pharmacological (2-OH-saclofen) and genetic (mice GABAB1 knockout) approaches. The results revealed that in wild-type mice, NIC (0.05 mg/kg) increased the concentration of 5-HT and 5-HIAA (p < 0.05) in the DRN, and NIC (0.8 mg/kg) increased the levels of 5-HT (p < 0.01) and NA (p < 0.05) in the LSN. Additionally, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors abolished these neurochemical changes induced by NIC (p < 0.01, p < 0.05, respectively). On the other hand, NIC 0.05 and 0.8 mg/kg increased (p < 0.01) the c-Fos expression in the DRN and LSN respectively, in wild-type mice. In addition, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors prevented the c-Fos alterations induced by NIC (p < 0.01). In summary, both approaches show that GABAB receptors would participate in the modulation of anxiolytic- and anxiogenic-like responses induced by NIC, suggesting the potential therapeutic target of these receptors for the tobacco addiction treatment.
Salgado-Puga, Karla; Rodríguez-Colorado, Javier; Prado-Alcalá, Roberto A; Peña-Ortega, Fernando
In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer's disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a KATP blocker (Tolbutamide) or a KATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both KATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that KATP are involved in Aβ-induced pathology and they heighten the potential role of KATP modulation as a plausible therapeutic strategy against AD.
Kumar, Amit; Singh, Nirmal
The study investigates the potential of Rolipram a phosphodiesterase-4 inhibitor in cognitive deficits induced by streptozotocin (STZ, 3mg/kg intracerebroventricularly) and natural ageing in mice. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was also estimated. The brain activity of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and ageing results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice and aged mice exhibited a marked accentuation of AChE activity, TBARS and MPO activity along with fall in GSH level. Further the stained micrographs of STZ treated mice and aged mice indicate pathological changes, severe neutrophilic infiltration and amyloid deposition. Rolipram treatment significantly attenuated STZ induced and age related memory deficits, biochemical and histopathological alterations. The findings demonstrate the potential of Rolipram in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-amyloid, anti-oxidative and anti-inflammatory effects. The study concludes that PDE-4 can be explored as a potential therapeutic target in dementia.
Peretti, C S
Anxious subjects present attentional disorders that are manifest with an increased bias towards threatening contents stimuli. In tasks derived from the Stroop task (such as emotional Stroop, a variant of the classic Stroop task) congruence between anxious themes or manifestations and stimuli content induces information processing changes leading to a slowness of response speed. In this case, results are similar to those obtained in signal detection tasks either when information is visually or auditorily presented. In anxious subjects an inconscious activation provoked by anxiogenic words is observed. Because such activation is independent from the semantic content of the words, an emotional priming has been hypothesized. Berck formulated an hypervigilance theory according to which anxiety provokes a selective distractibility regarding non pertinent stimuli. Such attentional selectivity would be responsible of a cognitive vulnerability in anxious subjects. State but not trait anxiety induces working memory performances deficit. On the bases of Baddeley's working memory framework, Eysenck proposed that anxiety uses part of the limited attentional capacity, placing the subject in a dual task situation. In that, he has to cope with pertinent information and anxiety generated information. If anxiety leads to better performance in simple tasks by recruiting motivational capacities, in tasks with high information content, anxious subjects performances are impaired. Changes in the long-term memory do not seem to fit with the theoretical models based on cognitive impairment observed in patients suffering from depressive states. Anxious subjects presented a memory bias towards anxiogenic information in implicit memory tasks. But experimental data are still too searce to describe implicit performance of anxious subjects and more systematic studies are therefore needed.
Cheng, Huaidong; Li, Wen; Gong, Liang; Xuan, Han; Huang, Zhonglian; Zhao, Hong; Wang, Long Sheng; Wang, Kai
In this study, we aimed to investigate the intrinsic hippocampal functional connectivity (FC) network and its relationship with prospective memory in patients with breast cancer suffering from chemotherapy-induced cognitive impairment (CICI). Thirty-four breast cancer patients before and after adjuvant chemotherapy (CB and CC, respectively) and 31 age- and education-matched cognitively normal (CN) women were recruited and subjected to a prospective memory task and a resting-state functional magnetic resonance imaging scan. Seed-based functional connectivity analysis was used to compare the hippocampal FC networks between CC and CN groups. Partial correction analysis was used to examine the association between the hippocampal FC network and prospective memory in the CC group. The cancer group that underwent chemotherapy obtained significantly poorer scores than the CN group on mini-mental state examination, verbal fluency test, digit span, and prospective memory examination. Compared to the CN group, CC group showed increased hippocampal connectivity in the frontal and parietal cortex, precuneus, posterior cingulate cortex, and the cerebellum. In addition, the increasing hippocampal FC networks were negatively correlated with prospective memory performance in the CC group. These findings suggest maladaptive hippocampal functioning as a mechanism underlying the impairment of prospective memory in patients experiencing CICI. PMID:28327626
Cheng, Huaidong; Li, Wen; Gong, Liang; Xuan, Han; Huang, Zhonglian; Zhao, Hong; Wang, Long Sheng; Wang, Kai
In this study, we aimed to investigate the intrinsic hippocampal functional connectivity (FC) network and its relationship with prospective memory in patients with breast cancer suffering from chemotherapy-induced cognitive impairment (CICI). Thirty-four breast cancer patients before and after adjuvant chemotherapy (CB and CC, respectively) and 31 age- and education-matched cognitively normal (CN) women were recruited and subjected to a prospective memory task and a resting-state functional magnetic resonance imaging scan. Seed-based functional connectivity analysis was used to compare the hippocampal FC networks between CC and CN groups. Partial correction analysis was used to examine the association between the hippocampal FC network and prospective memory in the CC group. The cancer group that underwent chemotherapy obtained significantly poorer scores than the CN group on mini-mental state examination, verbal fluency test, digit span, and prospective memory examination. Compared to the CN group, CC group showed increased hippocampal connectivity in the frontal and parietal cortex, precuneus, posterior cingulate cortex, and the cerebellum. In addition, the increasing hippocampal FC networks were negatively correlated with prospective memory performance in the CC group. These findings suggest maladaptive hippocampal functioning as a mechanism underlying the impairment of prospective memory in patients experiencing CICI.
Appelbaum, L Gregory; Cain, Matthew S; Darling, Elise F; Mitroff, Stephen R
Action video game playing has been experimentally linked to a number of perceptual and cognitive improvements. These benefits are captured through a wide range of psychometric tasks and have led to the proposition that action video game experience may promote the ability to extract statistical evidence from sensory stimuli. Such an advantage could arise from a number of possible mechanisms: improvements in visual sensitivity, enhancements in the capacity or duration for which information is retained in visual memory, or higher-level strategic use of information for decision making. The present study measured the capacity and time course of visual sensory memory using a partial report performance task as a means to distinguish between these three possible mechanisms. Sensitivity measures and parameter estimates that describe sensory memory capacity and the rate of memory decay were compared between individuals who reported high evels and low levels of action video game experience. Our results revealed a uniform increase in partial report accuracy at all stimulus-to-cue delays for action video game players but no difference in the rate or time course of the memory decay. The present findings suggest that action video game playing may be related to enhancements in the initial sensitivity to visual stimuli, but not to a greater retention of information in iconic memory buffers.
Keil, Margaret F; Briassoulis, George; Gokarn, Nirmal; Nesterova, Maria; Wu, T John; Stratakis, Constantine A
The role of cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling in the molecular pathways involved in fear and memory is well established. Prior studies in our lab reported that transgenic mice with an inactivating mutation in Prkar1a gene (codes for the 1-alpha regulatory subunit (R1α) of PKA) exhibited behavioral abnormalities including anxiety and depression. In the present study, we examined the role of altered PKA signaling on anxiety-like behaviors in Prkar1a(+/-) mice compared to wild-type (WT) littermates. The elevated plus maze (EPM) and marble bury (MB) tests were used to assess anxiety-like behavior. The hotplate test was performed to evaluate analgesia. We further examined the impact of the Prkar1a inactivating mutation on PKA activity in specific nuclei of the brain associated with anxiety-like behavior. Results for the MB test showed a genotype effect, with increased anxiety-like behavior in Prkar1a(+/-) mice, compared to WT littermates (p<0.05). MANOVA analysis showed a significant genotype difference in anxiety-like behavior in the EPM between WT and Prkar1a(+/-) mice on combined dependent variables (open arm time and open to total time ratio; p<0.05). Results of hotplate testing showed no genotype effect however; the expected sex difference was noted. Analysis of PKA activity showed the loss of one Prkar1a allele led to an increase in basal and cAMP-stimulated kinase activity in both the basolateral and central amygdala. These results suggest that the alteration in PKA signaling in Prkar1a(+/-) mice is not a ubiquitous effect; and supports the importance of cAMP/PKA pathway in neurobiological processes involved in anxiety and fear sensitization.
Chakravarty, Sumana; Reddy, Bommana R.; Sudhakar, Sreesha R.; Saxena, Sandeep; Das, Tapatee; Meghah, Vuppalapaty; Brahmendra Swamy, Cherukuvada V.; Kumar, Arvind; Idris, Mohammed M.
Anxiety and depression are major chronic mood disorders, and the etiopathology for each appears to be repeated exposure to diverse unpredictable stress factors. Most of the studies on anxiety and related mood disorders are performed in rodents, and a good model is chronic unpredictable stress (CUS). In this study, we have attempted to understand the molecular basis of the neuroglial and behavioral changes underlying CUS-induced mood disorders in the simplest vertebrate model, the zebrafish, Danio rerio. Zebrafish were subjected to a CUS paradigm in which two different stressors were used daily for 15 days, and thorough behavioral analyses were performed to assess anxiety and related mood disorder phenotypes using the novel tank test, shoal cohesion and scototaxis. Fifteen days of exposure to chronic stressors appears to induce an anxiety and related mood disorder phenotype. Decreased neurogenesis, another hallmark of anxiety and related disorders in rodents, was also observed in this zebrafish model. The common molecular markers of rodent anxiety and related disorders, corticotropin-releasing factor (CRF), calcineurin (ppp3r1a) and phospho cyclic AMP response element binding protein (pCREB), were also replicated in the fish model. Finally, using 2DE FTMS/ITMSMS proteomics analyses, 18 proteins were found to be deregulated in zebrafish anxiety and related disorders. The most affected process was mitochondrial function, 4 of the 18 differentially regulated proteins were mitochondrial proteins: PHB2, SLC25A5, VDAC3 and IDH2, as reported in rodent and clinical samples. Thus, the zebrafish CUS model and proteomics can facilitate not only uncovering new molecular targets of anxiety and related mood disorders but also the routine screening of compounds for drug development. PMID:23691016
Kinsey, Steven G; Bailey, Michael T; Sheridan, John F; Padgett, David A; Avitsur, Ronit
The experimental model, social disruption (SDR), is a model of social stress in which mice are repeatedly attacked and defeated in their home cage by an aggressive conspecific. In terms of the impact of this stressor on the immune response, SDR has been reported to cause hyperinflammation and glucocorticoid insensitivity. To this point however, the behavioral consequences of SDR have not been thoroughly characterized. Because social defeat has been reported to cause anxiety- and depressive-like behaviors, the current study was designed to assess whether SDR also causes anxiety- and depressive-like behaviors. Using the light/dark preference test and the open field test as tools to measure behaviors characteristic of anxiety, the data showed that C57BL/6 and CD-1 male mice subjected to SDR displayed increased anxiety-like behavior. The increase in anxiety-like behaviors persisted for at least 1 week after the cessation of the stressor. In contrast, depressive-like behaviors were not elicited by SDR as assessed by the forced swim test or the tail suspension test. These data indicate that social disruption stress causes an increase in anxiety-like behaviors, but not depressive-like behaviors.
Kinsey, Steven G.; Bailey, Michael T.; Sheridan, John F.; Padgett, David A.; Avitsur, Ronit
The experimental model, social disruption (SDR), is a model of social stress in which mice are repeatedly attacked and defeated in their home cage by an aggressive conspecific. In terms of the impact of this stressor on the immune response, SDR has been reported to cause hyperinflammation and glucocorticoid insensitivity. To this point however, the behavioral consequences of SDR have not been thoroughly characterized. Because social defeat has been reported to cause anxiety- and depressive-like behaviors, the current study was designed to assess whether SDR also causes anxiety- and depressive-like behaviors. Using the light/dark preference test and the open field test as tools to measure behaviors characteristic of anxiety, the data showed that C57BL/6 and CD-1 male mice subjected to SDR displayed increased anxiety-like behavior. The increase in anxiety-like behaviors persisted for at least one week after the cessation of the stressor. In contrast, depressive-like behaviors were not elicited by SDR as assessed by the forced swim test or the tail suspension test. These data indicate that social disruption stress causes an increase in anxiety-like behaviors, but not depressive-like behaviors. PMID:17178210
Rodrigues, André Felipe; Biasibetti, Helena; Zanotto, Bruna Stela; Sanches, Eduardo Farias; Pierozan, Paula; Schmitz, Felipe; Parisi, Mariana Migliorini; Barbé-Tuana, Florencia; Netto, Carlos Alexandre; Wyse, Angela T S
Tissue accumulation of galactose is a hallmark in classical galactosemia. Cognitive deficit is a symptom of this disease which is poorly understood. The aim of this study was to investigate the effects of intracerebroventricular administration of galactose on memory (inhibitory avoidance and novel object recognition tasks) of adult rats. We also investigated the effects of galactose on acetylcholinesterase (AChE) activity, immunocontent and gene expression in hippocampus and cerebral cortex. Wistar rats received a single injection of galactose (4mM) or saline (control). For behavioral parameters, galactose was injected 1h or 24h previously to the testing. For biochemical assessment, animals were decapitated 1h, 3h or 24h after galactose or saline injection; hippocampus and cerebral cortex were dissected. Results showed that galactose impairs the memory formation process in aversive memory (inhibitory avoidance task) and recognition memory (novel object recognition task) in rats. The activity of AChE was increased, whereas the gene expression of this enzyme was decreased in hippocampus, but not in cerebral cortex. These findings suggest that these changes in AChE may, at least in part, to lead to memory impairment caused by galactose. Taken together, our results can help understand the etiopathology of classical galactosemia.
Haider, Saida; Saleem, Sadia; Perveen, Tahira; Tabassum, Saiqa; Batool, Zehra; Sadir, Sadia; Liaquat, Laraib; Madiha, Syeda
Oxidative stress from generation of increased reactive oxygen species or free radicals of oxygen has been reported to play an important role in the aging. To investigate the relationship between the oxidative stress and memory decline during aging, we have determined the level of lipid peroxidation, activities of antioxidant enzymes, and activity of acetylcholine esterase (AChE) in brain and plasma as well as biogenic amine levels in brain from Albino-Wistar rats at age of 4 and 24 months. The results showed that the level of lipid peroxidation in the brain and plasma was significantly higher in older than that in the young rats. The activities of antioxidant enzymes displayed an age-dependent decline in both brain and plasma. Glutathione peroxidase and catalase activities were found to be significantly decreased in brain and plasma of aged rats. Superoxide dismutase (SOD) was also significantly decreased in plasma of aged rats; however, a decreased tendency (non-significant) of SOD in brain was also observed. AChE activity in brain and plasma was significantly decreased in aged rats. Learning and memory of rats in the present study was assessed by Morris Water Maze (MWM) and Elevated plus Maze (EPM) test. Short-term memory and long-term memory was impaired significantly in older rats, which was evident by a significant increase in the latency time in MWM and increase in transfer latency in EPM. Moreover, a marked decrease in biogenic amines (NA, DA, and 5-HT) was also found in the brain of aged rats. In conclusion, our data suggest that increased oxidative stress, decline of antioxidant enzyme activities, altered AChE activity, and decreased biogenic amines level in the brain of aged rats may potentially be involved in diminished memory function.
Farnsworth, Donald M., Jr.
While research continues to link increased math anxiety with reduced working memory, the exact nature of the relationship remains elusive. In addition, research regarding the extent of the impact math anxiety has on working memory is contradictory. This research clarifies the directional nature of math anxiety as it pertains to working memory, and…
Lee, Hyunchan; Noh, Jihyun
Social connection reduces the physiological reactivity to stressors, while social exclusion causes emotional distress. Stressful experiences in rats result in the facilitation of aversive memory and induction of anxiety. To determine the effect of social interaction, such as social connection, social exclusion and equality or inequality, on emotional change in adolescent distressed rats, the emotional alteration induced by restraint stress in individual rats following exposure to various social interaction circumstances was examined. Rats were assigned to one of the following groups: all freely moving rats, all rats restrained, rats restrained in the presence of freely moving rats and freely moving rats with a restrained rat. No significant difference in fear-memory and sucrose consumption between all groups was found. Change in body weight significantly increased in freely moving rats with a restrained rat, suggesting that those rats seems to share the stressful experience of the restrained rat. Interestingly, examination of the anxiety-like behavior revealed only rats restrained in the presence of freely moving rats to have a significant increase, suggesting that emotional distress intensifies in positions of social exclusion. These results demonstrate that unequally excluded social interaction circumstances could cause the amplification of distressed status and anxiety-related emotional alteration.
Logan, Ryan; Wynne, Olivia; Maglakelidze, George; Zhang, Changqing; O’Connell, Stephanie; Boyadjieva, Nadka I.; Sarkar, Dipak K.
