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Persistent firing is commonly reported in both cortical and subcortical neurons under a variety of behavioral conditions. Yet the mechanisms responsible for persistent activity are only partially resolved with support for both intrinsic and synaptic circuit-based mechanisms. Little also is known about physiological factors that enable epochs of persistent firing to continue beyond brief pauses and then spontaneously terminate. In the present study, we used intracellular recordings in rat (both sexes) neocortical and hippocampal brain slices to assess the ionic mechanisms underlying persistent firing dynamics. Previously, we showed that blockade of ether-á-go-go-related gene (ERG) potassium channels abolished intrinsic persistent firing in the presence of low concentrations of muscarinic receptor agonists and following optogenetic activation of cholinergic axons. Here we show the slow dynamics of ERG conductance changes allows persistent firing to outlast the triggering stimulus and even to initiate discharges following ∼7 s poststimulus firing pauses. We find that persistent firing dynamics is regulated by the interaction between ERG conductance and spike afterhyperpolarizations (AHPs). Increasing the amplitude of spike AHPs using either SK channel activators or a closed-loop reactive feedback system allows persistent discharges to spontaneously terminate in both neocortical neurons and hippocampal CA1 pyramidal cells. The interplay between ERG and the potassium channels that mediate spike AHPs grades the duration of persistent firing, providing a novel, generalizable mechanism to explain self-terminating persistent firing modes observed behaving animals. SIGNIFICANCE STATEMENT Many classes of neurons generate prolonged spiking responses to transient stimuli. These discharges often outlast the stimulus by seconds to minutes in some in vitro models of persistent firing. While recent work has identified key synaptic and intrinsic components that enable persistent spiking responses, less is known about mechanisms that can terminate and regulate the dynamics of these responses. The present study identified the spike afterhyperpolarizations as a potent mechanism that regulates the duration of persistent firing. We found that amplifying spike afterpotentials converted bistable persistent firing into self-terminating discharges. Varying the spike AHP amplitude grades the duration of persistent discharges, generating in vitro responses that mimic firing modes associated with neurons associated with short-term memory function.

The subthalamic nucleus (STN) is thought to be a central regulator of behavioral inhibition, which is thought to be a major determinant of impulsivity. Thus, it would be reasonable to hypothesize that STN function is related to impulsivity. However, it has been difficult to test this hypothesis because of the challenges in noninvasively and accurately measuring this structure's signal in humans. We utilized a novel approach for STN signal localization that entails identifying this structure directly on fMRI images for each individual participant in native space. Using this approach, we measured STN responses during the stop signal task in a sample of healthy adult participants. We confirmed that the STN exhibited selective activation during “Stop” trials. Furthermore, the magnitude of STN activation during successful Stop trials inversely correlated with individual differences in trait impulsivity as measured by a personality inventory. Time course analysis revealed that early STN activation differentiated successful from unsuccessful Stop trials, and individual differences in the magnitude of STN activation inversely correlated with stop signal RT, an estimate of time required to stop. These results are consistent with the STN playing a central role in inhibition and related behavioral proclivities, with implications for both normal range function and clinical syndromes of inhibitory dyscontrol. Moreover, the methods utilized in this study for measuring STN fMRI signal in humans may be gainfully applied in future studies to further our understanding of the role of the STN in regulating behavior and neuropsychiatric conditions.

There has been keen interest in measuring in vivo GABA. However, GABA signal is low and typically measured using techniques vulnerable to the confounding effects of in-scanner head movement. This issue is particularly problematic for clinical studies since it may lead to Type I or II error in testing for group differences. While solutions to mitigate the effects of movement have been proposed, fundamental and largely unexamined issues are the nature and scale of this effect. We developed a method to quantify and characterize head movement during GABA spectroscopy and found that two parameters of movement, displacement and instantaneous movement, were inversely correlated with and accounted for 12.1% and 20.2% variance of GABA estimates respectively. We conclude that head movement can significantly affect GABA measurements and the application of methods to account for movement may improve of GABA measurement accuracy and the detection of true group differences in clinical studies.

The ability to proactively control motor responses, particularly to overcome overlearned or automatic actions, is an essential prerequisite for adaptive, goal-oriented behavior. The substantia nigra (SN), an element of the BG, has figured prominently in current models of response selection. However, because of its small size and proximity to functionally distinct subcortical structures, it has been challenging to test the SN's involvement in response selection using conventional in vivo functional neuroimaging approaches. We developed a new fMRI localization method for directly distinguishing, on echo-planar images, the SN BOLD signal from that of neighboring structures, including the subthalamic nucleus (STN). Using this method, we tested the hypothesis that the SN supports the proactive control of response selection. We acquired high-resolution EPI volumes at 3 T from 16 healthy participants while they completed the Preparing to Overcome Prepotency task of proactive control. There was significantly elevated delay period signal selectively during high- compared with low-control trials in the SN. The STN did not show delay period activity in either condition. SN delay period signal was significantly inversely associated with task performance RTs across participants. These results suggest that our method offers a novel means for measuring SN BOLD responses, provides unique evidence of SN involvement in cognitive control in humans, and suggests a novel mechanism for proactive response selection.

// Naoko Hosono 1, 2 , Hideki Makishima 1, * , Reda Mahfouz 1 , Bartlomiej Przychodzen 1 , Kenichi Yoshida 3, 4 , Andres Jerez 1 , Thomas LaFramboise 5 , Chantana Polprasert 1 , Michael J. Clemente 1 , Yuichi Shiraishi 6 , Kenichi Chiba 6 , Hiroko Tanaka 7 , Satoru Miyano 6, 7 , Masashi Sanada 3, 4 , Edward Cui 5 , Amit K. Verma 8 , Michael A. McDevitt 9 , Alan F. List 10 , Yogen Saunthararajah 1 , Mikkael A. Sekeres 1, 12, 13 , Jacqueline Boultwood 13 , Seishi Ogawa 3, 4 , Jaroslaw P. Maciejewski 1, 11, * 1 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA 2 First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan 3 Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 4 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 5 Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA 6 Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 7 Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 8 Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, USA 9 Division of Hematology and Hematological Malignancy, Department of Internal Medicine and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 10 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 11 Leukemia Program, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA 12 Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA 13 LLR Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom * These authors contributed equally to this work Correspondence to: Jaroslaw P. Maciejewski, email: maciejj@ccf.org Keywords: MDS, del(5q), TP53, G3BP1 Received: June 20, 2016 Accepted: December 16, 2016 Published: December 23, 2016 ABSTRACT Background: Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms. Materials and Methods: To define the pathogenic molecular features associated with del(5q), next–generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5. Findings: A number of 5q genes with haploinsufficient expression and/or recurrent somatic mutations were identified; for these genes, CSNK1A1 and G3BP1 within the commonly deleted 5q region and DDX41 within a commonly retained region were most commonly affected by somatic mutations. These genes showed consistent haploinsufficiency in deleted cases; low expression/mutations of G3BP1 or DDX41 were associated with poor survival, likely due to decreased cellular function. The most common mutations on other chromosomes in patients with del(5q) included TP53 , and mutations of FLT3 (ITD or TKD), NPM1 or TET2 and were mutually exclusive. Serial sequencing allowed for definition of clonal architecture and dynamics, in patients with exome sequencing allelic imbalance for informative SNPs facilitated simultaneous approximation of clonal size of del(5q) and clonal burden for somatic mutations. Interpretation: Our results illuminate the spectrum of molecular defects characteristic of del(5q), their clinical impact and succession of stepwise evolution.