Faculty Bibliography

BACKGROUND:The choice for drugs over alternative reinforcers is a translational hallmark feature of drug addiction. The neural basis of such drug-biased choice is not well understood, particularly in individuals with protracted drug abstinence who cannot ethically participate in studies that offer drug-using opportunities. METHODS:We developed a functional magnetic resonance imaging drug-choice task to examine the choice for viewing drug-related images, rather than for actually consuming a drug. Actively using (n = 18) and abstaining (n = 19) individuals with a history of cocaine use disorder (CUD: dependence or abuse) and matched healthy control subjects (n = 26) participated. RESULTS:Individuals with CUD, especially those actively using cocaine outside the laboratory, made more choices than control subjects to view images depicting cocaine (especially when directly compared against images depicting an alternative appetitive reinforcer [food]). Functional magnetic resonance imaging data revealed that in individuals with CUD, the act of making drug-related choices engaged brain regions implicated in choice difficulty or ambivalence (i.e., dorsal anterior cingulate cortex, which was higher in all individuals with CUD than control subjects). Drug-related choices in CUD also engaged brain regions implicated in reward (e.g., midbrain/ventral tegmental area, which was most activated in active users, although this region was not hypothesized a priori). CONCLUSIONS:These results help clarify the neural mechanisms underlying drug-biased choice in human addiction, which, beyond mechanisms involved in value assignment or reward, may critically involve mechanisms that contribute to resolving difficult decisions. Future studies are needed to validate these behavioral and neural abnormalities as markers of drug seeking and relapse in treatment contexts.

Background: KAT P channels couple cellular metabolism and electrophysiology. Their molecular composition varies in different tissues and species. Rodent atrial KAT P channels have the SUR1 regulatory subunit, are activated by diazoxide and have been implicated in arrhythmogenesis in hypertension and excess beta-adrenergic tone. In contrast, human atrial KATP channels are insensitive to diazoxide and modulate APD only during extreme metabolic stress, where the SUR2A regulatory subunit is thought to be predominant. Objective: We hypothesized that changes in the human atrial action potential associated with beta-agonism are mediated by recruitment of SUR1-containing KATP channels. Methods: We used human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes where expression of a fuorescent reporter is driven by the atrial-specifc gene sarcolipin. Atrial specifcation was induced with retinoic acid. Di-4-ANBDQBS was used to perform optical action potential measurements on days 65-80 of differentiation. Excised patch clamping was used to evaluate KAT P channel density. Heterozygous ABCC8 (SUR1+/-) cells were generated using CRISPR/CAS9. Results: Optical mapping data are for APD90 with stimulation at 1.25 Hz The combination of isoproterenol (ISO, 10mu M) and rolipram (ROL, 10mu M) abbreviated APD compared to control (247.4+/-12.5ms, n=16 vs 344.2+/-22.9ms, n=22; p=0.002). This was ameliorated by 10mu M glibenclamide (312.0+/-18.9ms, n=23 vs 247.4+/-12.5ms, n=16; p=0.01). More patches from cells exposed to ISO and ROL had functional KATP channels (4/22 vs 0/24, p=0.045). Diazoxide shortened APD (267.3+/-21.7ms, n=20 vs 344.2+/-22.9ms, n=22; p=0.02). This was potentiated by prior beta-agonism (179.7+/-14.3ms, n=18 vs 267.3+/-21.7ms, n=20; p=0.002). Deletion of one ABCC8 allele ameliorated APD shortening with exposure to ISO, ROL, and diazoxide (240.9+/-18.2ms, n=14 vs 179.7+/-14.3ms, n=18; p=0.012). Functional KATP channel density after exposure to beta-agonists was reduced in SUR1+/-cells (1/40 vs 4/22, p=0.049). Conclusion: SUR1-containing KATP channels partially mediate beta-adrenergic APD shortening in human atrial cells and may represent a therapeutic target for atrial arrhythmia prevention