Background Alcohol exposure has adverse effects on stress physiology and behavioral reactivity. This is suggested to be due, in part, to the effect of alcohol on β-endorphin (β-EP) producing neurons in the hypothalamus. In response to stress, β-EP normally provides negative feedback to the HPA axis and interacts with other neurotransmitter systems in the amygdala to regulate behavior. We examined whether β-EP neuronal function in the hypothalamus reduces the corticosterone response to acute stress, attenuates anxiety-like behaviors, and modulates alcohol drinking in rats. Methods To determine if β-EP neuronal transplants modulate the stress response, anxiety behavior and alcohol drinking, we implanted differentiated β-EP neurons into the paraventricular nucleus of the hypothalamus (PVN) of normal, prenatal alcohol exposed, and alcohol-preferring (P) and non-preferring (NP) rats. We then assessed corticosterone levels in response to acute restraint stress and other markers of stress response in the brain, and anxiety-like behaviors in the elevated plus maze and open-field assays. Results We showed that β-EP neuronal transplants into the PVN reduced the peripheral corticosterone response to acute stress and attenuated anxiety-like behaviors. Similar transplants completely reduced the hyper-corticosterone response and elevated anxiety behaviors in prenatal alcohol exposed adult rats. Moreover, we showed that β-EP reduced anxiety behavior in P rats with minimal effects on alcohol drinking during and following restraint stress. Conclusions These data further establish a role of β-EP neurons in the hypothalamus for regulating physiological stress response and anxiety behavior, and resembles a potential novel therapy for treating stress-related psychiatric disorders in prenatal alcohol exposed children and those genetically predisposed to increased alcohol consumption. PMID:25623413
The central, lateral and basolateral amygdala (BLA) nuclei are essential for the formation of long-term memories including emotional and drug-related memories. Studying cellular and molecular mechanisms of memory in amygdala may lead to better understanding of how memory is formed and of fear and addiction-related disorders. A challenge is to identify molecules activated by learning that subserve cellular changes needed for memory formation and maintenance in amygdala. Recent studies show that activation of synaptic receptors during fear and drug-related learning leads to alteration in actin cytoskeleton dynamics and structure in amygdala. Such changes in actin cytoskeleton in amygdala are essential for fear and drug-related memories formation. Moreover, the actin cytoskeleton subserves, after learning, changes in neuronal morphogenesis and glutamate receptors trafficking in amygdala. These cellular events are involved in fear and drug-related memories formation. Actin polymerization is also needed for the maintenance of drug-associated memories in amygdala. Thus, the actin cytoskeleton is a key mediator between receptor activation during learning and cellular changes subserving long-term memory (LTM) in amygdala. The actin cytoskeleton may serve as a target for pharmacological treatment of fear memory associated with fear and anxiety disorders and drug addiction to prevent the debilitating consequences of these diseases. PMID:27065800
Cassol-Jr, Omar J; Comim, Clarissa M; Constantino, Larissa S; Rosa, Daniela V F; Mango, Luiz Alexandre V; Stertz, Laura; Kapczinski, Flávio; Romano-Silva, Marco A; Quevedo, João; Dal-Pizzol, Felipe
Sepsis is characterized by an intense inflammatory reaction with potential neurotoxic effects in the central nervous system and damage to memory and learning ability. We assessed the effects of acute low dose of MK-801 on the memory impairment, hippocampal BDNF levels and DARPP-32 expression ten days after sepsis. Under anesthesia, male Wistar rats underwent either cecal ligation and perforation (CLP) or sham. Then, the animals received either a single systemic injection of MK-801 (0.025 mg/kg) or saline solution. Ten days after CLP, the animals were submitted to the step-down inhibitory avoidance and object recognition tests. Also, the hippocampal BDNF protein levels and DARPP-32 expression were evaluated. MK-801 prevented cognitive impairment, but did not affect the hippocampal BDNF levels. DARPP-32 expression was significantly different only in the animals submitted to sepsis that received MK-801 treatment. Thus, we demonstrated that a single low dose of MK-801 prevented memory impairment without altering hippocampal DARPP-32 expression and BDNF levels.
Kollndorfer, K.; Krajnik, J.; Woitek, R.; Freiherr, J.; Prayer, D.; Schöpf, V.
Multiple sclerosis (MS) is a chronic neurological disease, frequently affecting attention and working memory functions. Functional imaging studies investigating those functions in MS patients are hard to compare, as they include heterogeneous patient groups and use different paradigms for cognitive testing. The aim of this study was to investigate alterations in neuronal activation between MS patients and healthy controls performing attention and working memory tasks. Two meta-analyses of previously published fMRI studies investigating attention and working memory were conducted for MS patients and healthy controls, respectively. Resulting maps were contrasted to compare brain activation in patients and healthy controls. Significantly increased brain activation in the inferior parietal lobule and the dorsolateral prefrontal cortex was detected for healthy controls. In contrast, higher neuronal activation in MS patients was obtained in the left ventrolateral prefrontal cortex and the right premotor area. With this meta-analytic approach previous results of investigations examining cognitive function using fMRI are summarized and compared. Therefore a more general view on cognitive dysfunction in this heterogeneous disease is enabled. PMID:24056084
Nakauchi, Sakura; Malvaez, Melissa; Su, Hailing; Kleeman, Elise; Dang, Richard; Wood, Marcelo A; Sumikawa, Katumi
Fetal nicotine exposure from smoking during pregnancy causes long-lasting cognitive impairments in offspring, yet little is known about the mechanisms that underlie this effect. Here we demonstrate that early postnatal exposure of mouse pups to nicotine via maternal milk impairs long-term, but not short-term, hippocampus-dependent memory during adolescence. At the Schaffer collateral (SC) pathway, the most widely studied synapses for a cellular correlate of hippocampus-dependent memory, the induction of N-methyl-D-aspartate receptor-dependent transient long-term potentiation (LTP) and protein synthesis-dependent long-lasting LTP are not diminished by nicotine exposure, but rather unexpectedly the threshold for LTP induction becomes lower after nicotine treatment. Using voltage sensitive dye to visualize hippocampal activity, we found that early postnatal nicotine exposure also results in enhanced CA1 depolarization and hyperpolarization after SC stimulation. Furthermore, we show that postnatal nicotine exposure induces pervasive changes to the nicotinic modulation of CA1 activity: activation of nicotinic receptors no longer increases CA1 network depolarization, acute nicotine inhibits rather than facilitates the induction of LTP at the SC pathway by recruiting an additional nicotinic receptor subtype, and acute nicotine no longer blocks LTP induction at the temporoammonic pathway. These findings reflect the pervasive impact of nicotine exposure during hippocampal development, and demonstrate an association of hippocampal memory impairments with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. The implication of our results is that nicotinic cholinergic-dependent plasticity is required for long-term memory formation and that postnatal nicotine exposure disrupts this form of plasticity.
Kiyota, Tomomi; Morrison, Christine M; Tu, Guihua; Dyavarshetty, Bhagyalaxmi; Weir, Robert A; Zhang, Gang; Xiong, Huangui; Gendelman, Howard E
Aberrations in hippocampal neurogenesis are associated with learning and memory, synaptic plasticity and neurodegeneration in Alzheimer's disease (AD). However, the linkage between them, β-amyloidosis and neuroinflammation is not well understood. To this end, we generated a mouse overexpressing familial AD (FAD) mutant human presenilin-1 (PS1) crossed with a knockout (KO) of the CC-chemokine ligand 2 (CCL2) gene. The PS1/CCL2KO mice developed robust age-dependent deficits in hippocampal neurogenesis associated with impairments in learning and memory, synaptic plasticity and long-term potentiation. Neurogliogenesis gene profiling supported β-amyloid independent pathways for FAD-associated deficits in hippocampal neurogenesis. We conclude that these PS1/CCL2KO mice are suitable for studies linking host genetics, immunity and hippocampal function.
Bianchi, Renzo; Laurent, Eric
In the present article, we discuss (1) the importance of assessing and statistically considering both clinical and subclinical forms of depression when examining the relationship between neuroticism and short-term plasticity within the working memory neural network, and (2) the hypothesis of an antagonism between neuroticism and conscientiousness in personality research. We suggest that (1) neuroticism and depression should be examined in a relational manner, and (2) neuroticism and conscientiousness should not be antagonized.
Ramos-Chávez, Lucio A.; Rendón-López, Christian R. R.; Zepeda, Angélica; Silva-Adaya, Daniela; Del Razo, Luz M.; Gonsebatt, María E.
Inorganic arsenic (iAs) is an important natural pollutant. Millions of individuals worldwide drink water with high levels of iAs. Chronic exposure to iAs has been associated with lower IQ and learning disabilities as well as memory impairment. iAs is methylated in tissues such as the brain generating mono and dimethylated species. iAs methylation requires cellular glutathione (GSH), which is the main antioxidant in the central nervous system (CNS). In humans, As species cross the placenta and are found in cord blood. A CD1 mouse model was used to investigate effects of gestational iAs exposure which can lead to oxidative damage, disrupted cysteine/glutamate transport and its putative impact in learning and memory. On postnatal days (PNDs) 1, 15 and 90, the expression of membrane transporters related to GSH synthesis and glutamate transport and toxicity, such as xCT, EAAC1, GLAST and GLT1, as well as LAT1, were analyzed. Also, the expression of the glutamate receptor N-methyl-D-aspartate (NMDAR) subunits NR2A and B as well as the presence of As species in cortex and hippocampus were investigated. On PND 90, an object location task was performed to associate exposure with memory impairment. Gestational exposure to iAs affected the expression of cysteine/glutamate transporters in cortex and hippocampus and induced a negative modulation of NMDAR NR2B subunit in the hippocampus. Behavioral tasks showed significant spatial memory impairment in males while the effect was marginal in females. PMID:25709567
Reinke, Britta; Ven, Vincent van de; Matura, Silke; Linden, David E J; Oertel-Knöchel, Viola
Potential abnormalities in the structure and function of the temporal lobes have been studied much less in bipolar disorder than in schizophrenia. This may not be justified because language-related symptoms, such as pressured speech and flight of ideas, and cognitive deficits in the domain of verbal memory are amongst the hallmark of bipolar disorder (BD), and contribution of temporal lobe dysfunction is therefore likely. In the current study, we examined resting-state functional connectivity (FC) between the auditory cortex (Heschl's gyrus [HG], planum temporale [PT]) and whole brain using seed correlation analysis in n = 21 BD euthymic patients and n = 20 matched healthy controls and associated it with verbal memory performance. In comparison to controls BD patients showed decreased functional connectivity between Heschl's gyrus and planum temporale and the left superior and middle temporal gyrus. Additionally, fronto-temporal functional connectivity with the right inferior frontal/precentral gyrus and the insula was increased in patients. Verbal episodic memory deficits in the investigated sample of BD patients and language-related symptoms might therefore be associated with a diminished FC within the auditory/temporal gyrus and a compensatory fronto-temporal pathway.
Seckin, Ayse Nazli; Ozdemir, Hulya; Ceylan, Ayca; Artac, Hasibe
Children with Down syndrome (DS) have a high incidence of recurrent respiratory tract infections, leukaemia and autoimmune disorders, suggesting immune dysfunction. The present study evaluated the role of the CD19 complex and memory B cells in the pathogenesis of immunodeficiency in children with DS. The expression levels (median fluorescein intensity-MFI) of CD19, CD21 and CD81 molecules on the surface of B cells and memory B cell subsets were studied in 37 patients and 39 healthy controls. Twenty-nine of the DS group had congenital cardiac disease. The B cell count was significantly low in children with DS compared with healthy age-matched controls for all three age groups (under 2 years; 2-6 years and older than 6 years). The MFI of CD19 was reduced in all the age groups, whereas that of CD21 was increased in those older than 2 years with DS. The expression level of CD81 was significantly increased in those older than 6 years. Age-related changes were also detected in memory B cell subsets. The frequency of CD27(+)IgD(+)IgM(+) natural effector B cells was reduced in children with DS who had needed hospitalisation admission due to infections. The observed intrinsic defects in B cells may be responsible for the increased susceptibility of children with DS to severe respiratory tract infections.
Karpova, Nina N.; Lindholm, Jesse Saku Olavi; Kulesskaya, Natalia; Onishchenko, Natalia; Vahter, Marie; Popova, Dina; Ceccatelli, Sandra; Castrén, Eero
Developmental exposure to low dose of methylmercury (MeHg) has a long-lasting effect on memory and attention deficits in humans, as well as cognitive performance, depression-like behavior and the hippocampal levels of the brain-derived neurotrophic factor (Bdnf)in mice. The Bdnf receptor TrkB is a key player of Bdnf signaling. Using transgenic animals, here we analyzed the effect of the full-length TrkB overexpression (TK+) on behavior impairments induced by perinatal MeHg. TK overexpression in the MeHg-exposed mice enhanced generalized anxiety and cue memory in the fear conditioning (FC) test. Early exposure to MeHg induced deficits in reversal spatial memory in the Morris water maze (MWM) test and depression-like behavior in the forced swim test (FST) in only wild-type (WT) mice but did not affect these parameters in TK+ mice. These changes were associated with TK+ effect on the increase in Bdnf 2, 3, 4 and 6 transcription in the hippocampus as well as with interaction of TK+ and MeHg factors for Bdnf 1, 9a and truncated TrkB.T1 transcripts in the prefrontal cortex. However, the MeHg-induced anxiety-like behavior in the elevated plus maze (EPM) and open field (OF) tests was ameliorated by TK+ background only in the OF test. Moreover, TK overexpression in the MeHg mice did not prevent significant stress-induced weight loss during the period of adaptation to individual housing in metabolic cages. These TK genotype-independent changes were primarily accompanied by the MeHg-induced hippocampal deficits in the activity-dependent Bdnf 1, 4 and 9a variants, TrkB.T1, and transcripts for important antioxidant enzymes glyoxalases Glo1 and Glo2 and glutathione reductase Gsr. Our data suggest a role of full-length TrkB in buffering against memory deficits and depression-like behavior in the MeHg mice but propose the involvement of additional pathways, such as the antioxidant system or TrkB.T1 signaling, in stress- or anxiety-related responses induced by developmental Me
Motaghinejad, Majid; Motevalian, Manijeh; Larijani, Setare Farokhi; Khajehamedi, Zohreh
Background: Methylphenidate (MPH), a neural stimulant, can cause damages to brain; the chronic neurochemical and behavioral effects of MPH remain unclear. Exercise lowers stress and anxiety and can act as non-pharmacologic neuroprotective agent. In this study protective effects of exercise in MPH-induced anxiety, depression and cognition impairment were investigated. Materials and Methods: Seventy adult male rats were divided randomly into five groups. Group 1 served as negative control, received normal saline (0.2 ml/rat) for 21 days, group 2 and 3 (as positive controls) received MPH (10 and 20 mg/kg) for 21 days. Groups 4 and 5 concurrently were treated with MPH (10 and 20 mg/kg) and forced exercise for 21 days. On day 21, Elevated Plus Maze (EPM), Open Field Test (OFT), Forced Swim Test (FST) and Tail Suspension Test (TST) were used to investigate the level of anxiety and depression in animals. In addition between 17th and 21th days, Morris Water Maze (MWM) was applied to evaluate the effect of MPH on spatial learning and memory. Results: MPH-treated animals indicated a reflective depression and anxiety in a dose-dependent manner in FST, EPM and TST which were significantly different from the control group and also can significantly attenuate the motor activity and anxiety in OFT. Forced exercise by treadmill can attenuate MPH-induced anxiety, depression and motor activity alteration in OFT. MPH also can disturb learning and memory in MWM and forced exercise can neutralize this effect of MPH. Conclusion: We conclude that forced exercise can be protective in brain against MPH-induced anxiety, depression and cognition alteration. PMID:26322282
Garcia-Knight, Miguel A; Nduati, Eunice; Hassan, Amin S; Gambo, Faith; Odera, Dennis; Etyang, Timothy J; Hajj, Nassim J; Berkley, James Alexander; Urban, Britta C; Rowland-Jones, Sarah L
Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV-unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age-dependent differences in the magnitude and polyfunctionality of IL-2 and TNF-α responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy
... for Parents for Kids for Teens Teens Home Body Mind Sexual Health Food & Fitness Diseases & Conditions Infections Q& ... Like other anxiety reactions, test anxiety affects the body and the mind. When you're under stress, your body releases ...
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The recovery of acetylcholinesterase activity and the progression of neuropathological and pathophysiological alterations in the rat basolateral amygdala after soman-induced status epilepticus: relation to anxiety-like behavior
Prager, Eric M.; Aroniadou-Anderjaska, Vassiliki; Almeida-Suhett, Camila P.; Figueiredo, Taiza H.; Apland, James P.; Rossetti, Franco; Olsen, Cara H.; Braga, Maria F.M.
Organophosphorus nerve agents are powerful neurotoxins that irreversibly inhibit acetylcholinesterase (AChE) activity. One of the consequences of AChE inhibition is the generation of seizures and status epilepticus (SE), which cause brain damage, resulting in long-term neurological and behavioral deficits. Increased anxiety is the most common behavioral abnormality after nerve agent exposure. This is not surprising considering that the amygdala, and the basolateral nucleus of the amygdala (BLA) in particular, plays a central role in anxiety, and this structure suffers severe damage by nerve agent-induced seizures. In the present study, we exposed male rats to lethal doses of the nerve agent soman, and determined the time course of recovery of AChE activity, along with the progression of neuropathological and pathophysiological alterations in the BLA, during a 30-day period after exposure. Measurements were taken at 24 hours, 7 days, 14 days, and 30 days after exposure, and at 14 and 30 days, anxiety-like behavior was also evaluated. We found that more than 90% of AChE is inhibited at the onset of SE, and AChE inhibition remains at this level 24 hours later, in the BLA, as well as in the hippocampus, piriform cortex, and prelimbic cortex, which we analyzed for comparison. AChE activity recovered by day 7 in the BLA and day 14 in the other three regions. Significant neuronal loss and neurodegeneration were present in the BLA at 24 hours and throughout the 30-day period. There was no significant loss of GABAergic interneurons in the BLA at 24 hours post-exposure. However, by day 7, the number of GABAergic interneurons in the BLA was reduced, and at 14 and 30 days after soman, the ratio of GABAergic interneurons to the total number of neurons was lower compared to controls. Anxiety-like behavior in the open-field and the acoustic startle response tests was increased at 14 and 30 days post-exposure. Accompanying pathophysiological alterations in the BLA – studied in
Lyons, Angela M; Thiele, Todd E
Neuropeptide Y (NPY) is a 36-amino-acid neuromodulator that is distributed throughout the central nervous system and has been implicated in a wide range of neurobiological responses including the integration of emotional behavior. The anxiolytic properties of NPY are modulated by NPY signaling in the hippocampus and in the central (CeA) and basolateral (BLA) nuclei of the amygdala. Recently, the neurotoxin saporin, when conjugated to NPY (NPY-SAP), was shown to selectively kill NPY receptor-expressing neurons and has been used as a tool to study the central NPY neurocircuitry involved with feeding behaviors. Here we determined if NPY-SAP can be used as a tool to study the central NPY neurocircuitry that modulates anxiety-like behaviors. BALB/cJ mice were given injection of either NPY-SAP or a control blank saporin (B-SAP) into the CeA or the basomedial hypothalamus (BMH) as a control injection site. The elevated zero maze test was used to assess anxiety-like behavior and NPY-SAP-induced lesions were verified using NPY Y1 receptor (Y1R) immunoreactivity (IR). Results showed that injection of NPY-SAP into the CeA site-specifically blunted Y1R IR in the CeA which was associated with a significant increase in anxiety-like behavior. Injection of NPY-SAP into the BMH, while locally blunting Y1R IR, promoted a compensatory increase of Y1R IR in the BLA and the CA3 region of the hippocampus which was associated with a significant reduction of anxiety-like behavior. The present set of experiments suggest that the NPY-SAP neurotoxin may be a useful tool for studying the NPY neurocircuitry that modulates anxiety-like behaviors.
Wegener, Gregers; Finger, Beate C; Elfving, Betina; Keller, Kirsten; Liebenberg, Nico; Fischer, Christina W; Singewald, Nicolas; Slattery, David A; Neumann, Inga D; Mathé, Aleksander A
Neuropeptide S (NPS) and its receptor (NPSR) have been implicated in the mediation of anxiolytic-like behaviour in rodents. However, little knowledge is available regarding the NPS system in depression-related behaviours, and whether NPS also exerts anxiolytic effects in an animal model of psychopathology. Therefore, the aim of this work was to characterize the effects of NPS on depression- and anxiety-related parameters, using male and female rats in a well-validated animal model of depression: the Flinders Sensitive Line (FSL), their controls, the Flinders Resistant Line (FRL), and Sprague-Dawley (SD) rats. We found that FSL showed greater immobility in the forced swim test (FST) than FRL, confirming their phenotype. However, NPS did not affect depression-related behaviour in any rat line. No significant differences in baseline anxiety levels between the FSL and FRL strains were observed, but FSL and FRL rats displayed less anxiety-like behaviour compared to SD rats. NPS decreased anxiety-like behaviour on the elevated plus-maze in all strains. The expression of the NPSR in the amygdala, periventricular hypothalamic nucleus, and hippocampus was equal in all male strains, although a trend towards reduced expression within the amygdala was observed in FSL rats compared to SD rats. In conclusion, NPS had a marked anxiolytic effect in FSL, FRL and SD rats, but did not modify the depression-related behaviour in any strain, in spite of the significant differences in innate level between the strains. These findings suggest that NPS specifically modifies anxiety behaviour but cannot overcome/reverse a genetically mediated depression phenotype.
