Dopamine-Induced Dissociation of BOLD and Neural Activity in Macaque Visual Cortex

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Neural Activity Changes Associated with Impulsive Responding in the Sustained Attention to Response Task

Humans can anticipate and prepare for uncertainties to achieve a goal. However, it is difficult to maintain this effort over a prolonged period of time. Inappropriate behavior is impulsively (or mindlessly) activated by an external trigger, which can result in serious consequences such as traffic crashes. Thus, we examined the neural mechanisms underlying such impulsive responding using functional magnetic resonance imaging (fMRI). Twenty-two participants performed a block-designed sustained attention to response task (SART), where each task block was composed of consecutive Go trials followed by a NoGo trial at the end. This task configuration enabled us to measure compromised preparation for NoGo trials during Go responses using reduced Go reaction times. Accordingly, parametric modulation analysis was conducted on fMRI data using block-based mean Go reaction times as an online marker of impulsive responding in the SART. We found that activity in the right dorsolateral prefrontal cortex (DLPFC) and the bilateral intraparietal sulcus (IPS) was positively modulated with mean Go reaction times. In addition, activity in the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) was negatively modulated with mean Go reaction times, albeit statistically weakly. Taken together, spontaneously reduced activity in the right DLPFC and the IPS and spontaneously elevated activity in the MPFC and the PCC were associated with impulsive responding in the SART. These results suggest that such a spontaneous transition of brain activity pattern results in impulsive responding in monotonous situations, which in turn, might cause human errors in actual work environments.     

Sustained Increase of PKA Activity in the Postcommissural Putamen of Dyskinetic Monkeys

Levodopa-induced dyskinesias (LID) are a frequent complication of Parkinson’s disease pharmacotherapy that causes significant disability and narrows the therapeutic window. Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood. Here, our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication. We examined the expression and downstream activity of dopamine receptors (DR) in the striatum of 1-methyl-4-phenyl-1,2,3,6 tetrahydropiridine (MPTP)-lesioned monkeys with and without l-DOPA treatment. Four monkeys were made dyskinetic and other four received a shorter course of l-DOPA and did not develop LID. Our results show that l-DOPA treatment induces an increase in DRD2 and DRD3 expression in the postcommissural putamen, but only DRD3 is correlated with the severity of LID. Dyskinetic monkeys show a hyperactivation of the canonical DRD1-signaling pathway, measured by an increased phosphorylation of protein kinase A (PKA) and its substrates, particularly DARPP32. In contrast, activation of the DRD2-signaling pathway, visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9, is associated with l-DOPA treatment, independently of the presence of dyskinesias. Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the DRD3 receptor and the DRD1 pathway with a sustained increase of PKA activity in the postcommissural putamen. Importantly, we found that all signaling changes related to long-term l-DOPA administration are exquisitely restricted to the postcommissural putamen, which may be related to the recurrent failure of pharmacological approaches.     

A Protein Kinase Activity Is Associated with and Specifically Phosphorylates the Neural Cell Adhesion Molecule LI

The neural cell adhesion molecule L1 is a phosphorylated integral membrane glycoprotein that is recovered from adult mouse brain by immunoaffinity chromatography as a set of polypeptides with apparent molecular masses of 200, 180, 140, 80, and 50 kilodaltons (L1-200, L1-180, L1-140, L1-80, and L1-50, respectively). In the present study, we show that two kinase activities are associated with immunopurified L1: One specifically phosphorylates L1-200 and L1-80 but not L1-180, L1-140, or L1-50. This pattern of phosphorylation corresponds to the one described for L1 after metabolic phosphate incorporation into cultures of cerebellar cells. In both cases, serine is the main amino acid that is labeled by radioactive phosphate. The kinase activity is not activated by Ca2+, calmodulin, phosphatidylserine, diolein, cyclic AMP, or cyclic GMP, a result suggesting that the enzyme is distinct from Ca2+/calmodulin-dependent kinases, from protein kinase C, or from cyclic AMP/cyclic GMP-dependent kinases and may belong to the independent kinase group. The other kinase phosphorylates only casein but not L1, utilizes GTP as well as ATP, and is strongly inhibited by heparin. Because the primary structure of the L1 protein does not contain consensus sequences characteristic for known kinases, we believe that the catalytic activities detectable in immunopurified L1 are due to kinases that are strongly enough associated with L1 to withstand the stringent purification procedures.     