Approved pharmacological treatments for alcohol use disorder are limited in their effectiveness, and new drugs that can easily be translated into the clinic are warranted. One of those candidates is oxytocin because of its interaction with several alcohol-induced effects. Alcohol dependent rats as well as postmortem brains of human alcoholics and controls were analyzed for the expression of the oxytocin system by qRT-PCR, in situ hybridization, receptor autoradiography ([125I]-OVTA binding) and immunohistochemistry. Alcohol self-administration and cue-induced reinstatement behavior was measured after intracerebroventricular injection of 10 nM oxytocin in dependent rats. Here we show a pronounced up-regulation of oxytocin receptors in brain tissues of alcohol dependent rats and deceased alcoholics, primarily in frontal and striatal areas. This up-regulation stems most likely from reduced oxytocin expression in hypothalamic nuclei. Pharmacological validation showed that oxytocin reduced cue-induced reinstatement response in dependent rats-an effect that was not observed in non-dependent rats. Finally, a clinical pilot study (German clinical trial number DRKS00009253) using functional magnetic resonance imaging in heavy social male drinkers showed that intranasal oxytocin (24 IU) decreased neural cue-reactivity in brain networks similar to those detected in dependent rats and humans with increased oxytocin receptor expression. These studies suggest that oxytocin might be used as an anti-craving medication and thus may positively affect treatment outcomes in alcoholics.Neuropsychopharmacology accepted article preview online, 01 November 2017. doi:10.1038/npp.2017.257.

In recent years, two-photon calcium imaging has become a standard tool to probe the function of neural circuits and to study computations in neuronal populations. However, the acquired signal is only an indirect measurement of neural activity due to the comparatively slow dynamics of fluorescent calcium indicators. Different algorithms for estimating spike rates from noisy calcium measurements have been proposed in the past, but it is an open question how far performance can be improved. Here, we report the results of the spikefinder challenge, launched to catalyze the development of new spike rate inference algorithms through crowd-sourcing. We present ten of the submitted algorithms which show improved performance compared to previously evaluated methods. Interestingly, the top-performing algorithms are based on a wide range of principles from deep neural networks to generative models, yet provide highly correlated estimates of the neural activity. The competition shows that benchmark challenges can drive algorithmic developments in neuroscience.

PURPOSE/OBJECTIVE:To compare estimates for the diffusional kurtosis in brain as obtained from a cumulant expansion (CE) of the diffusion MRI (dMRI) signal and from q-space (QS) imaging. THEORY AND METHODS/UNASSIGNED:were used to determine the diffusion displacement probability density function (dPDF) via Stejskal's formula. The kurtosis was then calculated directly from the second and fourth order moments of the dPDF. These two approximations were studied for in vivo human data obtained on a 3T MRI scanner using three orthogonal diffusion encoding directions. RESULTS:The whole brain mean values for the CE and QS kurtosis estimates differed by 16% or less in each of the considered diffusion encoding directions, and the Pearson correlation coefficients all exceeded 0.85. Nonetheless, there were large discrepancies in many voxels, particularly those with either very high or very low kurtoses relative to the mean values. CONCLUSION/CONCLUSIONS:Estimates of the diffusional kurtosis in brain obtained using CE and QS approximations are strongly correlated, suggesting that they encode similar information. However, for the choice of b-values employed here, there may be substantial differences, depending on the properties of the diffusion microenvironment in each voxel.

Protein histidine phosphatase 1 (PHPT-1) is an evolutionarily conserved 14 kDa protein that dephosphorylates phosphohistidine.PHPT-1

OBJECTIVE:Familial dysautonomia (FD) is an autosomal recessive disorder characterized by impaired development of sensory and afferent autonomic nerves. Untreated sleep-disordered breathing (SDB) has been reported to increase the risk of sudden unexpected death in FD. We aimed to describe the prevalence and characteristics of SDB in FD. PATIENTS/METHODS/METHODS:measurements during different sleep stages. RESULTS:Overall, 85% of adults and 91% of pediatric patients had some degree of SDB. Obstructive sleep apneas were more severe in adults (8.5 events/h in adults vs. 3.5 events/h in children, p = 0.04), whereas central apneas were more severe (10.8 vs. 2.8 events/h, p = 0.04) and frequent (61.8% vs. 45%, p = 0.017) in children. Overall, a higher apnea-hypopnea index was associated with increased severity of hypoxia and hypoventilation, although in a significant fraction of patients (67% and 46%), hypoxemia and hypoventilation occurred independent of apneas. CONCLUSION/CONCLUSIONS:monitoring during polysomnography in all patients with FD to detect SDB.