rudyvdbrink/CitationDatabase huggingface dataset:
A specific role of the human hippocampus in recall of temporal sequences.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009

There is a growing interest in how temporal order of episodic memories is represented within the medial temporal lobe (MTL). Animal studies suggest that the hippocampal formation (HF) is critical for retrieving the temporal order of past experiences. However, human imaging studies that have tested recency discrimination between pairs of previously encoded items have generally failed to report HF activation. We hypothesized that recalling a naturalistic sequence of past events would be particularly sensitive to HF function, attributable to greater involvement of associative processes. To test this prediction, we let subjects watch a novel movie and later, during functional magnetic resonance imaging, asked them to rearrange and "replay" scenes from the movie in correct order. To identify areas specifically involved in retrieval of temporal order, we used a control condition where subjects logically inferred the order of scenes from the same movie. Extensive MTL activation was observed during sequence recall. Activation within the right HF was specifically related to retrieval of temporal order and correlated positively with accuracy of sequence recall. Also, the bilateral parahippocampal cortex responded to retrieval of temporal order, but the activation here was not related to performance. Our study is the first to unequivocally demonstrate that correct sequence recall depends on HF.
ATP in neuron-glia bidirectional signalling.
Brain research reviews, 2011

ATP accomplishes important roles in brain, where it functions as neurotransmitter or co-transmitter, being stored and released either as single mediator or together with other neuromodulators. In the last years, the purinergic system has emerged as the most relevant mechanism for intercellular signalling in the nervous system, affecting communication between many types of neurons and all types of glia. In this review, we will focus on recently reported data which describe the role of ATP in bidirectional signalling between neurons and different populations of glial cells, in both peripheral and central system.
Lithium Pharmacogenetics: Where Do We Stand?
Drug development research, 2016

Preclinical Research Bipolar disorder (BPD) is a chronic and disabling psychiatric disorder with a prevalence of 0.8-1.2% in the general population. Although lithium is considered the first-line treatment, a large percentage of patients do not respond sufficiently. Moreover, lithium can induce severe side effects and has poor tolerance and a narrow therapeutic index. The genetics of lithium response has been largely investigated, but findings have so far failed to identify reliable biomarkers to predict clinical response. This has been largely determined by the highly complex phenotipic and genetic architecture of lithium response. To this regard, collaborative initiatives hold the promise to provide robust and standardized methods to disantenagle this complexity, as well as the capacity to collect large samples of patietnts, a crucial requirement to study the genetics of complex phenotypes. The International Consortium on Lithium Genetics (ConLiGen) has recently published the largest study so far on lithium response reporting significant associations for two long noncoding RNAs (lncRNAs). This result provides relevant insights into the pharmacogenetics of lithium supporting the involvement of the noncoding portion of the genome in modulating clinical response. Although a vast body of research is engaged in dissecting the genetic bases of response to lithium, the several drawbacks of lithium therapy have also stimulated multiple efforts to identify new safer treatments. A drug repurposing approach identified ebselen as a potential lithium mimetic, as it shares with lithium the ability to inhibit inositol monophosphatase. Ebselen, an antioxidant glutathione peroxidase mimetic, represents a valid and promising example of new potential therapeutic interventions for BD, but the paucity of data warrant further investigation to elucidate its potential efficacy and safety in the management of BPD. Nevertheless, findings provided by the growing field of pharmacogenomic research will ultimately lead to the identification of new molecular targets and safer treatments for BPD. Drug Dev Res 77 : 368-373, 2016. © 2016 Wiley Periodicals, Inc.
Stability of spontaneous, correlated activity in mouse auditory cortex.
PLoS computational biology, 2019

Neural systems can be modeled as complex networks in which neural elements are represented as nodes linked to one another through structural or functional connections. The resulting network can be analyzed using mathematical tools from network science and graph theory to quantify the system's topological organization and to better understand its function. Here, we used two-photon calcium imaging to record spontaneous activity from the same set of cells in mouse auditory cortex over the course of several weeks. We reconstruct functional networks in which cells are linked to one another by edges weighted according to the correlation of their fluorescence traces. We show that the networks exhibit modular structure across multiple topological scales and that these multi-scale modules unfold as part of a hierarchy. We also show that, on average, network architecture becomes increasingly dissimilar over time, with similarity decaying monotonically with the distance (in time) between sessions. Finally, we show that a small fraction of cells maintain strongly-correlated activity over multiple days, forming a stable temporal core surrounded by a fluctuating and variable periphery. Our work indicates a framework for studying spontaneous activity measured by two-photon calcium imaging using computational methods and graphical models from network science. The methods are flexible and easily extended to additional datasets, opening the possibility of studying cellular level network organization of neural systems and how that organization is modulated by stimuli or altered in models of disease.
Features of spatial and functional segregation and integration of the primate connectome revealed by trade-off between wiring cost and efficiency.
PLoS computational biology, 2017