Serum Total Cholinesterase Activity on Admission Is Associated with Disease Severity and Outcome in Patients with Traumatic Brain Injury

Background

Traumatic brain injury (TBI) is one of the leading causes of neurological disability. In this retrospective study, serum total cholinesterase (ChE) activities were analyzed in 188 patients for diagnostic as well as predictive values for mortality.

Methods and Findings

Within 72 hours after injury, serum ChE activities including both acetylcholinesterase and butyrylcholinesterase were measured. Disease severity was evaluated with Acute Physiology and Chronic Health Evaluation (APACHE) II score, Glasgow Coma Score, length of coma, post-traumatic amnesia and injury feature. Neurocognitive and functional scores were assessed using clinical records. Of 188 patients, 146 (77.7%) survived and 42 (22.3%) died within 90 days. Lower ChE activities were noted in the non-survivors vs. survivors (5.94±2.19 vs. 7.04±2.16 kU/L, p=0.023), in septic vs. non-infected patients (5.93±1.89 vs. 7.31±2.45 kU/L, p=0.0005) and in patients with extremely severe injury vs. mild injury (6.3±1.98 vs. 7.57±2.48 kU/L, p=0.049). The trajectories of serum ChE levels were also different between non-survivors and survivors, septic and non-infected patients, mild and severely injured patients, respectively. Admission ChE activities were closely correlated with blood cell counts, neurocognitive and functional scores both on admission and at discharge. Receiver operating characteristic analysis showed that the area under the curve for ChE was inferior to that for either APACHE II or white blood cell (WBC) count. However, at the optimal cutoff value of 5 kU/L, the sensitivity of ChE for correct prediction of 90-day mortality was 65.5% and the specificity was 86.4%. Kaplan-Meier analysis showed that lower ChE activity (<5 kU/L) was more closely correlated with poor survival than higher ChE activity (>5 kU/L) (p=0.04). After adjusting for other variables, ChE was identified as a borderline independent predictor for mortality as analyzed by Binary logistic regression (P=0.078).

Conclusions

Lowered ChE activity measured on admission appears to be associated with disease severity and outcome for TBI patients.     

喀斯特生境中猕猴的活动节律和时间分配

2006年9月至2007年8月,在广西弄岗国家级自然保护区选择一群猕猴(Macaca mulatta)作为观察对象,采用瞬时扫描取样法收集相关的行为数据,以日活动节律和活动时间分配为切人点,探讨猕猴对喀斯特石山生境的行为适应策略.结果表明,猕猴的日活动节律表现为上午和下午的觅食高峰,中午进入长时间的休息期.这可能与白天...     

Behavioral Responses Associated with a Human-Mediated Predator Shelter

Human activities in protected areas can affect wildlife populations in a similar manner to predation risk, causing increases in movement and vigilance, shifts in habitat use and changes in group size. Nevertheless, recent evidence indicates that in certain situations ungulate species may actually utilize areas associated with higher levels of human presence as a potential refuge from disturbance-sensitive predators. We now use four-years of behavioral activity budget data collected from pronghorn (Antilocapra americana) and elk (Cervus elephus) in Grand Teton National Park, USA to test whether predictable patterns of human presence can provide a shelter from predatory risk. Daily behavioral scans were conducted along two parallel sections of road that differed in traffic volume - with the main Teton Park Road experiencing vehicle use that was approximately thirty-fold greater than the River Road. At the busier Teton Park Road, both species of ungulate engaged in higher levels of feeding (27% increase in the proportion of pronghorn feeding and 21% increase for elk), lower levels of alert behavior (18% decrease for pronghorn and 9% decrease for elk) and formed smaller groups. These responses are commonly associated with reduced predatory threat. Pronghorn also exhibited a 30% increase in the proportion of individuals moving at the River Road as would be expected under greater exposure to predation risk. Our findings concur with the ‘predator shelter hypothesis’, suggesting that ungulates in GTNP use human presence as a potential refuge from predation risk, adjusting their behavior accordingly. Human activity has the potential to alter predator-prey interactions and drive trophic-mediated effects that could ultimately impact ecosystem function and biodiversity.     