Huang, Wenli; Huang, Donghong; Chen, Zirong; Ye, Wei; Lv, Zongxia; Diao, Limei; Zheng, Jinou
The aim of this study was to investigate the alterations in a verbal working memory (VWM)-related network in left temporal lobe epilepsy (lTLE) at rest. We evaluated 14 patients with lTLE and 14 control subjects by resting-state functional connectivity (RSFC). The region of interest was defined by the voxel with the highest Z-score during a VWM task according to functional magnetic resonance imaging in 16 healthy volunteers. Our study revealed that the network of RSFC was similar to the task-induced network in the healthy volunteers. Moreover, the patients with lTLE exhibited significantly decreased RSFC in the bilateral middle frontal gyrus, the inferior frontal gyrus and the inferior parietal lobule at rest compared to the control subjects. We found no significant correlation between the mean reaction time of the accurate responses in a 2-back task and the mean z-values within the regions that exhibited significant differences in RSFC at the individual level. The alterations in FCs of VWM-related network in lTLE suggested that epileptiform discharges can damage the brain regions, both local focus and remote areas and that the alterations were not associated with VWM performance.
Klein, Rachel G.
Because of their high prevalence and their negative long-term consequences, child anxiety disorders have become an important focus of interest. Whether pathological anxiety and normal fear are similar processes continues to be controversial. Comparative studies of child anxiety disorders are scarce, but there is some support for the current…
Dal Bosco, Lidiane; Weber, Gisele E. B.; Parfitt, Gustavo M.; Paese, Karina; Gonçalves, Carla O. F.; Serodre, Tiago M.; Furtado, Clascídia A.; Santos, Adelina P.; Monserrat, José M.; Barros, Daniela M.
Carbon nanotubes (CNT) are promising materials for biomedical applications, especially in the field of neuroscience; therefore, it is essential to evaluate the neurotoxicity of these nanomaterials. The present work assessed the effects of single-walled CNT functionalized with polyethylene glycol (SWCNT-PEG) on the consolidation and retrieval of contextual fear memory in rats and on oxidative stress parameters in the hippocampus. SWCNT-PEG were dispersed in water at concentrations of 0.5, 1.0, and 2.1 mg/mL and infused into the rat hippocampus. The infusion was completed immediately after training and 30 min before testing of a contextual fear conditioning task, resulting in exposure times of 24 h and 30 min, respectively. The results showed that a short exposure to SWCNT-PEG impaired fear memory retrieval and caused lipid peroxidation in the hippocampus. This response was transient and overcome by the mobilization of antioxidant defenses at 24 h. These effects occurred at low and intermediate but not high concentration of SWCNT-PEG, suggesting that the observed biological response may be related to the concentration-dependent increase in particle size in SWCNT-PEG dispersions. PMID:25738149
Schiller, Daniela; Kanen, Jonathan W.; LeDoux, Joseph E.; Monfils, Marie-H.; Phelps, Elizabeth A.
Controlling learned defensive responses through extinction does not alter the threat memory itself, but rather regulates its expression via inhibitory influence of the prefrontal cortex (PFC) over amygdala. Individual differences in amygdala–PFC circuitry function have been linked to trait anxiety and posttraumatic stress disorder. This finding suggests that exposure-based techniques may actually be least effective in those who suffer from anxiety disorders. A theoretical advantage of techniques influencing reconsolidation of threat memories is that the threat representation is altered, potentially diminishing reliance on this PFC circuitry, resulting in a more persistent reduction of defensive reactions. We hypothesized that timing extinction to coincide with threat memory reconsolidation would prevent the return of defensive reactions and diminish PFC involvement. Two conditioned stimuli (CS) were paired with shock and the third was not. A day later, one stimulus (reminded CS+) but not the other (nonreminded CS+) was presented 10 min before extinction to reactivate the threat memory, followed by extinction training for all CSs. The recovery of the threat memory was tested 24 h later. Extinction of the nonreminded CS+ (i.e., standard extinction) engaged the PFC, as previously shown, but extinction of the reminded CS+ (i.e., extinction during reconsolidation) did not. Moreover, only the nonreminded CS+ memory recovered on day 3. These results suggest that extinction during reconsolidation prevents the return of defensive reactions and diminishes PFC involvement. Reducing the necessity of the PFC–amygdala circuitry to control defensive reactions may help overcome a primary obstacle in the long-term efficacy of current treatments for anxiety disorders. PMID:24277809
Dutta, Avijit; Miaw, Shi-Chuen; Yu, Jhang-Sian; Chen, Tse-Ching; Lin, Chun-Yen; Lin, Yung-Chang; Chang, Chia-Shiang; He, Yueh-Chia; Chuang, Sheng-Hao; Yen, Ming-I; Huang, Ching-Tai
Cytokine storm has been postulated as one of the major causes of mortality in patients with severe respiratory viral infections such as influenza. With the help of an influenza Ag- specific mouse experimental system, we report that CD4(+) T cells contribute effector cytokines leading to lung inflammation in acute influenza. Although virus can no longer be detected from tissues 14 d postinfection, virus-derived Ag continues to drive a CD4(+) T cell response after viral clearance. Ag-specific CD4(+) T cells proliferate and evolve into memory CD4(+) T cells efficiently, but the production of effector cytokines is seriously hampered during this phase. This decoupling of proliferation and effector cytokine production doesn't appear in conjunction with increased suppression by regulatory T cells or decreased induction of transcription factors. Rather, GATA-3 and ROR-γt levels are elevated when compared with cells that have effector cytokine production. T-bet dominance over GATA-3 and ROR-γt decreases with the disarmament of effector cytokine production. Importantly, upon reinfection, these decoupled cells produce elevated levels of IFN-γ and were effective in virus eradication. These results provide a mechanism through altered T-bet dominance to dampen the cytokine storm without impeding the generation of memory T cells in influenza virus infection.
Steele, John W.; Brautigam, Hannah; Short, Jennifer A.; Sowa, Allison; Shi, Mengxi; Yadav, Aniruddha; Weaver, Christina M.; Westaway, David; Fraser, Paul E.; St George-Hyslop, Peter H.; Gandy, Sam; Hof, Patrick R.; Dickstein, Dara L.
Alzheimer's disease (AD) is a complex and slowly progressing dementing disorder that results in neuronal and synaptic loss, deposition in brain of aberrantly folded proteins, and impairment of spatial and episodic memory. Most studies of mouse models of AD have employed analyses of cognitive status and assessment of amyloid burden, gliosis, and molecular pathology during disease progression. Here, we sought to understand the behavioral, cellular, ultrastructural, and molecular changes that occur at a pathological stage equivalent to early stages of human AD. We studied the TgCRND8 mouse, a model of aggressive AD amyloidosis, at an early stage of plaque pathology (3 months of age) in comparison to their wild-type littermates and assessed changes in cognition, neuron and spine structure, and expression of synaptic glutamate receptor proteins. We found that, at this age, TgCRND8 mice display substantial plaque deposition in the neocortex and hippocampus and impairment on cued and contextual memory tasks. Of particular interest, we also observed a significant decrease in the number of neurons in the hippocampus. Furthermore, analysis of CA1 neurons revealed significant changes in apical and basal dendritic spine types, as well as altered expression of GluN1 and GluA2 receptors. This change in molecular architecture within the hippocampus may reflect a rising representation of inherently less stable thin spine populations, which can cause cognitive decline. These changes, taken together with toxic insults from amyloid-β protein, may underlie the observed neuronal loss. PMID:24415002
Oliveira, Ana Ca; Pereira, Maria Cs; Santana, Luana N da Silva; Fernandes, Rafael M; Teixeira, Francisco B; Oliveira, Gedeão B; Fernandes, Luanna Mp; Fontes-Júnior, Enéas A; Prediger, Rui D; Crespo-López, Maria E; Gomes-Leal, Walace; Lima, Rafael R; Maia, Cristiane do Socorro Ferraz
There is increasing evidence that heavy ethanol exposure in early life may produce long-lasting neurobehavioral consequences, since brain structural maturation continues until adolescence. It is well established that females are more susceptible to alcohol-induced neurotoxicity and that ethanol consumption is increasing among women, especially during adolescence. In the present study, we investigated whether chronic ethanol exposure during adolescence through early adulthood in female rats may induce hippocampal histological damage and neurobehavioral impairments. Female rats were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v) by gavage from the 35(th)-90(th) day of life. Ethanol-exposed animals displayed reduced exploration of the central area and increased number of fecal boluses in the open field test indicative of anxiogenic responses. Moreover, chronic high ethanol exposure during adolescence induced marked impairments on short-term memory of female rats addressed on social recognition and step-down inhibitory avoidance tasks. These neurobehavioral deficits induced by ethanol exposure during adolescence through early adulthood were accompanied by the reduction of hippocampal formation volume as well as the loss of neurons, astrocytes and microglia cells in the hippocampus. These results indicate that chronic high ethanol exposure during adolescence through early adulthood in female rats induces long-lasting emotional and memory deficits associated with morphological and molecular alterations in the hippocampus.
Bahous, Renata H; Jadavji, Nafisa M; Deng, Liyuan; Cosín-Tomás, Marta; Lu, Jessica; Malysheva, Olga; Leung, Kit-Yi; Ho, Ming-Kai; Pallàs, Mercè; Kaliman, Perla; Greene, Nicholas DE; Bedell, Barry J; Caudill, Marie A; Rozen, Rima
Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C>T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex.Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR 3 deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid.
Boelen, Paul A; Huntjens, Rafaele J C; van den Hout, Marcel A
Reduced memory specificity is associated with depression, post-traumatic stress disorder (PTSD), and some other forms of psychopathology. Reduced memory specificity is also associated with reduced specificity of envisioned future events. Research in this area has mostly relied on cue-word methods that include explicit instructions to develop specific memories of future events. These methods are limited in their ability to assess how participants habitually remember the past and imagine the future when the specificity constraints inherent in the cue-word task are removed. Sentence completions tasks have been developed that can be used to assess habitual patterns of memory and prospection. Little is known about the association of habitual memory and prospection with concurrently and prospectively assessed psychopathology. In the current study 142 participants completed sentence completion tasks tapping habitual memory and prospection at baseline and completed measures tapping psychological symptoms at baseline and 1 year later. Among other things, it was found that reduced memory specificity (but not reduced future specificity) was associated with concurrent and later depression, as well as with symptom levels of PTSD tapped 1 year beyond baseline.
King, Elizabeth C.; Pattwell, Siobhan S.; Sun, Alice; Glatt, Charles E.; Lee, Francis S.
The transition into and out of adolescence represents a unique developmental period during which neuronal circuits are particularly susceptible to modification by experience. Adolescence is associated with an increased incidence of anxiety disorders in humans,1–3 and an estimated 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents.4,5 Conserved neural circuitry between rodents and humans has facilitated neurodevelopmental studies of behavioral and molecular processes associated with fear learning and memory, which lie at the heart of many anxiety disorders. Here, we review the non-linear developmental aspects of fear learning and memory during a transition period into and out of adolescence and provide a discussion of the molecular mechanisms that may underlie these alterations in behavior. We provide a model that may help to inform novel treatment strategies for children and adolescents with fear-related disorders. PMID:24176014
Thakurta, Ishita Guha; Banerjee, Priyanjalee; Bagh, Maria Bindu; Ghosh, Arindam; Sahoo, Arghyadip; Chattopadhyay, Sita; Chakrabarti, Sasanka
This study has compared several synaptosomal parameters in three groups of rats: young (46 months), aged (22-24 months) and antioxidant supplemented aged rats (antioxidant supplementation given with the diet as a combination of N-acetylcysteine, α-lipoic acid and α-tocopherol from 18 months onwards till 22-24 months). The synaptosomes from aged rat brain, in comparison to those of young animals, exhibit an increased membrane potential with altered contents of Na(+) and K(+) under basal incubation condition and in the presence of depolarizing agents. The intrasynaptosomal Ca(2+) is also higher in aged than in young rat. These age-dependent changes in synaptosomal parameters are prevented markedly in the antioxidant supplemented group. When examined on T-maze, the aged animals are noticeably impaired in learning and memory functions, but the deficit is remarkably prevented in the antioxidant supplemented aged animals. It is suggested that the synaptosomal alterations partly contribute to the cognitive deficits of aged animals, and both are rescued by long-term antioxidant supplementation.
Soares, Félix A A; Dalla Corte, Cristiane L; Andrade, Edson R; Marina, Raquel; González, Paquita; Barrio, Juan P
The aim of this work was to test the hypothesis that a moderate intake of organic purple grape juice shows a positive radiomodifier effect over early behavioural damage following acute X-irradiation in mice. Anxiety-, locomotion-, and feeding-related responses to 6 Gy total body X-irradiation (TBI) were studied via open field, Rotarod, and feeding/drinking recording. Thirty-two male mice weighing 25-30 g were grouped according grape juice (J) or water (W) ad libitum drinking and either non-irradiated (N) or irradiated (R). 24 h post-TBI the access frequency to the center and corners of the open field was decreased, and the total stay in the corners increased, in RW vs. NW mice. Anxiety-related parameters decreased in RJ vs. RW mice. Rotarod latency times increased 72 h post-TBI in RJ vs RW mice. No overall changes in food and drink intake were observed along the experimental period. On the irradiation day, bout number was increased and bout duration was decreased in RW mice. The changes were reversed by purple grape juice intake. Grape juice intake before and after TBI can overcome several radiation-induced changes in behaviour within 24-72 hours after sub-lethal X-irradiation. This beneficial effect on short-term anxiety and mobilityrelated activities could probably be included in the list of flavonoid bio-effects. The present findings could be relevant in designing preventive interventions aimed to enhance body defense mechanisms against short-term irradiation damage.
Rokicki, Jaroslav; Li, Lucia; Imabayashi, Etsuko; Kaneko, Jun; Hisatsune, Tatsuhiro; Matsuda, Hiroshi
Carnosine and anserine are strong antioxidants, previously demonstrated to reduce cognitive decline in animal studies. We aimed to investigate their cognitive and neurophysiological effects, using functional MRI, on humans. Thirty-one healthy participants (age 40–78, 10 male/21 female) were recruited to a double-blind placebo-controlled study. Participants were assigned to twice-daily doses of imidazole dipeptide formula (n = 14), containing 500 mg (carnosine/anserine, ratio 1/3) or an identical placebo (n = 17). Functional MRI and neuropsychological assessments were carried out at baseline and after 3 months of supplementation. We analyzed resting state functional connectivity with the FSL fMRI analysis package. There were no differences in neuropsychological scores between the groups at baseline. After 3 months of supplementation, the carnosine/anserine group had better verbal episodic memory performance and decreased connectivity in the default mode network, the posterior cingulate cortex and the right fronto parietal network, as compared with the placebo group. Furthermore, there was a correlation between the extents of cognitive and neuroimaging changes. These results suggest that daily carnosine/anserine supplementation can impact cognitive function and that network connectivity changes are associated with its effects. PMID:26640437
Drexler, Shira Meir; Merz, Christian J; Hamacher-Dang, Tanja C; Tegenthoff, Martin; Wolf, Oliver T
The return of conditioned fear after successful extinction (eg, following exposure therapy) is a significant problem in the treatment of anxiety disorders and posttraumatic stress disorder (PTSD). Targeting the reconsolidation of fear memories may allow a more lasting effect as it intervenes with the original memory trace. Indeed, several pharmacological agents and behavioral interventions have been shown to alter (enhance, impair, or otherwise update) the reconsolidation of reactivated memories of different types. Cortisol is a stress hormone and a potent modulator of learning and memory, yet its effects on fear memory reconsolidation are unclear. To investigate whether cortisol intervenes with the reconsolidation of fear memories in healthy males and how specific this effect might be, we built a 3-day reconsolidation design with skin conductance response (SCR) as a measure of conditioned fear: Fear acquisition on day 1; reactivation/no-reactivation of one conditioned stimulus and pharmacological intervention on day 2; extinction learning followed by reinstatement and reinstatement test on day 3. The groups differed only in the experimental manipulation on day 2: Reactivation+Cortisol Group, Reactivation+Placebo Group, or No-reactivation+Cortisol Group. Our results revealed an enhancing effect of cortisol on reconsolidation of the reactivated memory. The effect was highly specific, strengthening only the memory of the reactivated conditioned stimulus and not the non-reactivated one. Our findings are in line with previous findings showing an enhancing effect of behavioral stress on the reconsolidation of other types of memories. These results have implications for the understanding and treatment of anxiety disorders and PTSD.
Kline, R. H.; Exposto, F. G.; O’Buckley, S. C.; Westlund, K. N.; Nackley, A. G.
Reduced catechol-O-methyltransferase (COMT) activity resulting from genetic variation or pharmacological depletion results in enhanced pain perception in humans and nociceptive behaviors in animals. Using phasic mechanical and thermal reflex tests (e.g. von Frey, Hargreaves), recent studies show that acute COMT-dependent pain in rats is mediated by β-adrenergic receptors (βARs). In order to more closely mimic the characteristics of human chronic pain conditions associated with prolonged reductions in COMT, the present study sought to determine volitional pain-related and anxiety-like behavioral responses following sustained as well as acute COMT inhibition using an operant 10–45°C thermal place preference task and a light/dark preference test. In addition, we sought to evaluate the effects of sustained COMT inhibition on generalized body pain by measuring tactile sensory thresholds of the abdominal region. Results demonstrated that acute and sustained administration of the COMT inhibitor OR486 increased pain behavior in response to thermal heat. Further, sustained administration of OR486 increased anxiety behavior in response to bright light, as well as abdominal mechanosensation. Finally, all pain-related behaviors were blocked by the non-selective βAR antagonist propranolol. Collectively, these findings provide the first evidence that stimulation of ARs following acute or chronic COMT inhibition drives cognitive-affective behaviors associated with heightened pain that affects multiple body sites. PMID:25659347
Kline, R H; Exposto, F G; O'Buckley, S C; Westlund, K N; Nackley, A G
Reduced catechol-O-methyltransferase (COMT) activity resulting from genetic variation or pharmacological depletion results in enhanced pain perception in humans and nociceptive behaviors in animals. Using phasic mechanical and thermal reflex tests (e.g. von Frey, Hargreaves), recent studies show that acute COMT-dependent pain in rats is mediated by β-adrenergic receptors (βARs). In order to more closely mimic the characteristics of human chronic pain conditions associated with prolonged reductions in COMT, the present study sought to determine volitional pain-related and anxiety-like behavioral responses following sustained as well as acute COMT inhibition using an operant 10-45°C thermal place preference task and a light/dark preference test. In addition, we sought to evaluate the effects of sustained COMT inhibition on generalized body pain by measuring tactile sensory thresholds of the abdominal region. Results demonstrated that acute and sustained administration of the COMT inhibitor OR486 increased pain behavior in response to thermal heat. Further, sustained administration of OR486 increased anxiety behavior in response to bright light, as well as abdominal mechanosensation. Finally, all pain-related behaviors were blocked by the non-selective βAR antagonist propranolol. Collectively, these findings provide the first evidence that stimulation of βARs following acute or chronic COMT inhibition drives cognitive-affective behaviors associated with heightened pain that affects multiple body sites.
