Regional brain catecholamines and memory: effects of footshock, amygdala implantation, and stimulation

Previous findings have revealed a correlation between post-training release of whole brain norepinephrine (NE) and later retention performance. The present experiment examined changes after a training footshock in NE levels, as well as the levels of the major central NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), dopamine (DA), and epinephrine (EPI) in eight brain regions. Brain levels of these amines and the metabolite were assessed 10 min after training in a one-trial inhibitory (passive) avoidance task. The results indicate that NE levels decreased significantly in neocortex, neostriatum, hypothalamus, frontal pole, septum, and brainstem, but not in hippocampus or thalamus. The decreases in NE levels were generally accompanied by increases in MHPG; the MHPG/NE ratio increased significantly in all areas in which decreases in NE were observed. DA levels decreased in neostriatum and increased in neocortex and brainstem. Epinephrine levels decreased only in the brainstem sample. Thus, the effects of training on NE are widespread, probably reflecting the release of the amine in most brain regions. Such findings are consistent with the view that posttraining release of brain NE may modulate the storage of new information in many brain regions. One especially potent treatment for modulating memory storage is electrical stimulation of the amygdala. Therefore, we also examined the effects of amygdala implantation and stimulation on brain catecholamine levels to determine whether such changes might be correlated with the effects of amygdala stimulation on memory. The results indicate that electrode implantation into the amygdala results in pervasive changes in NE levels in most brain regions tested. Against this modified baseline, the results of training and electrical stimulation were region specific and very difficult to interpret. The major conclusion which can be derived from this portion of the experiment is that the amygdala damage produced by electrode implantation produces a brain which is substantially different from that of intact animals.     

Eugenol as an anti-stress agent: modulation of hypothalamic-pituitary-adrenal axis and brain monoaminergic systems in a rat model of stress

Stress is the leading psychopathological cause for several mental disorders. Physiological and psychological responses to stress are mediated by the hypothalamic?pituitary?adrenal (HPA), sympathoadrenal system (SAS), and brain monoaminergic systems (BMS). Eugenol is reported to substantially modulate brain functions by regulating voltage-gated cation channels and release of neurotransmitters. This study was designed to evaluate the anti-stress effect of eugenol in the 4-h restraint model using rats. Ulcer index was measured as a parameter of the stress response. HPA axis and the SAS were monitored by estimating plasma corticosterone and norepinephrine (NE), respectively. Analysis of NE, serotonin (5-HT), dopamine, and their metabolites in discrete brain regions was performed to understand the role of BMS in the anti-stress effect of eugenol. Stress exposure increased the ulcer index as well as plasma corticosterone and NE levels. Eugenol pretreatment for 7 days decreased the stress-induced increase in ulcer index and plasma corticosterone but not NE levels, indicating a preferential effect on the HPA axis. Furthermore, eugenol showed a ?U?-shaped dose?response curve in decreasing ulcer index and plasma corticosterone levels. Eugenol also reversed the stress-induced changes in 5-HT levels in all brain regions, whereas NE levels were reversed in all brain regions except hippocampus. These results suggest that eugenol possesses significant anti-stress activity in the 4-h restraint model and the effect is due to modulation of HPA and BMS.     

Normal personality traits,rumination and stress generation among early adolescent girls

This study examined associations between personality and stress generation. Expanding upon prior work, we examined (a) the role of Positive Emotionality (PE), Negative Emotionality (NE), and Constraint (CON), and their lower-order facets, as predictors of acute and chronic interpersonal stress generation; (b) whether personality moderated effects of rumination on stress generation; and (c) whether personality increased exposure to independent (uncontrollable) stress. These questions were examined in a one-year study of 126 adolescent girls (M age = 12.39 years) using contextual stress interviews. NE predicted increases in acute and chronic interpersonal stress generation, but not independent stress. NE, CON and affiliative PE each moderated the effect of rumination on chronic interpersonal stress generation. These effects were driven by particular lower-order traits.     