Admixture in Humans of Two Divergent Plasmodium knowlesi Populations Associated with Different Macaque Host Species

Human malaria parasite species were originally acquired from other primate hosts and subsequently became endemic, then spread throughout large parts of the world. A major zoonosis is now occurring with Plasmodium knowlesi from macaques in Southeast Asia, with a recent acceleration in numbers of reported cases particularly in Malaysia. To investigate the parasite population genetics, we developed sensitive and species-specific microsatellite genotyping protocols and applied these to analysis of samples from 10 sites covering a range of >1,600 km within which most cases have occurred. Genotypic analyses of 599 P. knowlesi infections (552 in humans and 47 in wild macaques) at 10 highly polymorphic loci provide radical new insights on the emergence. Parasites from sympatric long-tailed macaques (Macaca fascicularis) and pig-tailed macaques (M. nemestrina) were very highly differentiated (FST = 0.22, and K-means clustering confirmed two host-associated subpopulations). Approximately two thirds of human P. knowlesi infections were of the long-tailed macaque type (Cluster 1), and one third were of the pig-tailed-macaque type (Cluster 2), with relative proportions varying across the different sites. Among the samples from humans, there was significant indication of genetic isolation by geographical distance overall and within Cluster 1 alone. Across the different sites, the level of multi-locus linkage disequilibrium correlated with the degree of local admixture of the two different clusters. The widespread occurrence of both types of P. knowlesi in humans enhances the potential for parasite adaptation in this zoonotic system.     

Characterizing Behavioral and Brain Changes Associated with Practicing Reasoning Skills

We have reported previously that intensive preparation for a standardized test that taxes reasoning leads to changes in structural and functional connectivity within the frontoparietal network. Here, we investigated whether reasoning instruction transfers to improvement on unpracticed tests of reasoning, and whether these improvements are associated with changes in neural recruitment during reasoning task performance. We found behavioral evidence for transfer to a transitive inference task, but no evidence for transfer to a rule generation task. Across both tasks, we observed reduced lateral prefrontal activation in the trained group relative to the control group, consistent with other studies of practice-related changes in brain activation. In the transitive inference task, we observed enhanced suppression of task-negative, or default-mode, regions, consistent with work suggesting that better cognitive skills are associated with more efficient switching between networks. In the rule generation task, we found a pattern consistent with a training-related shift in the balance between phonological and visuospatial processing. Broadly, we discuss general methodological considerations related to the analysis and interpretation of training-related changes in brain activation. In summary, we present preliminary evidence for changes in brain activation associated with practice of high-level cognitive skills.     

Self-Organizing Task Modules and Explicit Coordinate Systems in a Neural Network Model for 3-D Saccades

The goal of this study was to train an artificial neural network to generate accurate saccades in Listing's plane and then determine how the hidden units performed the visuomotor transformation. A three-layer neural network was successfully trained, using back-prop, to take in oculocentric retinal error vectors and three-dimensional eye orientation and to generate the correct head-centric motor error vector within Listing's plane. Analysis of the hidden layer of trained networks showed that explicit representations of desired target direction and eye orientation were not employed. Instead, the hidden-layer units consistently divided themselves into four parallel modules: a dominant "vector-propagation" class (approximately 50% of units) with similar visual and motor tuning but negligible position sensitivity and three classes with specific spatial relations between position, visual, and motor tuning. Surprisingly, the vector-propagation units, and only these, formed a highly precise and consistent orthogonal coordinate system aligned with Listing's plane. Selective "lesions" confirmed that the vector-propagation module provided the main drive for saccade magnitude and direction, whereas a balance between activity in the other modules was required for the correct eye-position modulation. Thus, contrary to popular expectation, error-driven learning in itself was sufficient to produce a "neural" algorithm with discrete functional modules and explicit coordinate systems, much like those observed in the real saccade generator.     