Buelow, Melissa T; Frakey, Laura L
Previous research has shown that math anxiety can influence the math performance level; however, to date, it is unknown whether math anxiety influences performance on working memory tasks during neuropsychological evaluation. In the present study, 172 undergraduate students completed measures of math achievement (the Math Computation subtest from the Wide Range Achievement Test-IV), math anxiety (the Math Anxiety Rating Scale-Revised), general test anxiety (from the Adult Manifest Anxiety Scale-College version), and the three Working Memory Index tasks from the Wechsler Adult Intelligence Scale-IV Edition (WAIS-IV; Digit Span [DS], Arithmetic, Letter-Number Sequencing [LNS]). Results indicated that math anxiety predicted performance on Arithmetic, but not DS or LNS, above and beyond the effects of gender, general test anxiety, and math performance level. Our findings suggest that math anxiety can negatively influence WAIS-IV working memory subtest scores. Implications for clinical practice include the utilization of LNS in individuals expressing high math anxiety.
Anxiey, in general, helps one to cope. It rouses a person to action and gears one up to face a threatening situation. It makes students study harder for exams, and keeps presenters on their toes when making speeches. But an anxiety disorder can prevent one from coping and can disrupt daily life. Anxiety disorders are not just a case of…
Karolides, Nicholas J., Ed.
The articles in this journal issue examine the characteristics of student writing apprehension, and teaching methods to alleviate it. The titles of the articles and their authors are as follows: (1) "Writing Anxiety: Reasons and Reduction Techniques" (Helen R. Heaton and Pauline M. Pray); (2) "Writing Anxiety and the Gifted Student…
Izquierdo, Ivan; Furini, Cristiane R G; Myskiw, Jociane C
Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general.
Boersma, Gretha J.; Treesukosol, Yada; Cordner, Zachary A.; Kastelein, Anneke; Choi, Pique; Moran, Timothy H.; Tamashiro, Kellie L.
Relapse rates are high amongst cases of Anorexia Nervosa (AN) suggesting that some alterations induced by AN may remain after weight restoration. Objective To study the consequences of AN without confounds of environmental variability, a rodent model of activity based anorexia (ABA) can be employed. We hypothesized that exposure to ABA during adolescence may have long-term consequences in taste function, cognition, and anxiety-like behavior after weight restoration. Methods To test this hypothesis we exposed adolescent female rats to ABA (1.5 hrs food access, combined with voluntary running wheel access) and compared their behavior to that of control rats after weight restoration was achieved. The rats were tested for learning /memory, anxiety, food preference and taste in a set of behavioral tests performed during the light period. Results Our data show that ABA exposure leads to reduced performance during the novel object recognition task, a test for contextual learning, without altering performance in the novel place recognition task or the Barnes maze, both tasks that test spatial learning. Furthermore, we do not observe alterations in unconditioned lick responses to sucrose nor quinine (described by humans as “sweet” and “bitter” respectively). Nor did we find alterations in anxiety-like behavior during an elevated plus maze or an open field test. Finally, preference for a diet high in fat was not altered. Discussion Overall our data suggest that ABA exposure during adolescence impairs contextual learning in adulthood without altering spatial leaning, taste, anxiety, or fat preference. PMID:26711541
Magalhães, Ana; Valentim, Ana; Venâncio, Carlos; Pereira, Mariana; Melo, Pedro; Summavielle, Teresa; Antunes, Luis
Ketamine administration has been associated with controversial behavioural impairments and psychotic episodes. Even though ketamine alone and in combination with midazolam or dexmedetomidine are frequently used in laboratory animals, the side-effects of such protocols are not well known. Therefore, our aim was to evaluate the effects of ketamine alone and in combination with midazolam or dexmedetomidine on emotional reactivity, as well as the effects on learning and memory in adult rats at least 48 h after anaesthesia. The evaluation of the potential influence of 100 mg/kg ketamine administered alone and in combination with midazolam (5 mg/kg), or dexmedetomidine (0.25 mg/kg) on spatial learning and recognition memory was studied in adult Wistar rats using the radial maze as well as object recognition and location tests. The influence of these combinations on emotional reactivity was investigated using the new exploration test and the elevated plus maze. Results showed that ketamine alone or in combination with midazolam or dexmedetomidine affected neither spatial and recognition memory, nor emotional reactivity. These results reinforce the safe clinical use of ketamine and its combinations in rats in a research context since the administration of these anaesthetic combinations did not produce significant changes with regard to spatial and recognition memory or emotional reactivity. Furthermore, these results indicate that the quality of scientific data produced in adult rat neurobehavioural research is not jeopardized by the use of these anaesthetic protocols.
Zhang, Yang; Lu, Shan; Liu, Chunlei; Zhang, Huimei; Zhou, Xuanhe; Ni, Changlin; Qin, Wen; Zhang, Quan
Type 2 diabetes mellitus (T2DM) can cause multidimensional cognitive deficits, among which working memory (WM) is usually involved at an early stage. However, the neural substrates underlying impaired WM in T2DM patients are still unclear. To clarify this issue, we utilized functional magnetic resonance imaging (fMRI) and independent component analysis to evaluate T2DM patients for alterations in brain activation and functional connectivity (FC) in WM networks and to determine their associations with cognitive and clinical variables. Twenty complication-free T2DM patients and 19 matched healthy controls (HCs) were enrolled, and fMRI data were acquired during a block-designed 1-back WM task. The WM metrics of the T2DM patients showed no differences compared with those of the HCs, except for a slightly lower accuracy rate in the T2DM patients. Compared with the HCs, the T2DM patients demonstrated increased activation within their WM fronto-parietal networks, and activation strength was significantly correlated with WM performance. The T2DM patients also showed decreased FC within and between their WM networks. Our results indicate that the functional integration of WM sub-networks was disrupted in the complication-free T2DM patients and that strengthened regional activity in fronto-parietal networks may compensate for the WM impairment caused by T2DM.
Zhang, Yang; Lu, Shan; Liu, Chunlei; Zhang, Huimei; Zhou, Xuanhe; Ni, Changlin; Qin, Wen; Zhang, Quan
Type 2 diabetes mellitus (T2DM) can cause multidimensional cognitive deficits, among which working memory (WM) is usually involved at an early stage. However, the neural substrates underlying impaired WM in T2DM patients are still unclear. To clarify this issue, we utilized functional magnetic resonance imaging (fMRI) and independent component analysis to evaluate T2DM patients for alterations in brain activation and functional connectivity (FC) in WM networks and to determine their associations with cognitive and clinical variables. Twenty complication-free T2DM patients and 19 matched healthy controls (HCs) were enrolled, and fMRI data were acquired during a block-designed 1-back WM task. The WM metrics of the T2DM patients showed no differences compared with those of the HCs, except for a slightly lower accuracy rate in the T2DM patients. Compared with the HCs, the T2DM patients demonstrated increased activation within their WM fronto-parietal networks, and activation strength was significantly correlated with WM performance. The T2DM patients also showed decreased FC within and between their WM networks. Our results indicate that the functional integration of WM sub-networks was disrupted in the complication-free T2DM patients and that strengthened regional activity in fronto-parietal networks may compensate for the WM impairment caused by T2DM. PMID:27021340
Jiang, Yong-Hui; Pan, Yanzhen; Zhu, Li; Landa, Luis; Yoo, Jong; Spencer, Corinne; Lorenzo, Isabel; Brilliant, Murray; Noebels, Jeffrey; Beaudet, Arthur L
Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal
van Ast, Vanessa A; Cornelisse, Sandra; Marin, Marie-France; Ackermann, Sandra; Garfinkel, Sarah N; Abercrombie, Heather C
It has long been known that cortisol affects learning and memory processes. Despite a wealth of research dedicated to cortisol effects on learning and memory, the strength or even directionality of the effects often vary. A number of the factors that alter cortisol's effects on learning and memory are well-known. For instance, effects of cortisol can be modulated by emotional arousal and the memory phase under study. Despite great advances in understanding factors that explain variability in cortisol's effects, additional modulators of cortisol effects on memory exist that are less widely acknowledged in current basic experimental research. The goal of the current review is to disseminate knowledge regarding less well-known modulators of cortisol effects on learning and memory. Since several models for the etiology of anxiety, such as post-traumatic stress disorder (PTSD), incorporate stress and the concomitant release of cortisol as important vulnerability factors, enhanced understanding of mechanisms by which cortisol exerts beneficial as opposed to detrimental effects on memory is very important. Further elucidation of the factors that modulate (or alter) cortisol's effects on memory will allow reconciliation of seemingly inconsistent findings in the basic and clinical literatures. The present review is based on a symposium as part of the 42nd International Society of Psychoneuroendocrinology Conference, New York, USA, that highlighted some of those modulators and their underlying mechanisms.
... fearful to talk at all in certain situations. Panic attacks. These episodes of anxiety can occur for no apparent reason. During a panic attack, a child typically has sudden and intense physical ...
... making life feel overwhelming or out of control. Obsessive compulsive disorder (OCD) . For a person with OCD, anxiety takes ... For Kids For Parents MORE ON THIS TOPIC Obsessive-Compulsive Disorder Taking Your Child to a Therapist Posttraumatic Stress ...
Silove, D; Manicavasagar, V; O'Connell, D; Blaszczynski, A
Attachment theory has proposed that early separation anxiety is a risk factor for adult anxiety disorder, with the recent focus being particularly on panic disorder. The results of empirical studies examining this link are, however, contradictory, possibly because of inconsistencies across studies in measuring memories of early separation anxiety. In the present study, a psychometrically sound measure, the Separation Anxiety Symptom Inventory (SASI) was used to compare memories of such early symptoms in panic disorder (including those with mild phobic-avoidance), generalised anxiety disorder and control subjects. Anxiety patients as a group returned higher SASI scores (p < 0.001) with a non-significant trend for panic disorder patients to score higher than those with generalised anxiety. These results suggest that early separation anxiety may be a harbinger of adult anxiety and that risk of panic disorder may be higher in the most severely affected youngsters. As a risk factor, early separation anxiety does not however appear to be uniquely related to adult panic disorder.
Miu, Andrei C.; Heilman, Renata M.; Opre, Adrian; Miclea, Mircea
Emotional arousal can both enhance and impair memory. Considering that both emotional memory and trait anxiety (TA) have been associated with adrenergic activity, the authors investigated whether there is an association between 2 opposite emotional memory biases and the TA. The authors used a procedure recently put forward by B. A. Strange, R.…
Clinard, Catherine T; Bader, Lauren R; Sullivan, Molly A; Cooper, Matthew A
Conditioned defeat is a model in Syrian hamsters (Mesocricetus auratus) in which normal territorial aggression is replaced by increased submissive and defensive behavior following acute social defeat. The conditioned defeat response involves both a fear-related memory for a specific opponent as well as anxiety-like behavior indicated by avoidance of novel conspecifics. We have previously shown that systemic injection of a 5-HT2a receptor antagonist reduces the acquisition of conditioned defeat. Because neural activity in the basolateral amygdala (BLA) is critical for the acquisition of conditioned defeat and BLA 5-HT2a receptors can modulate anxiety but have a limited effect on emotional memories, we investigated whether 5-HT2a receptor modulation alters defeat-induced anxiety but not defeat-related memories. We injected the 5-HT2a receptor antagonist MDL 11,939 (0 mM, 1.7 mM or 17 mM) or the 5-HT2a receptor agonist TCB-2 (0 mM, 8 mM or 80 mM) into the BLA prior to social defeat. We found that injection of MDL 11,939 into the BLA impaired acquisition of the conditioned defeat response and blocked defeat-induced anxiety in the open field, but did not significantly impair avoidance of former opponents in the Y-maze. Furthermore, we found that injection of TCB-2 into the BLA increased the acquisition of conditioned defeat and increased anxiety-like behavior in the open field, but did not alter avoidance of former opponents. Our data suggest that 5-HT2a receptor signaling in the BLA is both necessary and sufficient for the development of conditioned defeat, likely via modulation of defeat-induced anxiety.
Zhang, Jin-Bao; Chen, Ling; Lv, Zhu-Man; Niu, Xue-Yuan; Shao, Can-Can; Zhang, Chan; Pruski, Michal; Huang, Ying; Qi, Cong-Cong; Song, Ning-Ning; Lang, Bing; Ding, Yu-Qiang
Early-life sensory input plays a crucial role in brain development. Although deprivation of orofacial sensory input at perinatal stages disrupts the establishment of the barrel cortex and relevant callosal connections, its long-term effect on adult behavior remains elusive. In this study, we investigated the behavioral phenotypes in adult mice with unilateral transection of the infraorbital nerve (ION) at postnatal day 3 (P3). Although ION-transected mice had normal locomotor activity, motor coordination, olfaction, anxiety-like behaviors, novel object memory, preference for social novelty and sociability, they presented deficits in social memory and spatial memory compared with control mice. In addition, the social memory deficit was associated with reduced oxytocin (OXT) levels in the hypothalamus and could be partially restored by intranasal administration of OXT. Thus, early sensory deprivation does result in behavioral alterations in mice, some of which may be associated with the disruption of oxytocin signaling.
Alkozei, Anna; Cooper, Peter J.; Creswell, Cathy
Background Two specific cognitive constructs that have been implicated in the development and maintenance of anxiety symptoms are anxiety sensitivity and emotional reasoning, both of which relate to the experience and meaning of physical symptoms of arousal or anxiety. The interpretation of physical symptoms has been particularly implicated in theories of social anxiety disorder, where internal physical symptoms are hypothesized to influence the individual's appraisals of the self as a social object. Method The current study compared 75 children on measures of anxiety sensitivity and emotional reasoning: 25 with social anxiety disorder, 25 with other anxiety disorders, and 25 nonanxious children (aged 7–12 years). Results Children with social anxiety disorder reported higher levels of anxiety sensitivity and were more likely than both other groups to view ambiguous situations as anxiety provoking, whether physical information was present or not. There were no group differences in the extent to which physical information altered children's interpretation of hypothetical scenarios. Limitations This study is the first to investigate emotional reasoning in clinically anxious children and therefore replication is needed. In addition, those in both anxious groups commonly had comorbid conditions and, consequently, specific conclusions about social anxiety disorder need to be treated with caution. Conclusion The findings highlight cognitive characteristics that may be particularly pertinent in the context of social anxiety disorder in childhood and which may be potential targets for treatment. Furthermore, the findings suggest that strategies to modify these particular cognitive constructs may not be necessary in treatments of some other childhood anxiety disorders. PMID:24120086
Donner, Nina C.; Lowry, Christopher A.
Research has elucidated causal links between stress exposure and the development of anxiety disorders, but due to the limited use of female or sex-comparative animal models, little is known about the mechanisms underlying sex differences in those disorders. This is despite an overwhelming wealth of evidence from the clinical literature that the prevalence of anxiety disorders is about twice as high in women compared to men, in addition to gender differences in severity and treatment efficacy. We here review human gender differences in generalized anxiety disorder, panic disorder, posttraumatic stress disorder and anxiety-relevant biological functions, discuss the limitations of classic conflict anxiety tests to measure naturally occurring sex differences in anxiety-like behaviors, describe sex-dependent manifestation of anxiety states after gestational, neonatal, or adolescent stressors, and present animal models of chronic anxiety states induced by acute or chronic stressors during adulthood. Potential mechanisms underlying sex differences in stress-related anxiety states include emerging evidence supporting the existence of two anatomically and functionally distinct serotonergic circuits that are related to the modulation of conflict anxiety and panic-like anxiety, respectively. We discuss how these serotonergic circuits may be controlled by reproductive steroid hormone-dependent modulation of crfr1 and crfr2 expression in the midbrain dorsal raphe nucleus and by estrous stage-dependent alterations of γ-aminobutyric acid (GABAergic) neurotransmission in the periaqueductal gray, ultimately leading to sex differences in emotional behavior. PMID:23588380
Antion, Marcia D.; Merhav, Maayan; Hoeffer, Charles A.; Reis, Gerald; Kozma, Sara C.; Thomas, George; Schuman Erin M.; Rosenblum, Kobi; Klann, Eric
Protein synthesis is required for the expression of enduring memories and long-lasting synaptic plasticity. During cellular proliferation and growth, S6 kinases (S6Ks) are activated and coordinate the synthesis of de novo proteins. We hypothesized that protein synthesis mediated by S6Ks is critical for the manifestation of learning, memory, and…
Dudaee-Faass, Sigal; Marnane, Claire; Wagner, Renate
Two case reports are described in which patients presented for the treatment of multiple comorbid anxiety disorders, all of which appeared to derive from prolonged separation anxiety disorder. In particular, these adults had effectively altered their lifestyles to avoid separation, thereby displaying only ambiguous separation anxiety symptoms that…
Mitra, Shiladitya; Sameer Kumar, Ghantasala S.; Tiwari, Vivek; Lakshmi, B. Jyothi; Thakur, Suman S.; Kumar, Satish
WDR13 expresses from the X chromosome and has a highly conserved coding sequence. There have been multiple associations of WDR13 with memory. However, its detailed function in context of brain and behavior remains unknown. We characterized the behavioral phenotype of 2 month old male mice lacking the homolog of WDR13 gene (Wdr13−/0). Taking cue from analysis of its expression in the brain, we chose hippocampus for molecular studies to delineate its function. Wdr13−/0 mice spent less time in the central area of the open field test (OFT) and with the novel object in novel object recognition test (NOR) as compared to the wild-type. However, these mice didn't show any significant changes in total time spent in arms or in frequency of arm entries in elevated plus maze (EPM). In the absence of Wdr13, there was a significant upregulation of synaptic proteins, viz., SYN1, RAB3A, CAMK2A etc. accompanied with increased spine density of hippocampal CA1 neurons and better spatial memory in mice as measured by increased time spent in the target quadrant of Morris water maze (MWM) during probe test. Parallel study from our lab has established c-JUN, ER α/β, and HDAC 1,3,7 as interacting partners of WDR13. WDR13 represses transcription from AP1 (c-JUN responsive) and Estrogen Receptor Element (ERE) promoters. We hypothesized that absence of Wdr13 would result in de-regulated expression of a number of genes including multiple synaptic genes leading to the observed phenotype. Knocking down Wdr13 in Neuro2a cell lines led to increased transcripts of Camk2a and Nrxn2 consistent with in-vivo results. Summarily, our data provides functional evidence for the role of Wdr13 in brain. PMID:27625594
Brown, Laura B; Nicholson, Timothy R; Aybek, Selma; Kanaan, Richard A; David, Anthony S
Conversion disorder (CD) is a condition where neurological symptoms, such as weakness or sensory disturbance, are unexplained by neurological disease and are presumed to be of psychological origin. Contemporary theories of the disorder generally propose dysfunctional frontal control of the motor or sensory systems. Classical (Freudian) psychodynamic theory holds that the memory of stressful life events is repressed. Little is known about the frontal (executive) function of these patients, or indeed their general neuropsychological profile, and psychodynamic theories have been largely untested. This study aimed to investigate neuropsychological functioning in patients with CD, focusing on executive and memory function. A directed forgetting task (DFT) using words with variable emotional valence was also used to investigate memory suppression. 21 patients and 36 healthy controls completed a battery of neuropsychological tests and patients had deficits in executive function and auditory-verbal (but not autobiographical) memory. The executive deficits were largely driven by differences in IQ, anxiety and mood between the groups. A subgroup of 11 patients and 28 controls completed the DFT and whilst patients recalled fewer words overall than controls, there were no significant effects of directed forgetting or valence. This study provides some limited support for deficits in executive, and to a lesser degree, memory function in patients with CD, but did not find evidence of altered memory suppression to support the psychodynamic theory of repression.