Catecholamine depletion in mice upon reexposure to stress: mediation of the escape deficits produced by inescapable shock

Immediately following exposure to 60 inescapable shocks, Swiss-Webster mice had significantly reduced hypothalamic norepinephrine (NE). Within 24 hr NE levels returned to control values. Reexposure to as few as 10 shocks 24 hr after initial stress exposure resulted in a significant decline of hypothalamic NE. Moreover, at this interval after inescapable shock, escape performance was severely disrupted, with a large proportion of mice exhibiting numerous failures to escape shock. Increasing brain dopamine (DA) and NE by L-dopa treatment prior to inescapable shock prevented the escape deficits. Conversely, pairing five inescapable shocks with NE depletion by FLA-63, or both DA and NE depletion by alpha-methyl-p-tyrosine, disrupted escape performance 24 hr later. Residual drug effects, state dependence, or sustained amine turnover could not account for the behavioral changes observed. Data are discussed in terms of catecholamine mediation of escape performance through variations in response maintenance abilities. Furthermore, it is suggested that the long-term effects of inescapable shock may be due to sensitization effects or conditioned amine depletion.     

Context processing in older adults: evidence for a theory relating cognitive control to neurobiology in healthy aging.

A theory of cognitive aging is presented in which healthy older adults are hypothesized to suffer from disturbances in the processing of context that impair cognitive control function across multiple domains, including attention, inhibition, and working memory. These cognitive disturbances are postulated to be directly related to age-related decline in the function of the dopamine (DA) system in the prefrontal cortex (PFC). A connectionist computational model is described that implements specific mechanisms for the role of DA and PFC in context processing. The behavioral predictions of the model were tested in a large sample of older (N = 81) and young (N = 175) adults performing variants of a simple cognitive control task that placed differential demands on context processing. Older adults exhibited both performance decrements and, counterintuitively, performance improvements that are in close agreement with model predictions.     

Influence of brain-derived neurotrophic factor and catechol O-methyl transferase polymorphisms on effects of meditation on plasma catecholamines and stress

Meditation may show differential effects on stress and plasma catecholamines based on genetic polymorphisms in brain-derived neurotrophic factor (BDNF) and catechol O-methyl transferase (COMT). Eighty adults (40 men, 40 women; mean age 26 years) who practiced meditation regularly and 57 healthy control adults (35 men, 22 women; mean age 26 years) participated. Plasma catecholamines (norepinephrine (NE), epinephrine (E), and dopamine (DA)) concentrations were measured, and a modified form of the Stress Response Inventory was administered. The results were analyzed using two-way analysis of covariance (ANCOVA) with control and meditation subjects, gene polymorphism as factors, and meditation duration as the covariate. Two-way ANCOVA showed a significant interaction between control and meditation subjects, and BDNF Val66Met polymorphism on DA/NE+DA/E (p = 0.042) and NE/E+NE/DA (p = 0.046) ratios. A significant interaction was found for control and meditation subjects with COMT Val158Met polymorphism and plasma NE concentrations (p = 0.009). Post hoc ANCOVA in the meditation group, adjusted for meditation duration, showed significantly higher plasma NE concentrations for COMT Met carriers than COMT Val/Val subjects (p = 0.025). Significant differences of stress levels were found between the control and meditation subjects in BDNF Val/Met (p < 0.001) and BDNF Met/Met (p = 0.003), whereas stress levels in the BDNF Val/Val genotype did not differ between the control and meditation groups. This is the first evidence that meditation produces different effects on plasma catecholamines according to BDNF or COMT polymorphisms.     

