bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effective connectivity during autobiographical memory search
Authors: Nawa Norberto Eiji , Ando Hiroshi 
Published: October 2019

AbstractAutobiographical memory (AM) retrieval is known to recruit a widely distributed network of brain regions but much less is known regarding how these regions interact during the various phases that presumably take place during episodic memory retrieval in general and AM retrieval in particular. Here, we used dynamic causal modeling (DCM) to examine effective connectivity during cued AM search in a sub-network consisting of six major regions within this large network. Functional MRI data was acquired while participants were visually presented verbal cues describing common life events and requested to search for a personal memory that could be associated with each cue. We examined directed couplings between the ventromedial (vmPFC), dorsomedial (dmPFC) and dorsolateral prefrontal cortices (dlPFC), hippocampus, angular gyrus and a region in the posterior midline cortex (RSC/PCC/Prec), all located in the left hemisphere. Results indicated that during AM search, the vmPFC, dlPFC and RSC/PCC/Prec acted as primary drivers of activity in the rest of the network. Moreover, when AM search was completed successfully (Hits), an up-modulation of the effective connectivity of the hippocampus in the vmPFC and angular gyrus was observed. In the same way, there was an increase in the influence of the RSC/PCC/Prec in the activity of the dlPFC and dmPFC. Furthermore, during Hits the angular gyrus showed to have an inhibitory effect in all other nodes of the network. These results are consistent with the notion that midline cortical regions are crucial in supporting the retrieval of AMs, and highlight the interplay between the vmPFC and the RSC/PCC/Prec and the dlPFC during AM search.
Sex differences in electrophysiological properties of mouse mPOA neurons revealed by in vitro whole-cell recordings
Authors: Zhang Wen , Li Shuai-shuai , Jiao Zhuo-lei , Han Ying , Wang Zi-yue , Xu Xiao-Hong 
Published: October 2019

AbstractThe medial preoptic area (mPOA) of the hypothalamus is sexually dimorphic and controls sexually dimorphic display of male mating and parental care. Yet, despite extensive characterization of sex differences in the mPOA, we know surprisingly little about whether or how male and female mPOA neurons differ electrophysiologically, which relate more directly to neuronal firing and behavioral pattern generation. In this study, we performed whole-cell patch clamp recordings of the mPOA in acute brain slices cut from virgin adult mice, and compared in total 29 electrophysiological parameters between male and female mPOA neurons. We find that resting membrane potential (Vm), input resistance (Rm), time constant (τm), threshold (Vth) and minimum current (rheobase) required to generate an action potential differ significantly between male and female in a cell-type dependent manner. Nonetheless, there is little evidence for profuse sex differences in neuronal excitability, except for a higher probability of rebound neurons in males. Depletion of male gonadal hormones in adulthood partially de-masculinizes sexually dimorphic electrophysiological parameters, suggesting that some of these sex differences may establish during development. Furthermore, as a demonstration of the behavioral relevance of these sex differences, we show that pharmacologic blockage of currents mediated by T-type Ca2+ channel, which underlie rebound and tends to be larger in male mPOA neurons, result in behavioral deficits in male mating. In summary, we have identified key sex differences in electrophysiological properties of mPOA neurons that likely contribute to sexually dimorphic display of behaviors.Significance StatementSex represents an important biological variable that impact an individual’s behaviors, physiology and disease susceptibility. Indeed, sex differences in the nervous system manifest across many different levels and scales. Yet, throughout previous multifaceted investigations on sex differences in the brain, electrophysiological characterizations, which could potentially bridge cellular and molecular sex differences with sexually dimorphic brain functions and behaviors, remains scant. Here, focusing on an evolutionarily conserved sexually dimorphic nucleus, we investigated sex differences in electrophysiological properties of mPOA neurons and its modulation by gonadal hormones in adult males via in vitro whole-cell patch clamp. As a result, we identified novel sex differences in electrophysiological properties that likely contribute to sexually dimorphic display of behaviors and physiological functions.
A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome
Authors: Bekhouche Bahia , Tourville Aurore , Ravichandran Yamini , Tacine Rachida , Abrami Laurence , Dussiot Michael , Khau-Dancasius Andrea , Boccara Olivia , Khirat Meriem , Mangeney Marianne , Bellon Nathalia , Fraitag Sylvie , Hadj-Rabia Smail , Blanche Stéphane , Puel Anne , Etienne-Manneville Sandrine , van der Goot F. Gisou , Cherfils Jacqueline , Hermine Olivier , Casanova Jean-Laurent , Bodemer Christine , Smahi Asma , Delon Jérôme 
Published: October 2019