Polymorphisms in the Calcium-Sensing Receptor Gene Are Associated with Clinical Outcome of Neuroblastoma

Background

Neuroblastic tumors include the neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Clinical behavior of these developmental malignancies varies from regression to aggressive growth with metastatic dissemination. Several clinical, histological, genetic, and biological features are associated with this diversity of clinical presentations. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor with a key role in calcium homeostasis. We have previously reported that it is expressed in benign, differentiated neuroblastic tumors, but silenced by genetic and epigenetic events in unfavorable neuroblastomas. We have now analyzed three functionally relevant polymorphisms clustered at the signal transduction region of the CaSR (rs1801725, rs1042636 and rs1801726) to assess if genetic variants producing a less active receptor are associated with more aggressive disease course.

Methods

Polymorphisms were analyzed in DNA samples from 65 patients using specific Taqman Genotyping Assays.

Results

Mildly inactivating variant rs1801725 was associated with clinical stage 4 (P = 0.002) and the histological subgroup of undifferentiated neuroblastomas (P = 0.046). Patients harboring this polymorphism had significantly lower overall (P = 0.022) and event-free survival (P = 0.01) rates than those who were homozygous for the most common allele among Caucasians. However, this single locus genotype was not independently associated with outcome in multivariate analyses. Conversely, the tri-locus haplotype TAC was independently associated with an increased risk of death in the entire cohort (Hazard Ratio = 2.45; 95% Confidence Interval [1.14–5.29]; P = 0.022) and also in patients diagnosed with neuroblastomas (Hazard Ratio = 2.74; 95% Confidence Interval [1.20–6.25]; P = 0.016).

Conclusions

The TAC haplotype includes the moderately inactivating variant rs1801725 and absence of the gain-of-function rs1042636 polymorphism. Thus, its association with metastatic disease and poor outcome would add to our previous data and further support that inactivation of the CaSR gene is a mechanism associated with neuroblastoma malignant behavior.     

Behavioral and Other Characteristics Associated with HIV Viral Load in an Outpatient Clinic

Persons living with HIV (PLWH) who are engaged in care, yet not virally suppressed, represent a risk for transmission and opportunity for risk reduction interventions. This study describes characteristics of an outpatient clinic cohort of PLWH by laboratory confirmed viral suppression status and examines associations with demographics and sexual and drug use behaviors gathered through questionnaire. From a sample of 500 clinic patients, 438 were prescribed antiretroviral treatment (ART) and 62 were not. Among the 438 on ART, 72 (16.4%) were not virally suppressed at the most recent lab draw. Compared to individuals with a suppressed viral load, those that were unsuppressed were more likely to: be black (79.2% vs. 64.2%; p = 0.014); earn below $25,000/year (88.9% vs. 65.0%; p < 0.001); be of a younger age (47.8 vs. 50.0 mean years; p = 0.009); be on opiate substitution (14.1% vs. 6.3%; p = 0.023); and acknowledge poly-substance (38.9% vs. 24.4%; p = 0.012) and excessive alcohol use (13.9% vs. 6.0%; p = 0.019). Conversely, a smaller proportion of those with an unsuppressed viral load had multiple sex partners in the previous 30 days (39.8% vs. 58.5%; p = 0.003). In multivariable regression of those on ART, the prevalence of an unsuppressed viral load was 3% lower with each increasing year of age (aPR: 0.97; 95% CI: 0.95, 0.99) and 47% lower with income over $25,000/year (aPR: 0.33; 95% CI: 0.16, 0.70). In a separate analysis of all 500 subjects, ART was less frequently prescribed to blacks compared to whites, heterosexuals, those with lower education and income, and persons with active substance use. Findings confirm that a large proportion of PLWH and engaged in care were not virally suppressed and continued behaviors that risk transmission, indicating the need for screening, prevention counseling and access to ancillary services to lower the incidence of HIV infections.     

Serum Procalcitonin Levels are Associated with Clinical Outcome in Intracerebral Hemorrhage