Role of norepinephrine in the pathophysiology of neuropsychiatric disorders

The concatenation of convergent lines of evidence from basic to clinical research continues to reveal that norepinephrine (NE) is a crucial regulator of a myriad of behaviors ranging from stress response to memory formation. Furthermore, many neuropsychiatric disorders involve neurocircuitry that is directly modulated by NE. This report summarizes the physiological roles of NE, as well as the main findings implicating a role for NE system dysfunction in mood and anxiety disorders, posttraumatic stress disorder, attention-deficit/hyperactivity disorder, and Alzheimer's disease. In each of these disorders, there appears to be a complex dysregulation of NE function, with changes in locus ceruleus firing, NE availability, and both pre- and postsynaptic receptor regulation. Many symptoms of these disorders are attributable to abnormalities within distributed neural circuits regulated by NE. Appreciation of NE's role in modulating the neural circuitry mediating cognition and affect should help elucidate the pathophysiology of a variety of neuropsychiatric disorders and the development of novel treatments.     

Regulation of Peripheral Catecholamine Responses to Acute Stress in Young Adult and Aged F-344 Rats

Young adult (3-month-old) and aged (24-month-old) Fischer-344 male rats received i.v. infusions of 3H-labeled norepinephrine (NE) and epinephrine (EPI) to examine the effects of aging on the neuronal uptake of NE and sympathoadrenal release of NE and EPI. Spillovers of NE and EPI into plasma and their clearance from the circulation were estimated from plasma concentrations of endogenous and 3H-labeled NE and EPI. The efficiency of neuronal uptake was assessed from changes in plasma clearance of NE and concentrations of its intraneuronal metabolite, dihydroxyphenylglycol (DHPG), during immobilization stress or neuronal uptake blockade with desipramine. Stress-induced increases in plasma NE and higher plasma NE concentrations in aged compared to young adult rats were due to both decreases in NE clearance and increases in NE spillover. EPI spillover and clearance were reduced in aged compared to young adult rats, so that plasma EPI levels did not differ between groups. Young adult and aged rats had similar desipramine-induced decreases in NE clearance, whereas desipramine-sensitive decreases and stress-induced increases in plasma DHPG were larger in aged rats. This indicates that neuronal uptake is intact and that increased NE spillover at rest and during stress in aged rats reflects increased NE release from sympathetic nerves. The results show that aging is associated with divergent decreases in EPI release from the adrenal medulla and increases in NE release from sympathetic nerves. Increased plasma concentrations of NE in aged compared to young adult rats also result from decreased circulatory clearance of NE, but this does not reflect any age-related impairment of NE reuptake.     

Amygdala modulation of memory consolidation: interaction with other brain systems

There is a strong consensus that the amygdala is involved in mediating influences of emotional arousal and stress on learning and memory. There is extensive evidence that the basolateral amygdala (BLA) is a critical locus of integration of neuromodulatory influences regulating the consolidation of several forms of memory. Many drug and stress hormone influences converge in activating the release of norepinephrine (NE) within the BLA. Evidence from studies using in vivo microdialysis and high-performance liquid chromatography indicates that increases in amygdala NE levels assessed following inhibitory avoidance training correlate highly with subsequent retention. Other evidence indicates that NE influences on memory consolidation require muscarinic cholinergic activation within the BLA provided by projections from the nucleus basalis magnocellularis (NB). Evidence from several experiments indicates that activation of the BLA plays an essential role in modulating memory consolidation processes involving other brain regions. These findings provide strong support for the hypothesis that the BLA plays a critical role in regulating the consolidation of lasting memories of significant experiences.     

Blinking predicts enhanced cognitive control

Recent models have suggested an important role for neuromodulation in explaining trial-to-trial adaptations in cognitive control. The adaptation-by-binding model (Verguts & Notebaert, Psychological review, 115(2), 518–525, 2008), for instance, suggests that increased cognitive control in response to conflict (e.g., incongruent flanker stimulus) is the result of stronger binding of stimulus, action, and context representations, mediated by neuromodulators like dopamine (DA) and/or norepinephrine (NE). We presented a flanker task and used the Gratton effect (smaller congruency effect following incongruent trials) as an index of cognitive control. We investigated the Gratton effect in relation to eye blinks (DA related) and pupil dilation (NE related). The results for pupil dilation were not unequivocal, but eye blinks clearly modulated the Gratton effect: The Gratton effect was enhanced after a blink trial, relative to after a no-blink trial, even when controlling for correlated variables. The latter suggests an important role for DA in cognitive control on a trial-to-trial basis.     