Bernstein, Gail A; Layne, Ann E; Egan, Elizabeth A; Nelson, Lara P
The present study examined the relation between maternal anxiety symptoms and child anxiety symptoms and evaluated whether a reporting bias is associated with maternal anxiety. Fifty-seven mother-child pairs participated. All children had features or diagnoses of separation anxiety disorder (SAD), generalized anxiety disorder, and/or social phobia. Measures of maternal symptomatology and child anxiety were administered. Higher levels of maternal phobic anxiety on the Brief Symptom Inventory were significantly associated with higher levels of separation anxiety in children. After controlling for clinician rating of SAD severity, maternal phobic anxiety emerged as a significant predictor of maternal ratings of child separation anxiety, accounting for 19% of the variance. Phobic mothers endorsed levels of separation anxiety in their children that exceeded levels endorsed by clinicians, suggesting maternal overreporting.
Morrow, L.A.; Ryan, C.M.; Hodgson, M.J.; Robin, N. )
Exposure to organic solvents has been linked repeatedly to alterations in both personality and cognitive functioning. To assess the nature and extent of these changes more thoroughly, 32 workers with a history of exposure to mixtures of organic solvents and 32 age- and education-matched blue-collar workers with no history of exposure were assessed with a comprehensive battery of neuropsychological tests. Although both groups were comparable on measures of general intelligence, significant differences were found in virtually all other cognitive domains tested (Learning and Memory, Visuospatial, Attention and Mental Flexibility, Psychomotor Speed). In addition, Minnesota Multiphasic Personality Inventories of exposed workers indicated clinically significant levels of depression, anxiety, somatic concerns and disturbances in thinking. The reported psychological distress was unrelated to degree of cognitive deficit. Finally, several exposure-related variables were associated with poorer performance on tests of memory and visuospatial ability.
Koychev, Ivan; Ebmeier, Klaus P
Anxiety disorder in the elderly is twice as common as dementia and four to six times more common than major depression. Anxiety is associated with poorer quality of life, significant distress and contributes to the onset of disability. Mortality risks are also increased, through physical causes, especially cardiovascular disease, and suicide. Diagnosing anxiety disorders in older adults remains a challenge because of the significant overlap in symptoms between physical disorders (shortness of breath; abdominal and chest pain; palpitations) and depression (disturbed sleep; poor attention, concentration and memory; restlessness). Good history taking is crucial in elucidating whether the complaint is of new onset or a recurrence of a previous disorder. The presence of comorbid depression should be clarified. If present, its temporal relationship with the anxiety symptoms will indicate whether there is an independent anxiety disorder. A medication review is warranted, as a number of drugs may be causative (calcium channel blockers, alpha- and beta-blockers, digoxin, L-thyroxine, bronchodilators, steroids, theophylline, antihistamines) or may cause anxiety in withdrawal (e.g. benzodiazepines). Substance and alcohol abuse should be excluded, as withdrawal from either may cause anxiety. A new or exacerbated physical illness may be related to anxiety. Medical investigations will help clarify the extent to which a particular somatic symptom is the result of anxiety.
Wollin, S R; Plummer, J L; Owen, H; Hawkins, R M F; Materazzo, F
This study aimed to identify factors contributing to anxiety at induction of anaesthesia in children. One hundred and twenty children aged five to twelve years and scheduled for surgery requiring general anaesthesia were included. Children were interviewed and assessed prior to surgery. Parents completed anxiety measures prior to surgery and were interviewed after the induction of anaesthesia. The level of children's anxiety was determined at the time of induction of anaesthesia by the modified Yale Preoperative Anxiety Scale. Factors associated with increased levels of anxiety in the children included increased number of people in the room at induction of anaesthesia; longer waiting time between admission at the hospital and induction of anaesthesia; negative memories of previous hospital experiences; and having a mother who does not practise a religion. Suggestions for implementation of the findings and for future research are provided.
Mohammad, Farhan; Aryal, Sameer; Ho, Joses; Stewart, James Charles; Norman, Nurul Ayuni; Tan, Teng Li; Eisaka, Agnese; Claridge-Chang, Adam
Anxiety helps us anticipate and assess potential danger in ambiguous situations [1-3]; however, the anxiety disorders are the most prevalent class of psychiatric illness [4-6]. Emotional states are shared between humans and other animals , as observed by behavioral manifestations , physiological responses , and gene conservation . Anxiety research makes wide use of three rodent behavioral assays-elevated plus maze, open field, and light/dark box-that present a choice between sheltered and exposed regions . Exposure avoidance in anxiety-related defense behaviors was confirmed to be a correlate of rodent anxiety by treatment with known anxiety-altering agents [12-14] and is now used to characterize anxiety systems. Modeling anxiety with a small neurogenetic animal would further aid the elucidation of its neuronal and molecular bases. Drosophila neurogenetics research has elucidated the mechanisms of fundamental behaviors and implicated genes that are often orthologous across species. In an enclosed arena, flies stay close to the walls during spontaneous locomotion [15, 16], a behavior proposed to be related to anxiety . We tested this hypothesis with manipulations of the GABA receptor, serotonin signaling, and stress. The effects of these interventions were strikingly concordant with rodent anxiety, verifying that these behaviors report on an anxiety-like state. Application of this method was able to identify several new fly anxiety genes. The presence of conserved neurogenetic pathways in the insect brain identifies Drosophila as an attractive genetic model for the study of anxiety and anxiety-related disorders, complementing existing rodent systems.
Mohammad, Farhan; Aryal, Sameer; Ho, Joses; Stewart, James Charles; Norman, Nurul Ayuni; Tan, Teng Li; Eisaka, Agnese; Claridge-Chang, Adam
Summary Anxiety helps us anticipate and assess potential danger in ambiguous situations [1, 2, 3]; however, the anxiety disorders are the most prevalent class of psychiatric illness [4, 5, 6]. Emotional states are shared between humans and other animals , as observed by behavioral manifestations , physiological responses , and gene conservation . Anxiety research makes wide use of three rodent behavioral assays—elevated plus maze, open field, and light/dark box—that present a choice between sheltered and exposed regions . Exposure avoidance in anxiety-related defense behaviors was confirmed to be a correlate of rodent anxiety by treatment with known anxiety-altering agents [12, 13, 14] and is now used to characterize anxiety systems. Modeling anxiety with a small neurogenetic animal would further aid the elucidation of its neuronal and molecular bases. Drosophila neurogenetics research has elucidated the mechanisms of fundamental behaviors and implicated genes that are often orthologous across species. In an enclosed arena, flies stay close to the walls during spontaneous locomotion [15, 16], a behavior proposed to be related to anxiety . We tested this hypothesis with manipulations of the GABA receptor, serotonin signaling, and stress. The effects of these interventions were strikingly concordant with rodent anxiety, verifying that these behaviors report on an anxiety-like state. Application of this method was able to identify several new fly anxiety genes. The presence of conserved neurogenetic pathways in the insect brain identifies Drosophila as an attractive genetic model for the study of anxiety and anxiety-related disorders, complementing existing rodent systems. PMID:27020741
Balaji, Bhaskar; Kumar, Ekambaram Prem; Kumar, Anil
Effect of standardized Bacopa monniera (BM; family: Scrophulariaceae) extract (100 and 300 mg/kg) against sodium fluoride (NaF; 100 and 200 ppm)-induced behavioural, biochemical, and neuropathological alterations in mice was evaluated. Akinesia, rotarod (motor coordination), forced swim test (depression), open field test (anxiety), transfer latency (memory), cholinesterase (ChE), and oxidative stress (superoxide dismutase, catalase, glutathione peroxidase, and lipid peroxidation) were determined in mice treated with NaF for 30 days alone and in combination with BM. NaF induced motor incoordination, depression, and memory impairment, and these were prevented by coadministration of BM in mice. However, NaF did not alter the weight gain, feed/water consumption, and anxiety profile. Suppression of ChE levels and increased oxidative stress were observed in mice treated with NaF. Coadministration of BM significantly improved the memory, ChE levels, and antioxidant enzymes but failed to alter the fluoride levels in NaF-treated mice. Histopathological studies revealed that BM protected the neuropathological alterations induced by NaF.
Jeon, Seong Gak; Kim, Kyoung Ah; Chung, Hyunju; Choi, Junghyun; Song, Eun Ji; Han, Seung-Yun; Oh, Myung Sook; Park, Jong Hwan; Kim, Jin-il; Moon, Minho
Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic. PMID:27432189
Jeon, Seong Gak; Kim, Kyoung Ah; Chung, Hyunju; Choi, Junghyun; Song, Eun Ji; Han, Seung-Yun; Oh, Myung Sook; Park, Jong Hwan; Kim, Jin-Il; Moon, Minho
Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic.
Abramowitz, Jonathan S.; Olatunji, Bunmi O.; Deacon, Brett J.
Although clinical observations suggest that health-related anxiety is present, to some extent, in a number of anxiety disorders, this relationship has not been examined empirically. The present study therefore utilized the Short Health Anxiety Inventory (SHAI) to elucidate the structure of such symptoms among patients with anxiety disorders and to…
Beaumier, Coreen M; Rothman, Alan L
Secondary dengue virus (DENV) infection is a major factor contributing to the risk for severe disease, an effect that depends upon the sequence of infection with different DENV serotypes. We previously reported sequence-dependent effects of secondary DENV infection on CD8+ T-cell responses in mice. To further evaluate the effect of infection sequence, we analyzed DENV-specific CD4+ T-cell responses and their relationship to the CD8+ T-cell response. Serotype cross-reactivity of CD4+ T-cell responses also depended upon the sequence of serotypes in this model. Furthermore, adoptive transfer of memory CD4+ T cells altered the response of memory CD8+ T cells to secondary infection. These data demonstrate the interaction of different components of the T-cell response in determining the immunological outcome of secondary DENV infection.
Ricarte, Jorge Javier; Ros, Laura; Latorre, Jose Miguel; Muñoz, Maria Dolores; Aguilar, Maria Jose; Hernandez, Jose Vicente
Overgeneral schemas and lack of autobiographical memory (AM) specificity about our past experiences can predict mood disturbance. Rumination, functional avoidance and executive processes are the main explanatory variables of such overgenerality. However, in non-clinical samples, rumination predicts overgenerality most consistently after the induction of dysphoric mood. Anxiety also activates rumination. Furthermore, anxiety predicts memory performance and has effects on mood which are independent of the effects of rumination. So, what might be the role of anxiety in autobiographical memory performance? A sample of 210 voluntary participants reported measures of autobiographical memory, anxiety, rumination (brooding and reflection), functional avoidance and executive functions (semantic and phonetic verbal fluency task). Autobiographical performance (specificity) was negatively associated with brooding and age and positively with phonetic verbal fluency but not with functional avoidance and anxiety. However, anxiety and brooding were positively correlated even after controlling for depression scores. Moreover, using structural equation modeling, anxiety showed a significant indirect effect on autobiographical specificity through brooding rumination. These results suggest a possible association of anxiety with autobiographical recall through brooding rumination.
Alves, Anne C; Alchieri, João C; Barbosa, Gustavo A S
In this study we investigate the phenomenon of bruxism, defined as the act of clenching and/or grinding the teeth, a habit that compromises the orofacial region. It is often associated with emotional aspects, such as anxiety and stress, and may result in alterations to orofacial structures, functional modifications and social repercussions. The aim of this study was to determine a possible association between bruxism and anxiety underscoring the primary complaints related to masticatory function. Eighty volunteers participated in the study. They were divided into bruxers (N = 40) and non-bruxers (N = 40) of both sexes. The diagnosis of bruxism was made by clinical examination. The Trait-State Anxiety Inventory was used to assess anxiety levels and a questionnaire with structured questions related to daily activities, focusing on masticatory function (for the bruxism group), was applied to evaluate psychosocial aspects. The results of the study show a significant difference in state anxiety. Mean and standard deviation of state anxiety in the bruxism and non-bruxism groups was 42.7 +/- 9.6 and 38.6 +/- 8.2 (p < or = 0.04), respectively, while trait anxiety had a mean and standard deviation of 44.5 +/- 11.0 and 40.7 +/- 9.5 (p < or = 0.11). The main complaints of bruxers during mastication were facial pain and headache while chewing as well as the presence of clicking sounds in the jaw joint. Findings demonstrate an association between emotional factors such as anxiety and bruxism, resulting in compromised masticatory function.
Lopes, Teresa Silveira; Afonso, Rosa Marina Lopes Brás Martins; Ribeiro, Óscar Manuel
Working with past memories through reminiscence interventions has been practiced for several decades with successful outcomes on mental health in older adults. Few studies however have focused on autobiographical memory recall in older individuals with cognitive impairment. This study aims to analyze the impact of an individual reminiscence program in a group of older persons with cognitive decline living in nursing homes on the dimensions of cognition, autobiographical memory, mood, behavior and anxiety. A two-group pre-test and post-test design with single blinded assessment was conducted. Forty-one participants were randomized to an experimental group (n=20) and a control group (n=21). The first group attended five weekly individual reminiscence sessions. Changes in the outcome measures were examined for cognition (Montreal Cognitive Assessment; Autobiographical Memory Test), behavior (Alzheimer Disease Assessment Subscale Non-Cog) and emotional status (Cornell Scale for Depression in Dementia; Geriatric Depression Scale, and Geriatric Anxiety Inventory). Participants attending reminiscence sessions exhibited better outcomes compared to the control group in cognition, anxiety and depression (p<0.001), and presented a higher number of retrieved autobiographical events, specificity of evoked memories and positive valence of events (p<0.001), and also presented lower latency time for recalling events, and lower negative recalled events (p<0.01). This study supports the potential value of reminiscence therapy in improving the recall of autobiographical memory. Reminiscence therapy can be helpful to maintain or improve cognitive function, decrease anxiety and manage depressive symptoms and altered behavior, but further investigation is needed to clarify long-term effects.
Motaghinejad, Majid; Fatima, Sulail; Banifazl, Sanaz; Bangash, Mohammad Yasan; Karimian, Morteza
Background: Morphine dependency usually results in undesired outcomes such as anxiety, depression, and cognitive alterations. In this study, morphine was used to manage morphine dependence-induced anxiety, depression, and learning and memory disturbances. Materials and Methods: Forty rats were divided equally into five groups. Group 1 received saline for 21 days. Groups 2–5 were dependent by increasing administration of morphine (15–45 mg/kg) for 7 days. For the next 14 days, morphine was administered as the following regimen: Group 2: once daily; 45 mg/kg (positive controls), Group 3: the same dose with an increasing interval (6 h longer than the previous intervals each time), Group 4: the same dose with an irregular intervals (12, 24, 36 h intervals interchangeably), and Group 5: decreasing doses once daily (every time 2.5 mg/kg less than the former dosage). On days 22–26, elevated plus maze (EPM), open field test (OFT), forced swim test (FST), and tail suspension test (TST) were performed to investigate anxiety level and depression in animals. Between 17th and 21st days, Morris water maze (MWM) was used to evaluate the spatial learning and memory. Results: Chronic morphine administration caused depression and anxiety as observed by FST, EPM, and TST and decreased motor activity in OFT and caused impairment in learning and memory performance in MWM. Treatment with our protocol as increasing interval, irregular interval, and decreasing dosage of morphine caused marked reduction in depression, anxiety, and improved cognition performance compared with positive control group; and attenuated motor deficits in morphine-dependent rats, remarkably. Conclusions: Change in dosage regimens of morphine can reduce morphine-induced anxiety, depression, and cognitive impairments. PMID:28028518
Chen, I-Jung; Chang, Chi-Cheng
Introduction: This study explores the relationship among three variables--cognitive load, foreign language anxiety, and task performance. Cognitive load refers to the load imposed on working memory while performing a particular task. The authors hypothesized that anxiety consumes the resources of working memory, leaving less capacity for cognitive…
... t result in a loss of consciousness — may cause memory problems. Depression or other mental health disorders. Stress, anxiety or depression can cause forgetfulness, confusion, difficulty concentrating and other problems that ...
Lighthall, Frederick F.
The purpose of this pamphlet is to increase teachers' comprehension of anxiety and its relation to children's thinking and forgetting, to their problem solving ability and their sense of competence. The pamphlet describes four parts of the anxiety experience: 1) the anxiety cue, the particular thought, memory, or sensation which precipitates the…
Kheirbek, Mazen A.; Hen, René
IN BRIEF To keep memories from becoming jumbled, the brain must encode the distinct features of events and situations in a way that allows them to be distinguished from one another—a process called pattern separation. Pattern separation enables us to distinguish dangerous situations from similar ones that pose no risk. People with defects in this ability may be prone to anxiety disorders. The process occurs in one of the two regions of the brain that generate neurons throughout life. These fledgling cells seem to be critical to pattern separation. Interventions that specifically boost the ranks of rookie neurons could provide new ways to regulate mood and possibly treat conditions such as post-traumatic stress disorder. PMID:24974712
Young, Christina B; Wu, Sarah S; Menon, Vinod
Math anxiety is a negative emotional reaction to situations involving mathematical problem solving. Math anxiety has a detrimental impact on an individual's long-term professional success, but its neurodevelopmental origins are unknown. In a functional MRI study on 7- to 9-year-old children, we showed that math anxiety was associated with hyperactivity in right amygdala regions that are important for processing negative emotions. In addition, we found that math anxiety was associated with reduced activity in posterior parietal and dorsolateral prefrontal cortex regions involved in mathematical reasoning. Multivariate classification analysis revealed distinct multivoxel activity patterns, which were independent of overall activation levels in the right amygdala. Furthermore, effective connectivity between the amygdala and ventromedial prefrontal cortex regions that regulate negative emotions was elevated in children with math anxiety. These effects were specific to math anxiety and unrelated to general anxiety, intelligence, working memory, or reading ability. Our study identified the neural correlates of math anxiety for the first time, and our findings have significant implications for its early identification and treatment.