Procalcitonin (PCT) has emerged as a new prognostic inflammatory marker in a variety of diseases. This study aimed to evaluate whether PCT is associated with increased risk of unfavorable outcome in intracerebral hemorrhage (ICH) patients. During January 2015–December 2016, we conducted a prospective cohort investigation involved 251 primary ICH patients who were admitted within 24 h after the onset of symptoms. We assessed serum PCT levels for all patients at admission. The functional outcome after 3 months was evaluated by modified Rankin Scale (mRS) and dichotomized as favorable (mRS 0–2) and unfavorable (mRS 3–6). The independent risk factors for unfavorable outcome and mortality after 3 months were examined by binary logistic regression. Of 251 ICH patients, the median PCT concentration was 0.053 µg/L (interquartile range 0.035–0.078 µg/L). Unfavorable outcome and mortality at 3 months were observed in 161 (64.1%) and 51 (20.3%) patients, respectively. After adjusting for potential confounders, patients with PCT levels in the top quartile (>0.078 ug/L), compared with the lowest quartile (<0.035 μg/L) were more likely to have a higher risk of poor functional outcome [odds ratio (OR) 7.341; 95% confidence interval (CI) 2.770–21.114; P = 0.001] and mortality (OR 7.483; 95% CI 1.871–24.458, P = 0.006). Furthermore, the area under the receiver operating characteristic curve of PCT showed 0.701 (95% CI 0.635–0.767) for worse functional prognosis, and 0.652 (95% CI 0.569–0.735) for mortality. This study demonstrated that elevated PCT levels at admission were independently associated with unfavorable clinical outcome in ICH patients.     

Measuring Neural and Behavioral Activity During Ongoing Computerized Social Interactions: An Examination of Event-Related Brain Potentials

Social exclusion is a complex social phenomenon with powerful negative consequences. Given the impact of social exclusion on mental and emotional health, an understanding of how perceptions of social exclusion develop over the course of a social interaction is important for advancing treatments aimed at lessening the harmful costs of being excluded. To date, most scientific examinations of social exclusion have looked at exclusion after a social interaction has been completed. While this has been very helpful in developing an understanding of what happens to a person following exclusion, it has not helped to clarify the moment-to-moment dynamics of the process of social exclusion. Accordingly, the current protocol was developed to obtain an improved understanding of social exclusion by examining the patterns of event-related brain activation that are present during social interactions. This protocol allows greater precision and sensitivity in detailing the social processes that lead people to feel as though they have been excluded from a social interaction. Importantly, the current protocol can be adapted to include research projects that vary the nature of exclusionary social interactions by altering how frequently participants are included, how long the periods of exclusion will last in each interaction, and when exclusion will take place during the social interactions. Further, the current protocol can be used to examine variables and constructs beyond those related to social exclusion. This capability to address a variety of applications across psychology by obtaining both neural and behavioral data during ongoing social interactions suggests the present protocol could be at the core of a developing area of scientific inquiry related to social interactions.     

Nitrogenase Activity Associated with Halodule wrightii Roots

Nitrogen fixation (acetylene reduction) associated with roots of the seagrass Halodule wrightii was measured offshore near Beaufort and Moorhead City, N.C. Rates of acetylene reduction were higher in aerobic than in anaerobic assays and were linear for up to 5 days. The temperature range for acetylene reduction was 15 to 35°C with a maximum activity at 35°C. Nitrogenase activity was shown to vary seasonally with highest activities occurring during warmer summer months (23 μg of N₂ fixed per m² per day). At in situ temperature, nitrogenase activities associated with surface-sterilized and non-surface-sterilized roots were similar. One morphological bacterial type was isolated from surface-sterilized roots and identified as Klebsiella pneumoniae type 4B.     

Enhanced Food Anticipatory Activity Associated with Enhanced Activation of Extrahypothalamic Neural Pathways in Serotonin2C Receptor Null Mutant Mice

The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity). However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin_2C receptor (5-HT2CR) null mutant mice subjected to a daytime restricted feeding schedule exhibit enhanced food anticipatory activity compared to wild-type littermates, without phenotypic differences in the impact of restricted feeding on food consumption, body weight loss, or blood glucose levels. Moreover, we show that the enhanced food anticipatory activity in 5-HT2CR null mutant mice develops independent of external light cues and persists during two days of total food deprivation, indicating that food anticipatory activity in 5-HT2CR null mutant mice reflects the locomotor output of a food-entrainable oscillator. Whereas restricted feeding induces c-fos expression to a similar extent in hypothalamic nuclei of wild-type and null mutant animals, it produces enhanced expression in the nucleus accumbens and other extrahypothalamic regions of null mutant mice relative to wild-type subjects. These data suggest that 5-HT2CRs gate food anticipatory activity through mechanisms involving extrahypothalamic neural pathways.