The Effects of Uncontrollable, Unpredictable Aversive and Appetitive Events: Similar Effects Warrant Similar, but not Identical, Explanations?

Exposure to uncontrollable, unpredictable appetitive events produces a variety of cognitive debilitations and vegetative changes, as does exposure to uncontrollable, unpredictable aversive events. Similarities include impaired escape from aversive events, impaired discrimination, finicky consumption, analgesia, and body weight loss. However, in stark contrast, uncontrollable aversive stress causes reduced motor activity where as similar appetitive treatment does not; aversively induced debilitation is causally related to energy regulation, whereas the appetitively induced effects are not. Parallel mechanisms are suggested to explain these effects in terms of a revised anxiety account of the aversive effects, and a frustration account of the appetitive effects. Finally, factors likely to limit important research to resolve the many remaining issues are identified: negative presentation of animal research, political decision making, and ignorance and fear in committees which review the ethics of research.     

Stress,coping, executive function,and brain activation in adolescent offspring of depressed and nondepressed mothers

This study examined the associations among chronic stress, activation in the prefrontal cortex (PFC), executive function, and coping with stress in at-risk and a comparison sample of adolescents. Adolescents (N = 16; age 12–15) of mothers with (n = 8) and without (n = 8) a history of depression completed questionnaires, neurocognitive testing, and functional neuroimaging in response to a working memory task (N-back). Children of depressed mothers demonstrated less activation in the anterior PFC (APFC) and both greater and less activation than controls in distinct areas within the dorsal anterior cingulate cortex (dACC) in response to the N-back task. Across both groups, activation of the dorsolateral PFC (DLPFC; Brodmann area [BA9]) and APFC (BA10) was positively correlated with greater exposure to stress and negatively correlated with secondary control coping. Similarly, activation of the dACC (BA32) was negatively correlated with secondary control coping. Regression analyses revealed that DLPFC, dACC, and APFC activation were significant predictors of adolescents’ reports of their use of secondary control coping and accounted for the effects of stress exposure on adolescents’ coping. This study provides evidence that chronic stress may impact coping through its effects on the brain regions responsible for executive functions foundational to adaptive coping skills.     

前额叶在老年阶段的可塑性及相关机制

大量研究表明, 前额叶的结构和功能更容易受年老化影响; 然而, 近年来的研究发现, 前额叶的结构和功能在老年阶段具有一定的可塑性。对老年人进行认知训练, 能够延缓前额叶皮层厚度的萎缩, 提高白质完整性, 改善神经网络的功能连接和分化, 并可能通过调节多巴胺系统的活动改变前额叶皮质和皮质下结构的功能激活模式。有氧锻炼能够改善心脑血管功能, 保护和促进神经元的存活和生长, 引起前额叶灰质、白质体积的增加及功能激活的变化。认知训练与有氧锻炼等相结合的整合性训练不仅引起前额叶及相关认知功能的改变, 而且具有更好的生态学效度, 使老年人日常认知能力和生活质量得到提高。未来研究应采用多种技术手段, 从多个层面理解老年阶段前额叶的可塑性及相关机制; 加强对与前额叶关系密切的多种认知功能可塑性神经机制的研究; 并重视与整合性训练有关的前额叶可塑性。     

Changes in plasma corticosterone and cerebral biogenic amines and their catabolites during training and testing of mice in passive avoidance behavior