BackgroundAutoinflammatory diseases (AID) result from dysregulation of the first lines of innate immune responses. Recently, development of high throughput genome sequencing technology led to the rapid emergence of important knowledge in the genetic field. About 20 genes have been identified so far in monogenic forms of distinct AID. However, 70-90 % of patients with AID remain without genetic diagnosis.ObjectiveWe report the identification and characterization of a mutation in the C-terminal region of the Rho GTPase Cdc42 in a patient presenting a severe autoinflammatory phenotype.MethodsWe have analyzed the consequences of the mutation on the subcellular localization of the Cdc42 protein using imaging techniques. Molecular studies were performed using proteomic and biochemical experiments to provide mechanistic bases of the observed defects. Functional assays were also conducted using flow cytometry and cytokine production measurements.ResultsWe show that mutant Cdc42 is trapped in the Golgi apparatus due to the aberrant addition of a palmitate that both enhances the interaction of mutant Cdc42 with Golgi membranes and inhibit its extraction by GDP dissociation inhibitor (GDI), thus impairing its cytosol/membrane shuttling. At the functional level, mutant Cdc42 fails to sustain actin filaments polymerization and induces an exacerbated profile of pro-inflammatory cytokine production due to increased NF-κB activation.ConclusionsOur study now provides a molecular explanation for mutations that have been identified recently in our AID patient and others in the C-terminal part of Cdc42. Mutations located in this region of Cdc42 impair the intracellular localization of Cdc42, preventing its interaction with the plasma membrane. Thus, our results definitively link mutations in the CDC42 gene to a complex immune-hemato-autoinflammatory phenotype in humans.
FANCD2 tunes the UPR preventing mitochondrial stress-­induced common fragile site instability
Authors: Fernandes Philippe , Miotto Benoit , Saint-Ruf Claude , Nähse Viola , Ravera Silvia , Cappelli Enrico , Naim Valeria 
Published: October 2019

AbstractCommon fragile sites (CFSs) are genomic regions frequently involved in cancer-associated rearrangements. Most CFSs lie within large genes, and their instability relies on transcription- and replication-dependent mechanisms. Here, we uncover a role for the UBL5-dependent branch of the unfolded protein response pathway (UPR) in the maintenance of CFS stability. We show that genetic or pharmacological UPR activation induces CFS gene expression and concomitant relocalization of FANCD2, a master regulator of CFS stability, to CFSs. Furthermore, a genomic analysis of FANCD2 binding sites identified an enrichment for mitochondrial UPR transcriptional response elements in FANCD2 bound regions. We demonstrated that depletion of FANCD2 increases CFS gene transcription and their instability while also inducing mitochondrial dysfunction and triggering the activation of the UPR pathway. Depletion of UBL5, a mediator of the UPR, but not ATF4, reduces CFS gene expression and breakage in FANCD2-depleted cells. We thus demonstrate that FANCD2 recruitment and function at CFSs depends on transcription and UPR signaling, and in absence of transcription or UBL5, FANCD2 is dispensable for CFS stability. We propose that FANCD2 coordinates nuclear and mitochondrial activities by tuning the UPR to prevent genome instability.
Characterization of Arabidopsis thaliana promoter bidirectionality and antisense RNAs by depletion of nuclear RNA decay enzymes
Authors: Thieffry Axel , Bornholdt Jette , Ivanov Maxim , Brodersen Peter , Sandelin Albin 
Published: October 2019