Wang, Pengyun; Li, Juan; Li, Hui-Jie; Huo, Lijuan; Li, Rui
The present study conducted a quantitative meta-analysis aiming at assessing consensus across the functional neuroimaging studies of episodic memory in individuals with amnestic mild cognitive impairment (aMCI) and elucidating consistent activation patterns. An activation likelihood estimation (ALE) was conducted on the functional neuroimaging studies of episodic encoding and retrieval in aMCI individuals published up to March 31, 2015. Analyses covered 24 studies, which yielded 770 distinct foci. Compared to healthy controls, aMCI individuals showed statistically significant consistent activation differences in a widespread episodic memory network, not only in the bilateral medial temporal lobe and prefrontal cortex, but also in the angular gyrus, precunes, posterior cingulate cortex, and even certain more basic structures. The present ALE meta-analysis revealed that the abnormal patterns of widespread episodic memory network indicated that individuals with aMCI may not be completely “mild” in nature. PMID:27872591
Macbeth, Abbe H; Scharfman, Helen E; Maclusky, Neil J; Gautreaux, Claris; Luine, Victoria N
Recognition memory and anxiety were examined in nulliparous (NP: 0 litters) and multiparous (MP: 5-6 litters) middle-aged female rats (12 months old) to assess possible enduring effects of multiparity at least 3 months after the last litter was weaned. MP females performed significantly better than NP females on the non-spatial memory task, object recognition, and the spatial memory task, object placement. Anxiety as measured on the elevated plus maze did not differ between groups. Monoaminergic activity and levels were measured in prefrontal cortex, CA1 hippocampus, CA3 hippocampus, and olfactory bulb (OB). NP and MP females differed in monoamine concentrations in the OB only, with MP females having significantly greater concentrations of dopamine and metabolite DOPAC, norepinephrine and metabolite MHPG, and the serotonin metabolite 5-HIAA, as compared to NP females. These results indicate a long-term change in OB neurochemistry as a result of multiparity. Brain-derived neurotrophic factor (BDNF) was also measured in hippocampus (CA1, CA3, dentate gyrus) and septum. MP females had higher BDNF levels in both CA1 and septum; as these regions are implicated in memory performance, elevated BDNF may underlie the observed memory task differences. Thus, MP females (experiencing multiple bouts of pregnancy, birth, and pup rearing during the first year of life) displayed enhanced memory task performance but equal anxiety responses, as compared to NP females. These results are consistent with previous studies showing long-term changes in behavioral function in MP, as compared to NP, rats and suggest that alterations in monoamines and a neurotrophin, BDNF, may contribute to the observed behavioral changes.
... Old Feeding Your 1- to 2-Year-Old Separation Anxiety KidsHealth > For Parents > Separation Anxiety Print A ... help both of you get through it. About Separation Anxiety Babies adapt pretty well to other caregivers. ...
Jarome, Timothy J.; Kwapis, Janine L.; Werner, Craig T.; Parsons, Ryan G.; Gafford, Georgette M.; Helmstetter, Fred J.
Numerous studies have indicated that maintaining a fear memory after retrieval requires de novo protein synthesis. However, no study to date has examined how the temporal dynamics of repeated retrieval events affect this protein synthesis requirement. The present study varied the timing of a second retrieval of an established auditory fear memory…
de Sousa Fernandes Perna, E B; Theunissen, E L; Kuypers, K P C; Heckman, P; de la Torre, R; Farre, M; Ramaekers, J G
Previous studies have shown that single doses of MDMA can affect mood and impair memory in humans. The neuropharmacological mechanisms involved in MDMA-induced memory impairment are not clear. Memantine, an NMDA and alpha 7 nicotinic acetylcholine (ACh) receptor antagonist, was able to reverse MDMA-induced memory impairment in rats. This study investigated whether treatment with memantine can prevent MDMA-induced memory impairment in humans. 15 subjects participated in a double-blind, placebo controlled, within-subject design. Subjects received both pre-treatment (placebo/memantine 20 mg) (T1) and treatment (placebo/MDMA 75 mg) (T2) on separate test days. T1 preceded T2 by 120 min. Memory function was assessed 90 min after T2 by means of a Visual Verbal Learning Task, a Prospective Memory Task, the Sternberg Memory Task and the Abstract Visual Pattern Learning Task. Profile of Mood State and psychomotor performance were also assessed to control whether MDMA and memantine interactions would selectively pertain to memory or transfer to other domains as well. MDMA significantly impaired performance in the visual verbal learning task and abstract visual pattern learning task. Pre-treatment with memantine did not prevent MDMA-induced memory impairment in these two tasks. Both positive (vigour, arousal, elation) and negative mood effects (anxiety) were increased by MDMA. The responses were not altered by pretreatment with memantine which had no effect on memory or mood when given alone. These preliminary results suggest that memantine does not reverse MDMA-induced memory impairment and mood in humans. This article is part of the Special Issue entitled 'CNS Stimulants'.
Howland, J G; Cazakoff, B N; Zhang, Y
Infection during pregnancy (i.e., prenatal infection) increases the risk of psychiatric illnesses such as schizophrenia and autism in the adult offspring. The present experiments examined the effects of prenatal immune challenge on behavior in three paradigms relevant to these disorders: prepulse inhibition (PPI) of the acoustic startle response, locomotor responses to an unfamiliar environment and the N-methyl-d-aspartate antagonist MK-801, and three forms of recognition memory. Pregnant Long-Evans rats were exposed to the viral mimetic polyinosinic-polycytidylic acid (PolyI:C; 4 mg/kg, i.v.) on gestational day 15. Offspring were tested for PPI and locomotor activity before puberty (postnatal days (PNDs)35 and 36) and during young adulthood (PNDs 56 and 57). Four prepulse-pulse intervals (30, 50, 80, and 140 ms) were employed in the PPI test. Recognition memory testing was performed using three different spontaneous novelty recognition tests (object, object location, and object-in-place recognition) after PND 60. Regardless of sex, offspring of PolyI:C-treated dams showed disrupted PPI at 50-, 80-, and 140-ms prepulse-pulse intervals. In the prepubescent rats, we observed prepulse facilitation for the 30-ms prepulse-pulse interval trials that was selectively retained in the adult PolyI:C-treated offspring. Locomotor responses to MK-801 were significantly reduced before puberty, whereas responses to an unfamiliar environment were increased in young adulthood. Both male and female PolyI:C-treated offspring showed intact object and object location recognition memory, whereas male PolyI:C-treated offspring displayed significantly impaired object-in-place recognition memory. Females were unable to perform the object-in-place test. The present results demonstrate that prenatal immune challenge during mid/late gestation disrupts PPI and locomotor behavior. In addition, the selective impairment of object-in-place recognition memory suggests tasks that depend on prefrontal
Powell, Craig M.; Schoch, Susanne; Monteggia, Lisa; Barrot, Michel; Matos, Maria F.; Feldmann, Nicole; Südhof, Thomas C.; Nestler, Eric J.
Summary The active zone protein RIM1α is required both for maintaining normal probability of neurotransmitter release and for long-term presynaptic potentiation at brain synapses. We now demonstrate that RIM1α−/− mice exhibit normal coordination and anxiety-related behaviors but display severely impaired learning and memory. Mice with a synaptotagmin 1 mutation, which selectively lowers release probability, and mice with Rab3A deletion, which selectively abolishes presynaptic long-term potentiation, do not exhibit this abnormality. Our data suggest that a decrease in release probability or a loss of presynaptic LTP alone is not sufficient to cause major behavioral alterations, but the combination of presynaptic abnormalities in RIM1α−/− mice severely alters learning and memory. PMID:15066271
Chaby, L E; Cavigelli, S A; Hirrlinger, A M; Caruso, M J; Braithwaite, V A
Exposure to stress during adolescence can cause long-term changes in behavior and cognition. Anxiety diagnoses rise during adolescence and are increased by adverse experiences. Currently, it is unknown how long stress during adolescence alters anxiety in adulthood. We found that rats exposed to chronic unpredictable stress during adolescence expressed altered behavior 6.5 months later; showing increased anxiety in a feeding test in a novel environment. Although behavioral changes indicative of anxiety were detected in late adulthood, the basal levels of fecal corticoid metabolites in prior-stressed rats did not differ from unstressed, control rats.
Szafranski, Derek D; Barrera, Terri L; Norton, Peter J
Research suggests that test anxiety is associated with a number of maladaptive factors. The majority of test anxiety research includes the Test Anxiety Inventory (TAI) as a primary outcome variable. However, the TAI was normed on college undergraduates in 1980. The academic landscape has altered in a variety of ways in the past 30 years, which may result in out-of-date norms. This study examined changes in TAI scores in college undergraduates (n =437) as well as convergent validity with measures of trait anxiety and academic performance. Results indicated increases in TAI scores for females while holding constant for males. Additionally, females and males displayed positive correlations between the TAI and state-trait anxiety inventory, while only females displayed a significant negative correlation between the TAI and grade point average. Data provide evidence of changes in TAI scores. As a result, researchers should be careful when drawing conclusions based on original TAI norms, especially in the case of female undergraduates.
Bowman, Rachel E; Luine, Victoria; Diaz Weinstein, Samantha; Khandaker, Hameda; DeWolf, Sarah; Frankfurt, Maya
We have previously demonstrated that adolescent exposure of rats to bisphenol-A (BPA), an environmental endocrine disrupter, increases anxiety, impairs spatial memory, and decreases dendritic spine density in the CA1 region of the hippocampus (CA1) and medial prefrontal cortex (mPFC) when measured in adolescents in both sexes. The present study examined whether the behavioral and morphological alterations following BPA exposure during adolescent development are maintained into adulthood. Male and female, adolescent rats received BPA, 40μg/kg/bodyweight, or control treatments for one week. In adulthood, subjects were tested for anxiety and locomotor activity, spatial memory, non-spatial visual memory, and sucrose preference. Additionally, stress-induced serum corticosterone levels and dendritic spine density in the mPFC and CA1 were measured. BPA-treated males, but not females, had decreased arm visits on the elevated plus maze, but there was no effect on anxiety. Non-spatial memory, object recognition, was also decreased in BPA treated males, but not in females. BPA exposure did not alter spatial memory, object placement, but decreased exploration during the tasks in both sexes. No significant group differences in sucrose preference or serum corticosterone levels in response to a stress challenge were found. However, BPA exposure, regardless of sex, significantly decreased spine density of both apical and basal dendrites on pyramidal cells in CA1 but had no effect in the mPFC. Current data are discussed in relation to BPA dependent changes, which were present during adolescence and did, or did not, endure into adulthood. Overall, adolescent BPA exposure, below the current reference safe daily limit set by the U.S.E.P.A., leads to alterations in some behaviors and neuronal morphology that endure into adulthood.
Geng, Fengji; Mai, Xiaoqin; Zhan, Jianying; Xu, Lin; Shao, Jie; Meeker, John; Lozoff, Betsy
This study used event-related potentials to assess effects of low-level prenatal lead exposure on auditory recognition memory in 2-month-old infants. Infants were divided into four groups according to cord-blood lead concentration: 1) < 2.00 μg/dL, 2) 2.00-2.99 μg/dL, 3) 3.0-3.7 μg/dL, and 4) ≥ 3.7 μg/dL. The first group showed the normally expected differences in P2, P750, and LSW amplitudes elicited by mothers’ and strangers’ voices. These differences were not observed for one or more ERP components in the other groups. Thus, there was electrophysiological evidence of poorer auditory recognition memory at 2 months with cord-blood lead ≥ 2.00 μg/dL. PMID:25350757
Beaudreau, Sherry A.; O’Hara, Ruth
We examined the association of anxiety, depressive symptoms, and their co-occurrence on cognitive processes in 102 community-dwelling older adults. Participants completed anxiety and depression questionnaires, and measures of episodic and semantic memory, word fluency, processing speed/shifting attention, and inhibition. Participants with only increased anxiety had poorer processing speed/shifting attention, and inhibition, but depressive symptoms alone were not associated with any cognitive deficits. Although co-existing anxiety and depressive symptoms was associated with deficits in 3 cognitive domains, reductions in inhibition were solely attributed to anxiety. Findings suggest an excess cognitive load on inhibitory ability in normal older adults reporting mild anxiety. PMID:19485667
Moustafa, Ahmed A; Tindle, Richard; Ansari, Zaheda; Doyle, Margery J; Hewedi, Doaa H; Eissa, Abeer
Given that achievement in learning mathematics at school correlates with work and social achievements, it is important to understand the cognitive processes underlying abilities to learn mathematics efficiently as well as reasons underlying the occurrence of mathematics anxiety (i.e. feelings of tension and fear upon facing mathematical problems or numbers) among certain individuals. Over the last two decades, many studies have shown that learning mathematical and numerical concepts relies on many cognitive processes, including working memory, spatial skills, and linguistic abilities. In this review, we discuss the relationship between mathematical learning and cognitive processes as well as the neural substrates underlying successful mathematical learning and problem solving. More importantly, we also discuss the relationship between these cognitive processes, mathematics anxiety, and mathematics learning disabilities (dyscalculia). Our review shows that mathematical cognition relies on a complex brain network, and dysfunction to different segments of this network leads to varying manifestations of mathematical learning disabilities.
Moylan, Steven; Gustavson, Kristin; Karevold, Evalill; Øverland, Simon; Jacka, Felice N; Pasco, Julie A; Berk, Michael
Cigarette smoking is increased in people with trait anxiety and anxiety disorders, however no longitudinal data exist illuminating whether smoking in adolescence can influence the developmental trajectory of anxiety symptoms from early vulnerability in infancy to adult anxiety expression. Using The Tracing Opportunities and Problems in Childhood and Adolescence (TOPP) Study, a community-based cohort of children and adolescents from Norway who were observed from the age of 18 months to age 18-19 years, we explored the relationship between adolescent smoking, early vulnerability for anxiety in infancy (e.g. shyness, internalizing behaviors, emotional temperaments) and reported early adult anxiety. Structural equation modeling demonstrated that adolescent active smoking was positively associated with increased early adulthood anxiety (β = 0.17, p<0.05), after controlling for maternal education (proxy for socioeconomic status). Adolescent anxiety did not predict early adult smoking. Adolescent active smoking was a significant effect modifier in the relationship between some infant vulnerability factors and later anxiety; smoking during adolescence moderated the relationship between infant internalizing behaviors (total sample: active smokers: β = 0.85, p<0.01, non-active smokers: ns) and highly emotional temperament (total sample: active smokers: β = 0.55, p<0.01,non-active smokers: ns), but not shyness, and anxiety in early adulthood. The results support a model where smoking acts as an exogenous risk factor in the development of anxiety, and smoking may alter the developmental trajectory of anxiety from infant vulnerability to early adult anxiety symptom expression. Although alternative non-mutually exclusive models may explain these findings, the results suggest that adolescent smoking may be a risk factor for adult anxiety, potentially by influencing anxiety developmental trajectories. Given the known adverse health effects of cigarette smoking and
Fluoxetine normalizes disrupted light-induced entrainment, fragmented ultradian rhythms and altered hippocampal clock gene expression in an animal model of high trait anxiety- and depression-related behavior
Schaufler, Jörg; Ronovsky, Marianne; Savalli, Giorgia; Cabatic, Maureen; Sartori, Simone B.; Singewald, Nicolas; Pollak, Daniela D.
ABSTRACT Introduction Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs – also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated. Materials and methods The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular level were examined using mice selectively bred for high anxiety-related and co-segregating depression-like behavior (HAB) and normal anxiety/depression behavior mice (NAB). Results The length of the circadian period was increased in fluoxetine-treated HAB as compared to NAB mice while the number of activity bouts and light-induced entrainment were comparable. No difference in hippocampal Cry2 expression, previously reported to be dysbalanced in untreated HAB mice, was observed, while Per2 and Per3 mRNA levels were higher in HAB mice under fluoxetine treatment. Discussion The present findings provide evidence that fluoxetine treatment normalizes disrupted circadian locomotor activity and clock gene expression in a genetic mouse model of high trait anxiety and depression. An interaction between the molecular mechanisms mediating the antidepressant response to fluoxetine and the endogenous regulation of circadian rhythms in genetically based mood and anxiety disorders is proposed. PMID:26679264
Southwick, S M; Paige, S; Morgan, C A; Bremner, J D; Krystal, J H; Charney, D S
In this chapter we review trauma-related studies involving epinephrine (E), norepinephrine (NE), and serotonin (5-HT). Central catecholamine neurons seem to play a critical role in level of alertness, vigilance, orienting, selective attention, memory, fear conditioning, and cardiovascular responses to life-threatening stimuli. Evidence of catecholamine dysregulation in post-traumatic stress disorder (PTSD) includes exaggerated increases in heart rate and blood pressure when exposed to visual and auditory reminders of trauma, elevated 24-hour urine catecholamine excretion, decreased platelet alpha-2 adrenergic receptor number, exaggerated behavioral, cardiovascular, and biochemical responses to IY yohimbine, decreased cortical brain metabolism secondary to IV yohimbine, and clinical efficacy of adrenergic blocking agents. Serotonin seems to play numerous roles in the central nervous system, including regulation of sleep, aggression, appetite, cardiovascular and respiratory activity, motor output, anxiety, mood, neuroendocrine secretion, and analgesia. Evidence of serotonergic dysregulation in PTSD includes frequent symptoms of aggression, impulsivity, depression and suicidality, decreased platelet paroxetine binding, blunted prolactin response to fenfluramine, exaggerated reactivity to m-chloro-phenyl-piperazine, and clinical efficacy of serotonin reuptake inhibitors. It has been suggested that alterations in NE, E, and 5-HT may have relevance for symptoms commonly seen in survivors with PTSD, including hypervigilance, exaggerated startle, irritability, impulsivity, aggression, intrusive memories, depressed mood, and suicidality.
Bloemsma, J Monique; Boer, Frits; Arnold, Renée; Banaschewski, Tobias; Faraone, Stephen V; Buitelaar, Jan K; Sergeant, Joseph A; Rommelse, Nanda; Oosterlaan, Jaap
Previous research established that children with ADHD and comorbid anxiety have a later age of ADHD onset, show less off-task and hyperactive behavior, and have more school problems than children with ADHD alone. Comorbid anxiety appears to ameliorate behavioral inhibition deficits, worsen working memory problems, and lengthen reaction times in ADHD. This study investigated the effect of comorbid anxiety on a broad range of neurocognitive functions and includes child-, parent- and teacher reports of anxiety. The sample consisted of 509 children in the age range 5-19 years, including 238 children with a diagnosis of ADHD combined subtype and 271 normal control children. Children were tested on a broad battery of neurocognitive tasks that proved highly sensitive to ADHD in previous work. Linear Structural Equation Modeling (SEM) was used to estimate the effect of comorbid anxiety on the neurocognitive functions. Child reported anxiety was associated with slower motor speed and response speed and better behavioral inhibition. Teacher reported anxiety was related to worse time production. Parent reported anxiety was not significantly associated with any of the neurocognitive functions. Compared to parent and teacher reports of anxiety, child reported comorbid anxiety shows foremost the largest associations with the neurocognitive dysfunctions observed in children with ADHD. This stresses the importance of including child self-reported anxiety assessments in clinical and research practice.