Concentrations of cerebral biogenic amines and their catabolites, and of plasma corticosterone were determined 10 min after training and testing of passive avoidance behavior in mice. Training and testing of mice that had acquired the task well resulted in statistically significant increases of plasma corticosterone, of the DOPAC:DA ratio [an index of dopamine (DA) metabolism] in prefrontal cortex, and of MHPG:NE ratios [an index of norepinephrine (NE) metabolism] in hypothalamus and brain stem. There were also decreases of NE in hypothalamus and brain stem, and an increase of 5-HIAA:5-HT [an index of serotonin (5-HT) metabolism] and of tryptophan in brain stem. Some of these changes also occurred in mice merely exposed to the apparatus but not trained. Plasma corticosterone concentrations were significantly higher in mice that performed the task well compared to those that did not, and there were significant correlations between this measure and the avoidance performance. Although there was only one statistically significant correlation between a cerebral metabolite and the avoidance performance (a decrease in hypothalamic NE), there were indications of relationships between cerebral biogenic amine metabolism and the performance. The patterns of neurochemical and endocrine changes closely resemble those previously observed in response to various stressors. Thus, the changes could reflect stress responses, which may or may not be related directly to the performance of the avoidance task.     

Rostro‐caudal and dorso‐ventral gradients in medial and lateral prefrontal cortex during cognitive control of affective and cognitive interference

Characterizing the anatomical substrates of major brain functions such as cognition and emotion is of utmost importance to the ongoing efforts of understanding the nature of psychiatric ailments and their potential treatment. The aim of our study was to investigate how the brain handles affective and cognitive interferences on cognitive processes. Functional magnetic resonance imaging investigation was performed on healthy individuals, comparing the brain oxygenation level dependent activation patterns during affective and cognitive counting Stroop tasks. The affective Stroop task activated rostral parts of medial prefrontal cortex (PFC) and rostral and ventral parts of lateral PFC, while cognitive Stroop activated caudal parts of medial PFC and caudal and dorsal parts of lateral PFC. Our findings suggest that the brain may handle affective and cognitive interference on cognitive processes differentially, with affective interference preferentially activating rostral and ventral PFC networks and cognitive interference activating caudal and dorsal PFC networks.     

Sources of openness/intellect: cognitive and neuropsychological correlates of the fifth factor of personality

We characterize Openness/Intellect as motivated cognitive flexibility, or cognitive exploration, and develop a neuropsychological model relating it to dopaminergic function and to the functions of the prefrontal cortex (PFC). Evidence is reviewed for sources of Openness/Intellect shared with Extraversion and sources unique to Openness/Intellect. The hypothesis that the cognitive functions of the dorsolateral PFC are among the latter was tested using standard measures of cognitive ability and a battery of tasks associated with dorsolateral PFC function (N=175). Dorsolateral PFC function, as well as both fluid and crystallized cognitive ability, was positively related to Openness/Intellect but no other personality trait. Additionally, facet level analysis supported the characterization of Openness/Intellect as a primarily cognitive trait.     

Dopamine and cognitive functioning: brain imaging findings in Huntington's disease and normal aging

Recent brain imaging studies in Huntington's disease (HD) and normal aging suggest a relationship between central dopaminergic neurotransmission and cognitive performance. Results demonstrate substantial losses in dopamine (DA) function in both HD and aging. Moreover, HD patients and older adults show deficits across multiple cognitive domains, including episodic memory, speed of processing, and executive functioning. Although few studies are available at present, there is converging evidence that multiple measures of pre- and postsynaptic DA biochemistry are (a) highly interrelated, and (b) strongly associated with the cognitive deficits that accompany HD and aging. There is also emerging evidence that DA neurotransmission influences cognitive performance independent of HD or age. In general, the research reviewed in this article indicates that the nigrostriatal DA system is an important component of a frontostriatal circuitry that is critically involved in cognitive functioning.     