ABSTRACTIn animals, transcription by RNA polymerase II initiates bidirectionally from gene promoters to produce pre-mRNAs on the forward strand and promoter upstream transcripts (PROMPTs) on the reverse strand. PROMPTs are rapidly degraded by the nuclear exosome. Similarly, active enhancer regions in animals initiate transcription of exosome-sensitive enhancer RNAs (eRNAs). Previous studies based on nascent RNA approaches concluded that Arabidopsis thaliana does not produce PROMPTs. Here, we used steady-state RNA sequencing methods in mutants defective in nuclear RNA decay, including by the exosome, to reassess the existence of PROMPTs and eRNAs in A. thaliana. While PROMPTs are overall rare in A. thaliana, about 100 clear cases of exosome-sensitive PROMPTs and 113 loci producing eRNA-like transcripts were identified. In addition, we found ∼200 transcription start sites within 3’-UTR-encoding regions that produce unspliced exosome-sensitive antisense RNAs covering much of the cognate pre-mRNA. A typical representative of this class of RNAs is the previously characterized non-coding RNA controlling the expression of the key seed dormancy regulator, DELAY OF GERMINATION1. Exosome-sensitive antisense RNAs are overrepresented in transcription factor genes, suggesting a potential for widespread control of gene expression. Lastly, we assess the use of alternative promoters in A. thaliana and compare the accuracy of existing TSS annotations.
Deep brain stimulation modulates directional frontolimbic connectivity in obsessive‐compulsive disorder
Authors: Fridgeirsson Egill Axfjord , Figee Martijn , Luigjes Judy , van den Munckhof Pepijn , Schuurman P.Richard , Wingen Guido van , Denys Damiaan 
Published: October 2019

AbstractDeep brain stimulation (DBS) is effective for patients with treatment‐refractory obsessive‐compulsive disorder. DBS of the ventral anterior limb of the internal capsule (vALIC) rapidly improves mood and anxiety with optimal stimulation parameters. To understand these rapid effects of vALIC‐DBS, we studied functional interactions within the affective amygdala circuit. We compared resting state functional magnetic resonance imaging data during chronic stimulation versus one week of stimulation discontinuation in patients, and obtained two resting state scans from matched healthy volunteers to account for test‐retest effects. Imaging data were analyzed using functional connectivity analysis and dynamic causal modelling. Improvement in mood and anxiety following DBS was associated with reduced amygdala‐insula functional connectivity. Directional connectivity analysis revealed that DBS increased the impact of the ventromedial prefrontal cortex on the amygdala, and decreased the impact of the amygdala on the insula. These results highlight the importance of the amygdala circuit in the pathophysiology of OCD, and suggest a neural systems model through which negative mood and anxiety are modulated by vALIC‐DBS for OCD and possibly other psychiatric disorders.One Sentence SummaryDeep brain stimulation improves mood and anxiety in obsessive‐compulsive disorder by altering connectivity between the amygdala, insula and prefrontal cortex.
Protein Interactome of the Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) in Th17 Cells
Authors: Khan Mohd Moin , Välikangas Tommi , Khan Meraj Hasan , Moulder Robert , Ullah Ubaid , Bhosale Santosh Dilip , Komsi Elina , Butt Umar , Qiao Xi , Westermarck Jukka , Elo Laura L , Lahesmaa Riitta 
Published: October 2019