Vilar-Pereira, Glaucia; Ruivo, Leonardo Alexandre de Souza; Lannes-Vieira, Joseli
The existence of the nervous form of Chagas disease is a matter of discussion since Carlos Chagas described neurological disorders, learning and behavioural alterations in Trypanosoma cruzi-infected individuals. In most patients, the clinical manifestations of the acute phase, including neurological abnormalities, resolve spontaneously without apparent consequence in the chronic phase of infection. However, chronic Chagas disease patients have behavioural changes such as psychomotor alterations, attention and memory deficits, and depression. In the present study, we tested whether or not behavioural alterations are reproducible in experimental models. We show that C57BL/6 mice chronically infected with the Colombian strain of T. cruzi (150 days post-infection) exhibit behavioural changes as (i) depression in the tail suspension and forced swim tests, (ii) anxiety analysed by elevated plus maze and open field test sand and (iii) motor coordination in the rotarod test. These alterations are neither associated with neuromuscular disorders assessed by the grip strength test nor with sickness behaviour analysed by temperature variation sand weight loss. Therefore, chronically T. cruzi-infected mice replicate behavioural alterations (depression and anxiety) detected in Chagas disease patients opening an opportunity to study the interconnection and the physiopathology of these two biological processes in an infectious scenario. PMID:26676323
Gilkey, Jeffrey C.; Duesterhaus, Michelle A.; Peter, Frank J.; Renn, Rosemarie A.; Baker, Michael S.
A first-in-first-out (FIFO) microelectromechanical memory apparatus (also termed a mechanical memory) is disclosed. The mechanical memory utilizes a plurality of memory cells, with each memory cell having a beam which can be bowed in either of two directions of curvature to indicate two different logic states for that memory cell. The memory cells can be arranged around a wheel which operates as a clocking actuator to serially shift data from one memory cell to the next. The mechanical memory can be formed using conventional surface micromachining, and can be formed as either a nonvolatile memory or as a volatile memory.
Gilkey, Jeffrey C.; Duesterhaus, Michelle A.; Peter, Frank J.; Renn, Rosemarie A.; Baker, Michael S.
A first-in-first-out (FIFO) microelectromechanical memory apparatus (also termed a mechanical memory) is disclosed. The mechanical memory utilizes a plurality of memory cells, with each memory cell having a beam which can be bowed in either of two directions of curvature to indicate two different logic states for that memory cell. The memory cells can be arranged around a wheel which operates as a clocking actuator to serially shift data from one memory cell to the next. The mechanical memory can be formed using conventional surface micromachining, and can be formed as either a nonvolatile memory or as a volatile memory.
Kennedy, Susan J.; Rapee, Ronald M.; Edwards, Susan L.
The efficacy of early intervention for preschool-aged children at risk of anxiety disorders is investigated. Brief early intervention delivered through parents can reduce anxiety and associated risk and may alter the developmental trajectory of anxiety in some young children.
Chapa, Deborah W; Akintade, Bimbola; Son, Heesook; Woltz, Patricia; Hunt, Dennis; Friedmann, Erika; Hartung, Mary Kay; Thomas, Sue Ann
Depression and anxiety are common comorbid conditions in patients with heart failure. Patients with heart failure and depression have increased mortality. The association of anxiety with increased mortality in patients with heart failure is not established. The purpose of this article is to illustrate the similarities of the underlying pathophysiology of heart failure, depression, and anxiety by using the Biopsychosocial Holistic Model of Cardiovascular Health. Depression and anxiety affect biological processes of cardiovascular function in patients with heart failure by altering neurohormonal function via activation of the hypothalamic-pituitary-adrenal axis, autonomic dysregulation, and activation of cytokine cascades and platelets. Patients with heart failure and depression or anxiety may exhibit a continued cycle of heart failure progression, increased depression, and increased anxiety. Understanding the underlying pathophysiological relationships in patients with heart failure who experience comorbid depression and/or anxiety is critical in order to implement appropriate treatments, educate patients and caregivers, and educate other health professionals.
Kendig, Michael D; Boakes, Robert A; Rooney, Kieron B; Corbit, Laura H
Although increasing consumption of sugar drinks is recognized as a significant public health concern, little is known about (a) the cognitive effects resulting from sucrose consumption; and (b) whether the long-term effects of sucrose consumption are more pronounced for adolescents. This experiment directly compared performance on a task of spatial learning and memory (the Morris Water Maze) and sensitivity to outcome devaluation following 28 days of 2-h/day access to a 10% sucrose solution in adolescent and young-adult Wistar rats. Sucrose groups developed elevated fasting blood glucose levels after the diet intervention, despite drawing <15% of calories from sucrose and gaining no more weight than controls. In subsequent behavioral testing, sucrose groups were impaired on the Morris Water Maze, with some residual deficits in spatial memory observed more than 6 weeks after the end of sucrose exposure. Further, results from outcome devaluation testing indicated that in the older cohort of rats, those fed sucrose showed reduced sensitivity to devaluation of the outcome, suggestive of differences in instrumental learning following sucrose exposure. Data provide strong evidence that sucrose consumption can induce deficits in spatial cognition and reward-oriented behavior at levels that resemble patterns of sugar drink consumption in young people, and which can remain long after exposure.
Cheng, Ruey-Kuang; MacDonald, Christopher J; Williams, Christina L; Meck, Warren H
Choline availability in the maternal diet has a lasting effect on brain and behavior of the offspring. To further delineate the impact of early nutritional status, we examined effects of prenatal-choline supplementation on timing, emotion, and memory performance of adult male and female rats. Rats that were given sufficient choline (CON: 1.1 g/kg) or supplemental choline (SUP: 5.0 g/kg) during embryonic days (ED) 12-17 were trained with a differential reinforcement of low-rate (DRL) schedule that was gradually transitioned through 5-, 10-, 18-, 36-, and 72-sec criterion times. We observed that SUP-females emitted more reinforced responses than CON-females, which were more efficient than both groups of males. In addition, SUP-males and SUP-females exhibited a reduction in burst responding (response latencies <2 sec) compared with both groups of CON rats. Furthermore, despite a reduced level of burst responding, the SUP-males made more nonreinforced responses prior to the DRL criterion as a result of maintaining the previous DRL criterion following transition to a new criterion. In summary, long-lasting effects of prenatal-choline supplementation were exhibited by reduced frustrative DRL responding in conjunction with the persistence of temporal memory in SUP-males and enhanced temporal exploration and response efficiency in SUP-females.
Johnson, Philip L; Molosh, Andrei; Fitz, Stephanie D; Arendt, Dave; Deehan, Gerald A; Federici, Lauren M; Bernabe, Cristian; Engleman, Eric A; Rodd, Zachary A; Lowry, Christopher A; Shekhar, Anantha
The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT(a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle-treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ~40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC.
Johnson, Philip L.; Molosh, Andrei; Fitz, Stephanie D.; Arendt, Dave; Deehan, Gerald A.; Federici, Lauren M.; Bernabe, Cristian; Engleman, Eric A.; Rodd, Zachary A.; Lowry, Christopher A.; Shekhar, Anantha
The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT (a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5 days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle-treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ∼40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC. PMID:26476009
Leão, Anderson H F F; Medeiros, André M; Apolinário, Gênedy K S; Cabral, Alícia; Ribeiro, Alessandra M; Barbosa, Flávio F; Silva, Regina H
The plus-maze discriminative avoidance task (PMDAT) has been used to investigate interactions between aversive memory and an anxiety-like response in rodents. Suitable performance in this task depends on the activity of the basolateral amygdala, similar to other aversive-based memory tasks. However, the role of spatial cues and hippocampal-dependent learning in the performance of PMDAT remains unknown. Here, we investigated the role of proximal and distal cues in the retrieval of this task. Animals tested under misplaced proximal cues had diminished performance, and animals tested under both misplaced proximal cues and absent distal cues could not discriminate the aversive arm. We also assessed the role of the dorsal hippocampus (CA1) in this aversive memory task. Temporary bilateral inactivation of dorsal CA1 was conducted with muscimol (0.05 μg, 0.1 μg, and 0.2 μg) prior to the training session. While the acquisition of the task was not altered, muscimol impaired the performance in the test session and reduced the anxiety-like response in the training session. We also performed a spreading analysis of a fluorophore-conjugated muscimol to confirm selective inhibition of CA1. In conclusion, both distal and proximal cues are required to retrieve the task, with the latter being more relevant to spatial orientation. Dorsal CA1 activity is also required for aversive memory formation in this task, and interfered with the anxiety-like response as well. Importantly, both effects were detected by different parameters in the same paradigm, endorsing the previous findings of independent assessment of aversive memory and anxiety-like behavior in the PMDAT. Taken together, these findings suggest that the PMDAT probably requires an integration of multiple systems for memory formation, resembling an episodic-like memory rather than a pure conditioning behavior. Furthermore, the concomitant and independent assessment of emotionality and memory in rodents is relevant to
Loxton, David; Canales, Juan J
A high proportion of young methamphetamine (MA) users simultaneously consume alcohol. However, the potential neurological and behavioural alterations induced by such a drug combination have not been systematically examined. We studied in adolescent rats the long-term effects of alcohol, MA, and alcohol and MA combined on anxiety-like behaviour, memory, and neurogenesis in the adult hippocampus. Rats received saline, ethanol (ETOH, 1.5g/kg), MA (MA, 2mg/kg), or ethanol and MA combined (ETHOH-MA, 1.5g/kg ethanol plus 2mg/kg MA) via oral gavage, once daily for 5 consecutive days. Open field (OF), elevated plus maze (EPM) and radial arm maze (RAM) tests were conducted following a 15-day withdrawal period. The results showed alterations in exploratory behaviour in the OF in the MA and ETOH-MA groups, and anxiety-like effects in the EPM in all three drug treatment groups. All three drug groups exhibited reference memory deficits in the RAM, but only the combination treatment group displayed alterations in working memory. Both MA and ETOH-MA treatments increased the length of doublecortin (DCX)-void gaps in the dentate gyrus but only ETOH-MA treatment increased the number of such gaps. An increased number and length of DCX-void gaps correlated with decreased exploratory activity in the OF, and impaired working memory in the RAM was associated with an augmented number of gaps. These findings suggest that alterations in adult hippocampal neurogenesis are linked to the persistent cognitive and behavioural deficits produced by alcohol and MA exposure.
Loureiro, Michael; Lecourtier, Lucas; Engeln, Michel; Lopez, Joëlle; Cosquer, Brigitte; Geiger, Karin; Kelche, Christian; Cassel, Jean-Christophe; Pereira de Vasconcelos, Anne
Current views posit the dorsal hippocampus (DHipp) as contributing to spatial memory processes. Conversely, the ventral hippocampus (VHipp) modulates stress, emotions and affects. Arguments supporting this segregation include differences in (i) connectivity: the DHipp is connected with the entorhinal cortex which receives visuospatial neocortical inputs; the VHipp is connected with both the amygdala and hypothalamus, (ii) electrophysiological characteristics: there is a larger proportion of place cells in the DHipp than in the VHipp, and an increasing dorsoventral gradient in the size of place fields, suggesting less refined spatial coding in the VHipp, and (iii) consequences of lesions: spatial memory is altered after DHipp lesions, less dramatically, sometimes not, after VHipp lesions. Using reversible inactivation, we report in rats, that lidocaine infusions into the DHipp or VHipp right before a probe trial impair retrieval performance in a water-maze task. This impairment was found at two post-acquisition delays compatible with recent memory (1 and 5 days). Pre-training blockade of the VHipp did not prevent task acquisition and drug-free retrieval, on the contrary to pre-training blockade of DHipp, which altered performance in a subsequent drug-free probe trial. Complementary experiments excluded possible locomotor, sensorimotor, motivational or anxiety-related biases from data interpretation. Our conclusion is that a spatial memory can be acquired with the DHipp, less efficiently with the VHipp, and that the retrieval of such a memory and/or the expression of its representation engages the dorsoventral axis of the hippocampus when the task has been learnt with an entirely functional hippocampus.
Rao, Stephen M.; Bonner-Jackson, Aaron; Nielson, Kristy A.; Seidenberg, Michael; Smith, J. Carson; Woodard, John L.; Durgerian, Sally
Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer’s disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N=24) and non-carriers (N=21). All participants, ages 65–85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57 months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the
Iwasaki, Mayumi; Paszkowski, Jerzy
Epigenetics refers to heritable changes in patterns of gene expression that occur without alterations in DNA sequence. The epigenetic mechanisms involve covalent modifications of DNA and histones, which affect transcriptional activity of chromatin. Since chromatin states can be propagated through mitotic and meiotic divisions, epigenetic mechanisms are thought to provide heritable 'cellular memory'. Here, we review selected examples of epigenetic memory in plants and briefly discuss underlying mechanisms.
Lovallo, William R; Enoch, Mary-Anne; Acheson, Ashley; Cohoon, Andrew J; Sorocco, Kristen H; Hodgkinson, Colin A; Vincent, Andrea S; Goldman, David
Exposure to stress during critical periods of development can have adverse effects on adult health behaviors, and genetic vulnerabilities may enhance these stress effects. We carried out an exploratory examination of psychological, physiological, and behavioral characteristics of 252 healthy young adults for the impact of early-life adversity (ELA) in relation to the G-to-A single nucleotide polymorphism (SNP), rs9296158, of the FKBP5 gene. FKBP5 is a molecular cochaperone that contributes to the functional status of the glucocorticoid receptor (GR) and to the quality of corticosteroid signaling. FKBP5 expression is upregulated by cortisol exposure during stressful episodes, with greater upregulation seen in A-allele carriers. As such, FKBP5 expression and GR function may be environmentally sensitive in A-allele carriers and therefore suitable for the study of gene-by-environment (G × E) interactions. Compared with FKBP5, GG homozygotes (N=118), A-allele carriers (N = 132) without psychiatric morbidity had progressively worse performance on the Stroop color-word task with increasing levels of ELA exposure (Genotype × ELA, F=5.14, P=0.007), indicating a G × E interaction on working memory in early adulthood. In addition, heart rate response to mental stress was diminished overall in AA/AG-allele carriers (F=5.15, P=0.024). Diminished working memory and attenuated autonomic responses to stress are both associated with risk for alcoholism and other substance use disorders. The present data suggest that FKBP5 in the GR pathway may be a point of vulnerability to ELA, as seen in this group of non-traumatized young adults. FKBP5 is accordingly a potential target for more extensive studies of the impact of ELA on health and health behaviors in adulthood.
Blanco, Eduardo; Galeano, Pablo; Holubiec, Mariana I; Romero, Juan I; Logica, Tamara; Rivera, Patricia; Pavón, Francisco J; Suarez, Juan; Capani, Francisco; Rodríguez de Fonseca, Fernando
Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLα and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARα) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA.
Blanco, Eduardo; Galeano, Pablo; Holubiec, Mariana I.; Romero, Juan I.; Logica, Tamara; Rivera, Patricia; Pavón, Francisco J.; Suarez, Juan; Capani, Francisco; Rodríguez de Fonseca, Fernando
Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLα and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARα) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA. PMID:26578900
Lecourtier, L; Antal, M-C; Cosquer, B; Schumacher, A; Samama, B; Angst, M-J; Ferrandon, A; Koning, E; Cassel, J-C; Nehlig, A
Neonatal ventral hippocampal lesions (NVHL) in rats are considered a potent developmental model of schizophrenia. After NVHL, rats appear normal during their preadolescent time, whereas in early adulthood, they develop behavioral deficits paralleling symptomatic aspects of schizophrenia, including hyperactivity, hypersensitivity to amphetamine (AMPH), prepulse and latent inhibition deficits, reduced social interactions, and spatial working and reference memory alterations. Surprisingly, the question of the consequences of NVHL on postnatal neurobehavioral development has not been addressed. This is of particular importance, as a defective neurobehavioral development could contribute to impairments seen in adult rats. Therefore, at several time points of the early postsurgical life of NVHL rats, we assessed behaviors accounting for neurobehavioral development, including negative geotaxis and grip strength (PD11), locomotor coordination (PD21), and open-field (PD25). At adulthood, the rats were tested for anxiety levels, locomotor activity, as well as spatial reference memory performance. Using a novel task, we also investigated the consequences of the lesions on procedural-like memory, which had never been tested following NVHL. Our results point to preserved neurobehavioral development. They also confirm the already documented locomotor hyperactivity, spatial reference memory impairment, and hyperresponsiveness to AMPH. Finally, our rseults show for the first time that NVHL disabled the development of behavioral routines, suggesting dramatic procedural memory deficits. The presence of procedural memory deficits in adult rats subjected to NHVL suggests that the lesions lead to a wider range of cognitive deficits than previously shown. Interestingly, procedural or implicit memory impairments have also been reported in schizophrenic patients.
Kihlstrom, J F
Hypnotized subjects respond to suggestions from the hypnotist for imaginative experiences involving alterations in perception and memory. Individual differences in hypnotizability are only weakly related to other forms of suggestibility. Neuropsychological speculations about hypnosis focus on the right hemisphere and/or the frontal lobes. Posthypnotic amnesia refers to subjects' difficulty in remembering, after hypnosis, the events and experiences that transpired while they were hypnotized. Posthypnotic amnesia is not an instance of state-dependent memory, but it does seem to involve a disruption of retrieval processes similar to the functional amnesias observed in clinical dissociative disorders. Implicit memory, however, is largely spared, and may underlie subjects' ability to recognize events that they cannot recall. Hypnotic hypermnesia refers to improved memory for past events. However, such improvements are illusory: hypermnesia suggestions increase false recollection, as well as subjects' confidence in both true and false memories. Hypnotic age regression can be subjectively compelling, but does not involve the ablation of adult memory, or the reinstatement of childlike modes of mental functioning, or the revivification of memory. The clinical and forensic use of hypermnesia and age regression to enhance memory in patients, victims and witnesses (e.g. recovered memory therapy for child sexual abuse) should be discouraged. PMID:9415925
Meneses, Alfredo; Perez-Garcia, Georgina; Ponce-Lopez, Teresa; Tellez, Ruth; Castillo, Carlos
The serotonin transporter (SERT) has been associated to diverse functions and diseases, though seldom to memory. Therefore, we made an attempt to summarize and discuss the available publications implicating the involvement of the SERT in memory, amnesia and anti-amnesic effects. Evidence indicates that Alzheimer's disease and drugs of abuse like d-methamphetamine (METH) and (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") have been associated to decrements in the SERT expression and memory deficits. Several reports have indicated that memory formation and amnesia affected the SERT expression. The SERT expression seems to be a reliable neural marker related to memory mechanisms, its alterations and potential treatment. The pharmacological, neural and molecular mechanisms associated to these changes are of great importance for investigation.
Sarid, Orly; Cwikel, Julie; Czamanski-Cohen, Johanna; Huss, Ephrat
This paper presents an overview of a combined, evaluated protocol, cognitive behavioural and art therapy treatment (CB-ART), for the treatment of women with perinatal mood and anxiety disorders (PMADs). The protocol integrates cognitive behavioural interventions and art therapy. CB-ART focuses on changing distressing image, symptom or memory (ISM) that interferes with functioning. The method directs clients to identify compositional elements that characterize their stressful ISM and to alter the element in their imagination, in bodily sensations and on the page. Examples are provided to illustrate the therapeutic process.