An analysis of rat prefrontal cortex in mediating executive function

While it is acknowledged that species specific differences are an implicit condition of comparative studies, rodent models of prefrontal function serve a significant role in the acquisition of converging evidence on prefrontal function across levels of analysis and research techniques. The purpose of the present review is to examine whether the prefrontal cortex (PFC) in rats supports a variety of processes associated with executive function including working memory, temporal processing, planning (prospective coding), flexibility, rule learning, and decision making. Therefore, in this review we examined changes associated with working memory processes for spatial locations, visual objects, odors, tastes, and response domains or attributes, temporal processes including temporal order, sequence learning, prospective coding, behavioral flexibility associated with reversal learning and set shifting, paired associate learning, and decision making based on effort, time discounting, and uncertainty following damage to the PFC in rats. In addition, potential parallel processes of executive function in monkeys and humans based on several theories of subregional differentiation within the PFC will be presented. Specifically, theories based on domain or attribute specificity (Goldman-Rakic, 1996), level of processing (Petrides, 1996), rule learning based on complexity (Wise, Murray, & Gerfen, 1996), executive functions based on connectivity with other brain regions associated with top-down control (Miller & Cohen, 2001), are presented and applied to PFC function in rats with the aim of understanding subregional specificity in the rat PFC. The data suggest that there is subregional specificity within the PFC of rats, monkey and humans and there are parallel cognitive functions of the different subregions of the PFC in rats, monkeys and humans.     

Attenuated response to methamphetamine sensitization and deficits in motor learning and memory after selective deletion of β-catenin in dopamine neurons

In the present study, we analyzed mice with a targeted deletion of β-catenin in DA neurons (DA-βcat KO mice) to address the functional significance of this molecule in the shaping of synaptic responses associated with motor learning and following exposure to drugs of abuse. Relative to controls, DA-βcat KO mice showed significant deficits in their ability to form long-term memories and displayed reduced expression of methamphetamine-induced behavioral sensitization after subsequent challenge doses with this drug, suggesting that motor learning and drug-induced learning plasticity are altered in these mice. Morphological analyses showed no changes in the number or distribution of tyrosine hydroxylase-labeled neurons in the ventral midbrain. While electrochemical measurements in the striatum determined no changes in acute DA release and uptake, a small but significant decrease in DA release was detected in mutant animals after prolonged repetitive stimulation, suggesting a possible deficit in the DA neurotransmitter vesicle reserve pool. However, electron microscopy analyses did not reveal significant differences in the content of synaptic vesicles per terminal, and striatal DA levels were unchanged in DA-βcat KO animals. In contrast, striatal mRNA levels for several markers known to regulate synaptic plasticity and DA neurotransmission were altered in DA-βcat KO mice. This study demonstrates that ablation of β-catenin in DA neurons leads to alterations of motor and reward-associated memories and to adaptations of the DA neurotransmitter system and suggests that β-catenin signaling in DA neurons is required to facilitate the synaptic remodeling underlying the consolidation of long-term memories.     

EEG theta/beta ratio as a potential biomarker for attentional control and resilience against deleterious effects of stress on attention

Anxious stress compromises cognitive executive performance. This occurs, for instance, in cognitive performance anxiety (CPA), in which anxiety about one’s cognitive performance causes that performance to actually deteriorate (e.g., test anxiety). This is thought to result from a prefrontal cortically (PFC) mediated failure of top-down attentional control over stress-induced automatic processing of threat-related information. In addition, stress-induced increased catecholamine influx into the PFC may directly compromise attentional function. Previous research has suggested that the ratio between resting state electroencephalographic (EEG) low- and high-frequency power (the theta/beta ratio) is related to trait attentional control, which might moderate these effects of stress on attentional function. The goals of the present study were to test the novel prediction that theta/beta ratio moderates the deleterious effects of CPA-like anxious stress on state attentional control and to replicate a previous finding that the theta/beta ratio is related to self-reported trait attentional control. After recording of baseline frontal EEG signals, 77 participants performed a stress induction or a control procedure. Trait attentional control was assessed with the Attentional Control Scale, whereas stress-induced changes in attentional control and anxiety were measured with self-report visual analogue scales. The hypothesized moderating influence of theta/beta ratio on the effects of stress on state attentional control was confirmed. Theta/beta ratio explained 28% of the variance in stress-induced deterioration of self-reported attentional control. The negative relationship between theta/beta ratio and trait attentional control was replicated (r = –.33). The theta/beta ratio reflects, likely prefrontally mediated, attentional control, and should be a useful biomarker for the study of CPA and other anxiety–cognition interactions.