ABSTRACTCancerous inhibitor of protein phosphatase 2A (CIP2A) is involved in immune response, cancer progression, and in Alzheimer’s disease. However, an understanding of the mechanistic basis of its function in this wide spectrum of physiological and pathological processes is limited due to its poorly characterized interaction networks. Here we present the first systematic characterization of the CIP2A interactome by affinity-purification mass spectrometry combined with validation by selected reaction monitoring targeted mass spectrometry (SRM-MS) analysis in Th17 cells. In addition to the known regulatory subunit of protein phosphatase PP2A, the catalytic subunit of protein PP2A was found to be interacting with CIP2A. Furthermore, the regulatory (PPP1R18, and PPP1R12A) and catalytic (PPP1CA) subunits of phosphatase PP1 were identified among the top novel CIP2A interactors. Evaluation of the ontologies associated with the proteins in this interactome revealed that they were linked with RNA metabolic processing and splicing, protein traffic, cytoskeleton regulation and ubiquitin-mediated protein degradation processes. Taken together, this network of protein-protein interactions will be important for understanding and further exploring the biological processes and mechanisms regulated by CIP2A both in physiological and pathological conditions.Highlights▪ The first characterisation of the CIP2A interactome in Th17 cells.▪ Key interactions were validated by targeted SRM-MS proteomics, western blot and confocal microscopy.▪ Pathway analysis of the interactome revealed interrelationships with proteins across a broad range of processes, in particular associated with mRNA processing.
ILF3 contributes to the establishment of the antiviral type I interferon program
Authors: Watson Samir F. , Bellora Nicolas , Macias Sara 
Published: October 2019

AbstractUpon detection of viral infections, cells activate the expression of type I interferons (IFNs) and pro-inflammatory cytokines to control viral dissemination. As part of their antiviral response, cells also trigger the translational shutoff response which prevents translation of viral mRNAs and cellular mRNAs in a non-selective manner. Intriguingly, mRNAs encoding for antiviral factors bypass this translational shutoff, suggesting the presence of additional regulatory mechanisms enabling expression of the self-defence genes. Here, we identified the dsRNA binding protein ILF3 as an essential host factor required for efficient translation of the central antiviral cytokine,IFNB1, and a subset of interferon-stimulated genes. By combining polysome profiling and next-generation sequencing, ILF3 was also found to be necessary to establish the dsRNA-induced transcriptional and translational programs. We propose a central role for the host factor ILF3 in enhancing expression of the antiviral defence mRNAs in cellular conditions where cap-dependent translation is compromised.
Precise coupling of the thalamic head-direction system to hippocampal ripples
Authors: Viejo Guillaume , Peyrache Adrien 
Published: October 2019

AbstractThe anterior thalamus is a key relay of neuronal signals within the limbic system. During sleep, the occurrence of hippocampal sharp wave-ripples (SWRs), believed to mediate consolidation of explicit memories, is modulated by thalamocortical network activity, yet how information is routed around SWRs and how this communication depends on neuronal dynamics remains unclear. Here, by simultaneously recording ensembles of neurons in the anterior thalamus and local field potentials in the CA1 area of the hippocampus, we show that the head-direction (HD) cells of the anterodorsal nucleus are set in stable directions immediately before SWRs. This response contrasts with other thalamic cells that exhibit diverse couplings to the hippocampus related to their intrinsic dynamics but independent of their anatomical location. Thus, our data suggest a specific and homogeneous contribution of the HD signal to hippocampal activity and a diverse and cell-specific coupling of non-HD neurons.
Evolution of the acoustic startle response of Mexican cavefish
Authors: Paz Alexandra , McDole Brittnee , Kowalko Johanna E. , Duboue Erik R. , Keene Alex C. 
Published: October 2019

