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Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP). Additionally, cocaine fails to elevate extracellular DA. Given that amphetamine and methylphenidate, unlike cocaine, lack high-affinity interactions with the serotonin (5-HT) transporter (SERT), we hypothesized that the lack of cocaine-induced hyperlocomotion in DAT Val559 mice arises from SERT blockade and augmented 5-HT signaling relative to cocaine actions on wildtype animals. Consistent with this idea, the SERT blocker fluoxetine abolished methylphenidate-induced locomotor activity in DAT Val559 mice, mimicking the effects seen with cocaine. Additionally, a cocaine analog (RTI-113) with greater selectivity for DAT over SERT retains locomotor activation in DAT Val559 mice. Furthermore, genetic elimination of high-affinity cocaine interactions at SERT in DAT Val559 mice, or specific inhibition of 5-HT receptors in these animals, restored cocaine-induced locomotion, but did not restore cocaine-induced elevations of extracellular DA. Our findings reveal a significant serotonergic plasticity arising in the DAT Val559 model that involves enhanced 5-HT signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.
The emotional attentional blink (EAB) refers to a temporary impairment in the ability to identify a target when it is preceded by an emotional distractor. It is thought to occur because the emotional salience of the distractor exogenously captures attention for a brief duration, rendering the target unattended and preventing it from reaching awareness. Here we tested the extent to which the EAB can be attenuated by inducing a diffuse top-down attentional state, which has been shown to improve target identification in an analogous attentional phenomenon, the attentional blink. Rapid sequences of landscape images were presented centrally, and participants reported the orientation of a ± 90° rotation of a landscape target. To induce a diffuse state of attention, participants were given a secondary task of monitoring for the appearance of a colored dot in the periphery. We found that emotional distractors impaired target recognition performance to comparable extents, regardless of whether or not participants concurrently performed the peripheral-monitoring task. Moreover, we found that performance of the secondary task led to an impaired ability to ignore neutral distractors. Subjective ratings of target vividness mirrored the behavioral accuracy, with frequent reports of intermediate levels of vividness suggesting that the EAB might impair target visibility in a graded manner. Our results demonstrate that the EAB is robust to manipulations of top-down attention, suggesting that the temporary capture of attention by emotionally salient stimuli involves processes that are distinct from those that produce the attentional blink.
OBJECTIVES - The ventrolateral prefrontal cortex (vlPFC) has been speculated to play an important role in complex processes that allow emotional factors to influence human cognition. Accumulating evidence from human neuroimaging studies, in conjunction with studies of patients with lesions and animal models, shed light on the role of the vlPFC in emotion regulation (ER). This review aims to discuss and integrate recent findings related to vlPFC's role in ER in the context of aging, drawing from diverse sources, and suggest future directions for research utilizing transcranial magnetic stimulation (TMS).
METHODS/DESIGN - We summarize findings from the existing literature investigating the neural basis of frontal-lobe mediated ER and then highlight major findings from recent studies directly comparing healthy younger and older adult groups. We conclude by pointing to unaddressed questions worth pursuing in future research.
RESULTS AND DISCUSSION - We propose future research directions utilizing TMS to answer key unaddressed questions. Moreover, we discuss the potential advantages, challenges, and limitations of using TMS as a complement to the existing neuroimaging methods in ER.
© 2018 John Wiley & Sons, Ltd.
Transient upregulation of GluN2B-containing NMDA receptors (R) in the nucleus accumbens (NAc) is proposed as an intermediate to long-term AMPAR plasticity associated with persistent cocaine-related behaviors. However, cell type- and input-specific contributions of GluN2B underlying lasting actions of cocaine remain to be elucidated. We utilized GluN2B cell type-specific knockouts and optogenetics to deconstruct the role of GluN2B in cocaine-induced NAc synaptic and behavioral plasticity. While reward learning was unaffected, loss of GluN2B in D1 dopamine receptor-expressing cells (D1) led to prolonged retention of reward memory. In control mice, prefrontal cortex (PFC)-D1(+) NAc AMPAR function was unaffected by cocaine exposure, while midline thalamus (mThal)-D1(+) NAc AMPAR function was potentiated but diminished after withdrawal. In D1-GluN2B mice, the potentiation of mThal-D1(+) NAc AMPAR function persisted following withdrawal, corresponding with continued expression of cocaine reward behavior. These data suggest NAc GluN2B-containing NMDARs serve a feedback role and may weaken reward-related memories.
Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
BACKGROUND AND OBJECTIVES - Incidence of ESKD is three times higher in black Americans than in whites, and CKD prevalence continues to rise among black Americans. Community-based kidney disease screening may increase early identification and awareness of black Americans at risk, but it is challenging to implement. This study aimed to identify participants' perspectives of community kidney disease screening. The Health Belief Model provides a theoretic framework for conceptualization of these perspectives and optimization of community kidney disease screening activities.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - Researchers in collaboration with the Tennessee Kidney Foundation conducted three focus groups of adults in black American churches in Nashville, Tennessee. Questions examined views on CKD information, access to care, and priorities of kidney disease health. Content analysis was used. Guided by the Health Belief Model, themes were generated, and additional themes were derived from the data using an inductive approach.
RESULTS - Thirty-two black Americans completed the study in 2014. Participants were mostly women (79%) with a mean age of 56 years old (range, 24-78). Two major categories of barriers to kidney disease screening were identified: () participant factors, including limited kidney disease knowledge, spiritual/religious beliefs, emotions, and culture of the individual; and () logistic factors, including lack of convenience and incentives and poor advertisement. Potential facilitators of CKD screening included provision of CKD education, convenience of screening activities, and use of culturally sensitive and enhanced communication strategies. Program recommendations included partnering with trusted community members, selecting convenient locations, tailored advertising, and provision of compensation.
CONCLUSIONS - Findings of this study suggest that provider-delivered culturally sensitive education and stakeholder engagement are critical to increase trust, decrease fear, and maximize participation and early identification of kidney disease among black Americans considering community screening.
Copyright © 2018 by the American Society of Nephrology.
Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M) to oppose cAMP-dependent dopamine receptor subtype 1 (D) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons. This induces a tonic inhibition of transmission at direct pathway synapses and D-mediated activation of motor activity. These studies provide important new insights into the unique role of M in regulating BG function and challenge the prevailing hypothesis of the centrality of striatal ChIs in opposing dopamine regulation of BG output.
Copyright © 2017 Elsevier Inc. All rights reserved.
Conventional Doppler ultrasound is useful for visualizing fast blood flow in large resolvable vessels. However, frame rate and tissue clutter caused by movement of the patient or sonographer make visualizing slow flow with ultrasound difficult. Patient and sonographer motion causes spectral broadening of the clutter signal, which limits ultrasound's sensitivity to velocities greater than 5-10 mm/s for typical clinical imaging frequencies. To address this, we propose a clutter filtering technique that may increase the sensitivity of Doppler measurements to at least as low as 0.52 mm/s. The proposed technique uses plane wave imaging and an adaptive frequency and amplitude demodulation scheme to decrease the bandwidth of tissue clutter. To test the performance of the adaptive demodulation method at suppressing tissue clutter bandwidths due to sonographer hand motion alone, six volunteer subjects acquired data from a stationary phantom. Additionally, to test in vivo feasibility, arterial occlusion and muscle contraction studies were performed to assess the efficiency of the proposed filter at preserving signals from blood velocities 2 mm/s or greater at a 7.8 MHz center frequency. The hand motion study resulted in initial average bandwidths of 175 Hz (8.60mm/s), which were decreased to 10.5 Hz (0.52 mm/s) at -60 dB using our approach. The in vivo power Doppler studies resulted in 4.73 dB and 4.80 dB dynamic ranges of the blood flow with the proposed filter and 0.15 dB and 0.16 dB dynamic ranges of the blood flow with a conventional 50 Hz high-pass filter for the occlusion and contraction studies, respectively.
In this meta-analytic and narrative review, we examine several overarching issues related to the study of coping, emotion regulation, and internalizing and externalizing symptoms of psychopathology in childhood and adolescence, including the conceptualization and measurement of these constructs. We report a quantitative meta-analysis of 212 studies (N = 80,850 participants) that measured the associations between coping and emotion regulation with symptoms of internalizing and externalizing psychopathology. Within the meta-analysis we address the association of broad domains of coping and emotion regulation (e.g., total coping, emotion regulation), intermediate factors of coping and emotion regulation (e.g., primary control coping, secondary control coping), and specific coping and emotion regulation strategies (e.g., emotional expression, cognitive reappraisal) with internalizing and externalizing symptoms. For cross-sectional studies, which made up the majority of studies included, we examine 3 potential moderators: age, measure quality, and single versus multiple informants. Finally, we separately consider findings from longitudinal studies as these provide stronger tests of the effects. After accounting for publication bias, findings indicate that the broad domain of emotion regulation and adaptive coping and the factors of primary control coping and secondary control coping are related to lower levels of symptoms of psychopathology. Further, the domain of maladaptive coping, the factor of disengagement coping, and the strategies of emotional suppression, avoidance, and denial are related to higher levels of symptoms of psychopathology. Finally, we offer a critique of the current state of the field and outline an agenda for future research. (PsycINFO Database Record
(c) 2017 APA, all rights reserved).
BACKGROUND - Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood.
METHODS - We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice.
RESULTS - Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ-tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation.
CONCLUSIONS - Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated.
Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.