Curran, Christine P.; Genter, Mary Beth; Patel, Krishna V.; Schaefer, Tori L.; Skelton, Matthew R.; Williams, Michael T.; Vorhees, Charles V.
Background: Both coplanar and noncoplanar polychlorinated biphenyls (PCBs) exhibit neurotoxic effects in animal studies, but individual congeners do not always produce the same effects as PCB mixtures. Humans genetically have > 60-fold differences in hepatic cytochrome P450 1A2 (CYP1A2)-uninduced basal levels and > 12-fold variability in aryl hydrocarbon receptor (AHR)affinity; because CYP1A2 is known to sequester coplanar PCBs and because AHR ligands include coplanar PCBs, both genotypes can affect PCB response. Objectives: We aimed to develop a mouse paradigm with extremes in Cyp1a2 and Ahr genotypes to explore genetic susceptibility to PCB-induced developmental neurotoxicity using an environmentally relevant mixture of PCBs. Methods: We developed a mixture of eight PCBs to simulate human exposures based on their reported concentrations in human tissue, breast milk, and food supply. We previously characterized specific differences in PCB congener pharmacokinetics and toxicity, comparing high-affinity–AHR Cyp1a2 wild-type [Ahrb1_Cyp1a2(+/+)], poor-affinity–AHR Cyp1a2 wild-type [Ahrd_Cyp1a2(+/+)], and high-affinity–AHR Cyp1a2 knockout [Ahrb1_Cyp1a2(–/–)] mouse lines [Curran CP, Vorhees CV, Williams MT, Genter MB, Miller ML, Nebert DW. 2011. In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes. Toxicol Sci 119:189–208]. Dams received a mixture of three coplanar and five noncoplanar PCBs on gestational day 10.5 and postnatal day (PND) 5. In the present study we conducted behavioral phenotyping of exposed offspring at PND60, examining multiple measures of learning, memory, and other behaviors. Results: We observed the most significant deficits in response to PCB treatment in Ahrb1_Cyp1a2(–/–) mice, including impaired novel object recognition and increased failure rate in the Morris water maze. However, all PCB-treated genotypes showed significant differences on
Manteghi, Fariborz; Nasehi, Mohammad; Zarrindast, Mohammad-Reza
Fear memory and learning cause behavioural patterns such as fight or flight responses, which increase survival probability, but unfit processing of fear memory and learning can lead to maladaptive behaviours and maladies such as phobias, Post-Traumatic Stress Disorder (PTSD) and anxiety disorders. The growing prevalence of these maladies shows the need to quest novel methods for their treatment. We used anodal transcranial direct current stimulation (tDCS) on the right frontal region as a precondition neuromodulator and arachidonylcyclopropylamide (ACPA), a selective CB1 cannabinoid receptor agonist, as a fear memory impairing agent to assess their effects on contextual and auditory fear conditioning (reliable model for fear studies). Right frontal anodal tDCS (0.2 mA for. 20 minutes) 24 hours before the train did not alter contextual and auditory learning and memory in short-term (24 hrs after the training phase). Moreover, intraperitoneal pre-train injection of ACPA (0.1 mg/kg) alone, decreased both contextual and auditory learning and memory in short- but not long-term. Right frontal anodal tDCS improved short-term contextual fear memory in subthreshold doses of ACPA. On the other hand, right frontal anodal tDCS in long-term improved (lower doses of ACPA) and restored (higher doses of ACPA) both fear memories. These findings showed that, aforementioned approach could cause durable learning and memory improvements. Also this combined modality could be useful for fear extinction training and maladies which inflict amnesia. PMID:28337114
Hansen, Fernanda; Pandolfo, Pablo; Galland, Fabiana; Torres, Felipe Vasconcelos; Dutra, Márcio Ferreira; Batassini, Cristiane; Guerra, Maria Cristina; Leite, Marina Concli; Gonçalves, Carlos-Alberto
Diabetes is associated with loss of cognitive function and increased risk for Alzheimer's disease (AD). Advanced glycation end products (AGEs) are elevated in diabetes and AD and have been suggested to act as mediators of the cognitive decline observed in these pathologies. Methylglyoxal (MG) is an extremely reactive carbonyl compound that propagates glycation reactions and is, therefore, able to generate AGEs. Herein, we evaluated persistent behavioral and biochemical parameters to explore the hypothesis that elevated exogenous MG concentrations, induced by intracerebroventricular (ICV) infusion, lead to cognitive decline in Wistar rats. A high and sustained administration of MG (3μmol/μL; subdivided into 6days) was found to decrease the recognition index of rats, as evaluated by the object-recognition test. However, MG was unable to impair learning-memory processes, as shown by the habituation in the open field (OF) and Y-maze tasks. Moreover, a single high dose of MG induced persistent alterations in anxiety-related behavior, diminishing the anxiety-like parameters evaluated in the OF test. Importantly, MG did not alter locomotion behavior in the different tasks performed. Our biochemical findings support the hypothesis that MG induces persistent alterations in the hippocampus, but not in the cortex, related to glyoxalase 1 activity, AGEs content and glutamate uptake. Glial fibrillary acidic protein and S100B content, as well as S100B secretion (astroglial-related parameters of brain injury), were not altered by ICV MG administration. Taken together, our data suggest that MG interferes directly in brain function and that the time and the levels of exogenous MG determine the different features that can be seen in diabetic patients.
Math anxiety affects both sexes, and is not the cause of imbalance in mathematical professions. Attempts to broaden perceptions of mathematics deal only with the symptoms of math anxiety. The principal cause is the methodology used to teach mathematics. Problem-solving processes must be employed. (MNS)
Kwon, Yong Tae; Balogh, Seth A.; Davydov, Ilia V.; Kashina, Anna S.; Yoon, Jeong Kyo; Xie, Youming; Gaur, Arti; Hyde, Lynn; Denenberg, Victor H.; Varshavsky, Alexander
The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. N-terminal asparagine and glutamine are tertiary destabilizing residues, in that they are enzymatically deamidated to yield secondary destabilizing residues aspartate and glutamate, which are conjugated to arginine, a primary destabilizing residue. N-terminal arginine of a substrate protein is bound by the Ubr1-encoded E3α, the E3 component of the ubiquitin-proteasome-dependent N-end rule pathway. We describe the construction and analysis of mouse strains lacking the asparagine-specific N-terminal amidase (NtN-amidase), encoded by the Ntan1 gene. In wild-type embryos, Ntan1 was strongly expressed in the branchial arches and in the tail and limb buds. The Ntan1−/− mouse strains lacked the NtN-amidase activity but retained glutamine-specific NtQ-amidase, indicating that the two enzymes are encoded by different genes. Among the normally short-lived N-end rule substrates, only those bearing N-terminal asparagine became long-lived in Ntan1−/− fibroblasts. The Ntan1−/− mice were fertile and outwardly normal but differed from their congenic wild-type counterparts in spontaneous activity, spatial memory, and a socially conditioned exploratory phenotype that has not been previously described with other mouse strains. PMID:10805755
... different parts. Some of them are important for memory. The hippocampus (say: hih-puh-KAM-pus) is one of the more important parts of the brain that processes memories. Old information and new information, or memories, are ...
Saito, Yoshiko; Horwitz, Elaine K.; Garza, Thomas J.
Discusses the possibility of anxiety in response to foreign- or second-language reading. Introduces the construct of foreign-language reading anxiety, offers a scale for its measurement, and reports on a preliminary study of reading anxiety in 30 intact first-semester classes of Spanish, Russian, and Japanese. (VWL)
Putwain, David William
Recent changes to educational policy which have focused attention on the use of high stakes testing as performance and accountability measures have renewed interest in test anxiety both in the UK and the USA. The aim of this paper is to provide a critical examination of the test anxiety construct, and explore the ways in which test anxiety is…
Suinn, Richard M.; Deffenbacher, Jerry L.
Provides detailed information on anxiety management training, a relaxation-based, self-control therapy for the treatment of generalized anxiety, phobias, anger, and other stress-related disorders. Describes in detail the specific procedures of anxiety management training, summarizes research findings, and outlines means for deciding on proper use…
Huberty, Thomas J.
Anxiety is one of the most basic human emotions and occurs in every person at some time, most often when someone is apprehensive about uncertain outcomes of an event or set of circumstances. Anxiety can serve an adaptive function, however, and is also a marker for typical development. In the school setting, anxiety is experienced often by students…
anxious students is especially debilitated on tasks calling for short and intermediate term memory (Mueller, 1980). It is reasoned that for highly...conclusions. Culler and Holahan (1980) found that high, compared to low test anxious subjects had significantly poorer study habits and spent more time...relevance to anxiety was a category called "Students’ Affective Thought, " which was divided into subsidiary categories. A number of affective
Benton, Jeremy P; Christopher, Andrew N; Walter, Mark I
To assess how different facets of aging anxiety contributed to the prediction of tangible and existential death anxiety, 167 Americans of various Christian denominations completed a battery of questionnaires. Multiple regression analyses, controlling for demographic variables and previously demonstrated predictors of death anxiety, revealed that the aging anxiety dimensions of physical appearance concern and fear of losses each positively predicted tangible death anxiety. In addition, the aging anxiety dimension of fear of losses predicted existential death anxiety. Results are discussed with respect to the multifaceted nature of death anxiety and how different forms of aging anxiety contribute to anxieties about death.
Banks, Jonathan B; Tartar, Jaime L; Tamayo, Brittney A
A large and growing body of research demonstrates the impact of psychological stress on working memory. However, the typical study approach tests the effects of a single biological or psychological factor on changes in working memory. The current study attempted to move beyond the standard single-factor assessment by examining the impact of 2 possible factors in stress-related working memory impairments. To this end, 60 participants completed a working memory task before and after either a psychological stressor writing task or a control writing task and completed measures of both cortisol and mind wandering. We also included a measure of state anxiety to examine the direct and indirect effect on working memory. We found that mind wandering mediated the relationship between state anxiety and working memory at the baseline measurement. This indirect relationship was moderated by cortisol, such that the impact of mind wandering on working memory increased as cortisol levels increased. No overall working memory impairment was observed following the stress manipulation, but increases in state anxiety and mind wandering were observed. State anxiety and mind wandering independently mediated the relationship between change in working memory and threat perception. The indirect paths resulted in opposing effects on working memory. Combined, the findings from this study suggest that cortisol enhances the impact of mind wandering on working memory, that state anxiety may not always result in stress-related working memory impairments, and that high working memory performance can protect against mind wandering.
Sipos, Kornel; Bodo, Michael; Szalay, Piroska; Szucs, Attila
In order to test the hypothesis that anxiety is a risk factor for cardiovascular disease, specifically stroke, we simultaneously measured anxiety and cerebral vascular alternation, using a computer-based system, "Cerberus." Sixty nine psychiatric patients (including an alcoholic subgroup) were selected as subjects for measurements conducted in Kecskemet, Hungary. The five-item short form of anxiety test (STAI) was administered twice during the same session. Between each test, brain pulse waves were recorded by rheoencephalogram (REG). A REG peak time above 180 milliseconds was considered a cerebrovascular alteration (modified after Jenkner). Data were sorted into two groups: low anxiety (N=10) and high anxiety (N=10). Significant differences were found between cardiovascular risk factors (p< 0.001), REG peak time (p<0.043), and heart rate (p< 0.045). Six subjects showed cerebrovascular alteration in the high anxiety group, and two in the low anxiety group. For the two anxiety groups, there were no significant differences in body mass index, cardiovascular sympathetic-parasympathetic balance, age and symptoms of transient ischemic attack. The correlation of REG and age was significantly different only for the alcoholic subgroup (Szalay et al, 2007). These data support the hypothesis that a correlation exists between cerebrovascular disorder and anxiety in the studied population.
Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Franco-Lira, Maricela; Zhu, Hongtu; Lu, Zhaohua; Solorio, Edelmira; Torres-Jardón, Ricardo; D'Angiulli, Amedeo
Children's urban air pollution exposures result in systemic and brain inflammation and the early hallmarks of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most prevalent genetic risk for AD. We assessed whether APOE in healthy children modulates cognition, olfaction, and metabolic brain indices. The Wechsler Intelligence Scale for Children (WISC-R) and the University of Pennsylvania Smell Identification Test were administered to 50 Mexico City Metropolitan Area children (13.4 ± 4.8 years, 28 APOE ε3 and 22 APOE ε4). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myo-inositol (mI)/Cr, and NAA/mI were calculated using proton magnetic resonance spectroscopy in the white matter of the frontal and parietal lobes, hippocampus, and pons. APOE ε4 versus ε3 children had a reduced NAA/Cr ratio in the right frontal white matter and decrements on attention, short-term memory, and below-average scores in Verbal and Full Scale IQ (>10 points). APOE modulated the group effects between WISC-R and left frontal and parietal white matter, and hippocampus metabolites. Soap was the predominantly failed odor in urban children and, in APOE ε4 versus ε3 carriers, strongly correlated with left hippocampus mI/Cr ratio. APOE modulates responses to air pollution in the developing brain. APOE ε4 carriers could have a higher risk of developing early AD if they reside in a polluted environment. APOE, cognition, and olfaction testing and targeted magnetic resonance spectroscopy may contribute to the assessment of urban children and their results could provide new paths toward the unprecedented opportunity for early neuroprotection and AD prevention.
Ehgoetz Martens, K A; Szeto, J Y Y; Muller, A J; Hall, J M; Gilat, M; Walton, C C; Lewis, S J G
Research on the implications of anxiety in Parkinson's disease (PD) has been neglected despite its prevalence in nearly 50% of patients and its negative impact on quality of life. Previous reports have noted that neuropsychiatric symptoms impair cognitive performance in PD patients; however, to date, no study has directly compared PD patients with and without anxiety to examine the impact of anxiety on cognitive impairments in PD. This study compared cognitive performance across 50 PD participants with and without anxiety (17 PDA+; 33 PDA-), who underwent neurological and neuropsychological assessment. Group performance was compared across the following cognitive domains: simple attention/visuomotor processing speed, executive function (e.g., set-shifting), working memory, language, and memory/new verbal learning. Results showed that PDA+ performed significantly worse on the Digit Span forward and backward test and Part B of the Trail Making Task (TMT-B) compared to the PDA- group. There were no group differences in verbal fluency, logical memory, or TMT-A performance. In conclusion, anxiety in PD has a measurable impact on working memory and attentional set-shifting.
Nuñez, Mia; Gregory, Josh; Zinbarg, Richard E
Retrieval inhibition of negative associations is important for exposure therapy for anxiety, but the relationship between memory inhibition and anxiety is not well understood-anxiety could either be associated with enhanced or deficient inhibition. The present study tested these two competing hypotheses by measuring retrieval inhibition of negative stimuli by related neutral stimuli. Non-clinically anxious undergraduates completed measures of trait and state anxiety and completed a retrieval induced forgetting task. Adaptive forgetting varied with state anxiety. Low levels of state anxiety were associated with no evidence for retrieval inhibition for either threatening or non-threatening categories. Participants in the middle tertile of state anxiety scores exhibited retrieval inhibition for non-threatening categories but not for threatening categories. Participants in the highest tertile of state anxiety, however, exhibited retrieval inhibition for both threatening and non-threatening categories with the magnitude of retrieval inhibition being greater for threatening than non-threatening categories. The data are in line with the avoidance aspect of the vigilance-avoidance theory of anxiety and inhibition. Implications for cognitive behavioural therapy practices are discussed.
Réus, Gislaine Z; Dos Santos, Maria Augusta B; Abelaira, Helena M; Quevedo, João
Anxiety disorders pose one of the largest threats to global mental health, and they predominantly emerge early in life. Social anxiety disorder, also known as social phobia, is the most common of all anxiety disorders. Moreover, it has severe consequences and is a disabling disorder that can cause an individual to be unable to perform the tasks of daily life. Social anxiety disorder is associated with the subsequent development of major depression and other mental diseases, as well as increased substance abuse. Although some neurobiological alterations have been found to be associated with social anxiety disorder, little is known about this disorder. Animal models are useful tools for the investigation of this disorder, as well as for finding new pharmacological targets for treatment. Thus, this review will highlight the main animal models of anxiety associated with social phobia.
Engel, Kirsten; Bandelow, Borwin; Gruber, Oliver; Wedekind, Dirk
Neuroimaging studies have gained increasing importance in validating neurobiological network hypotheses for anxiety disorders. Functional imaging procedures and radioligand binding studies in healthy subjects and in patients with anxiety disorders provide growing evidence of the existence of a complex anxiety network, including limbic, brainstem, temporal, and prefrontal cortical regions. Obviously, "normal anxiety" does not equal "pathological anxiety" although many phenomena are evident in healthy subjects, however to a lower extent. Differential effects of distinct brain regions and lateralization phenomena in different anxiety disorders are mentioned. An overview of neuroimaging investigations in anxiety disorders is given after a brief summary of results from healthy volunteers. Concluding implications for future research are made by the authors.
Steptoe, A; Kearsley, N
Three hundred and forty adults (including sports players, recreational exercisers, mediators and sedentary controls) completed three inventories purporting to measure cognitive and somatic aspects of anxiety. These were the Cognitive-Somatic Anxiety Questionnaire (CSAQ) devised by Schwartz, Davidson & Goleman (Psychosomatic Medicine, 40, 321-328, 1978), the Worry-Emotionality Scale (WES, Morris, Davis & Hutchens, Journal of Educational Psychology, 73, 541-555, 1981) and the Lehrer-Woolfolk (1982) Anxiety Symptom Questionnaire (LWASQ). Factor analysis of the CSAQ and WES identified distinct cognitive and somatic anxiety factors in both inventories. Higher somatic than cognitive ratings were recorded on the CSAQ and WES, while the pattern was reversed on the LWASQ. The CSAQ can tentatively be recommended as a useful measure of these two anxiety components. We were unable to confirm an observation made previously in the literature that practice of meditation is associated with reduced cognitive anxiety, or that exercise is linked with lower somatic anxiety.
Bateson, Melissa; Brilot, Ben; Nettle, Daniel
Anxiety disorders are among the most common mental illnesses, with huge attendant suffering. Current treatments are not universally effective, suggesting that a deeper understanding of the causes of anxiety is needed. To understand anxiety disorders better, it is first necessary to understand the normal anxiety response. This entails considering its evolutionary function as well as the mechanisms underlying it. We argue that the function of the human anxiety response, and homologues in other species, is to prepare the individual to detect and deal with threats. We use a signal detection framework to show that the threshold for expressing the anxiety response ought to vary with the probability of threats occurring, and the individual's vulnerability to them if they do occur. These predictions are consistent with major patterns in the epidemiology of anxiety. Implications for research and treatment are discussed.
Gass, Carlton S; Curiel, Rosie E
The potential impact of test anxiety on cognitive testing was examined in a sample of 300 predominantly male veteran referrals who were administered a comprehensive neu