AbstractThe ability to detect threatening sensory stimuli and initiate an escape response is essential for survival and under stringent evolutionary pressure. In diverse fish species, acoustic stimuli activate Mauthner neurons, which initiate a stereotypical C-start escape response. This reflexive behavior is highly conserved across aquatic species and provides a model for investigating the neural mechanism underlying the evolution of escape behavior. Here, we define evolved differences in the C-start response between populations of the Mexican cavefish,Astyanax mexicanus. Cave populations ofA. mexicanusinhabit in an environment devoid of light and macroscopic predation, resulting in evolved differences in diverse morphological and behavioral traits. We find that the C-start is present in multiple populations of cavefish and river-dwelling surface fish, but response kinematics and probability differ between populations. The Pachón population of cavefish have an increased response probability, a slower response and reduction of the maximum bend angle, revealing evolved differences between surface and cave populations. In two other independently evolved populations of cavefish, the response probability and the kinematics of the response differ from one another, as well as from surface fish, suggesting the independent evolution of differences in the C-start response. Investigation of surface-cave hybrids reveals a relationship between angular speed and peak angle, suggesting these two kinematic characteristics are related at the genetic or functional levels. Together, these findings provide support for the use ofA. mexicanusas a model to investigate the evolution of escape behavior.
Flexible recruitment of memory-based choice representations by human medial-frontal cortex
Authors: Minxha Juri , Adolphs Ralph , Fusi Stefano , Mamelak Adam N. , Rutishauser Ueli 
Published: October 2019

SummaryDecisions in complex environments rely on flexibly utilizing past experience as required by context and instructions1. This process depends on the medial frontal cortex (MFC) and the medial temporal lobe (MTL)2-5, but it remains unknown how these structures jointly implement flexible memory retrieval6,7. We recorded single neurons in MFC and MTL while human subjects switched8 between making memory- and categorization-based decisions9,10. Here we show that MFC rapidly implements changing task demands by utilizing different subspaces of neural activity during different types of decisions. In contrast, no effect of task demands was seen in the MTL. Choices requiring memory retrieval selectively engaged phase-locking of MFC neurons to field potentials in the theta-frequency band in the MTL. Choice-selective neurons in MFC signaled abstract yes-no decisions independent of behavioral response modality (button press or saccade). These findings reveal a novel mechanism for flexibly and selectively engaging memory retrieval11-14 and show that unlike perceptual decision-making15, memory-related information is only represented in frontal cortex when choices require it.
Correlated activity favors synergistic processing in local cortical networksin vitroat synaptically-relevant timescales
Authors: Sherrill Samantha P. , Timme Nicholas M. , Beggs John M. , Newman Ehren L. 
Published: October 2019

ABSTRACTNeural information processing is widely understood to depend on correlations in neuronal activity. However, whether correlation is favorable or not is contentious. Here, we sought to determine how correlated activity and information processing are related in cortical circuits. Using recordings of hundreds of spiking neurons in organotypic cultures of mouse neocortex, we asked whether mutual information between neurons that feed into a common third neuron increased synergistic information processing by the receiving neuron. We found that mutual information and synergistic processing were positively related at synaptic timescales (0.05-14 ms), where mutual information values were low. This effect was mediated by the increase in information transmission—of which synergistic processing is a component—that resulted as mutual information grew. However, at extrasynaptic windows (up to 3000 ms), where mutual information values were high, the relationship between mutual information and synergistic processing became negative. In this regime, greater mutual information resulted in a disproportionate increase in redundancy relative to information transmission. These results indicate that the emergence of synergistic processing from correlated activity differs according to timescale and correlation regime. In a low-correlation regime, synergistic processing increases with greater correlation, and in a high correlation regime, synergistic processing decreases with greater correlation.AUTHOR SUMMARYIn the present work, we address the question of whether correlated activity in functional networks of cortical circuits supports neural computation. To do so, we combined network analysis with information theoretic tools to analyze the spiking activity of hundreds of neurons recorded from organotypic cultures of mouse somatosensory cortex. We found that, at timescales most relevant to direct neuronal communication, neurons with more correlated activity predicted greater computation, suggesting that correlated activity does support computation in cortical circuits. Importantly, this result reversed at timescales less relevant to direct neuronal communication, where even greater correlated activity predicted decreased computation. Thus, the relationship between correlated activity and computation depends on the timescale and the degree of correlation in neuronal interactions.