The primate connectome, possessing a characteristic global topology and specific regional connectivity profiles, is well organized to support both segregated and integrated brain function. However, the organization mechanisms shaping the characteristic connectivity and its relationship to functional requirements remain unclear. The primate brain connectome is shaped by metabolic economy as well as functional values. Here, we explored the influence of two competing factors and additional advanced functional requirements on the primate connectome employing an optimal trade-off model between neural wiring cost and the representative functional requirement of processing efficiency. Moreover, we compared this model with a generative model combining spatial distance and topological similarity, with the objective of statistically reproducing multiple topological features of the network. The primate connectome indeed displays a cost-efficiency trade-off and that up to 67% of the connections were recovered by optimal combination of the two basic factors of wiring economy and processing efficiency, clearly higher than the proportion of connections (56%) explained by the generative model. While not explicitly aimed for, the trade-off model captured several key topological features of the real connectome as the generative model, yet better explained the connectivity of most regions. The majority of the remaining 33% of connections unexplained by the best trade-off model were long-distance links, which are concentrated on few cortical areas, termed long-distance connectors (LDCs). The LDCs are mainly non-hubs, but form a densely connected group overlapping on spatially segregated functional modalities. LDCs are crucial for both functional segregation and integration across different scales. These organization features revealed by the optimization analysis provide evidence that the demands of advanced functional segregation and integration among spatially distributed regions may play a significant role in shaping the cortical connectome, in addition to the basic cost-efficiency trade-off. These findings also shed light on inherent vulnerabilities of brain networks in diseases.
Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009

Alzheimer's disease is associated with an increased risk of unprovoked seizures. However, the underlying mechanisms of seizure induction remain elusive. Here, we performed video-EEG recordings in mice carrying mutant human APPswe and PS1dE9 genes (APdE9 mice) and their wild-type littermates to determine the prevalence of unprovoked seizures. In two recording episodes at the onset of amyloid beta (Abeta) pathogenesis (3 and 4.5 months of age), at least one unprovoked seizure was detected in 65% of APdE9 mice, of which 46% had multiple seizures and 38% had a generalized seizure. None of the wild-type mice had seizures. In a subset of APdE9 mice, seizure phenotype was associated with a loss of calbindin-D28k immunoreactivity in dentate granular cells and ectopic expression of neuropeptide Y in mossy fibers. In APdE9 mice, persistently decreased resting membrane potential in neocortical layer 2/3 pyramidal cells and dentate granule cells underpinned increased network excitability as identified by patch-clamp electrophysiology. At stimulus strengths evoking single-component EPSPs in wild-type littermates, APdE9 mice exhibited decreased action potential threshold and burst firing of pyramidal cells. Bath application (1 h) of Abeta1-42 or Abeta25-35 (proto-)fibrils but not oligomers induced significant membrane depolarization of pyramidal cells and increased the activity of excitatory cell populations as measured by extracellular field recordings in the juvenile rodent brain, confirming the pathogenic significance of bath-applied Abeta (proto-)fibrils. Overall, these data identify fibrillar Abeta as a pathogenic entity powerfully altering neuronal membrane properties such that hyperexcitability of pyramidal cells culminates in epileptiform activity.
Retinal Ganglion Cell Diversity and Subtype Specification from Human Pluripotent Stem Cells.
Stem cell reports, 2018

Retinal ganglion cells (RGCs) are the projection neurons of the retina and transmit visual information to postsynaptic targets in the brain. While this function is shared among nearly all RGCs, this class of cell is remarkably diverse, comprised of multiple subtypes. Previous efforts have identified numerous RGC subtypes in animal models, but less attention has been paid to human RGCs. Thus, efforts of this study examined the diversity of RGCs differentiated from human pluripotent stem cells (hPSCs) and characterized defined subtypes through the expression of subtype-specific markers. Further investigation of these subtypes was achieved using single-cell transcriptomics, confirming the combinatorial expression of molecular markers associated with these subtypes, and also provided insight into more subtype-specific markers. Thus, the results of this study describe the derivation of RGC subtypes from hPSCs and will support the future exploration of phenotypic and functional diversity within human RGCs.
Ghrelin signaling contributes to fasting-induced attenuation of hindbrain neural activation and hypophagic responses to systemic cholecystokinin in rats.
American journal of physiology. Regulatory, integrative and comparative physiology, 2020

In rats, overnight fasting reduces the ability of systemic cholecystokinin-8 (CCK) to suppress food intake and to activate cFos in the caudal nucleus of the solitary tract (cNTS), specifically within glucagon-like peptide-1 (GLP-1) and noradrenergic (NA) neurons of the A2 cell group. Systemic CCK increases vagal sensory signaling to the cNTS, an effect that is amplified by leptin and reduced by ghrelin. Since fasting reduces plasma leptin and increases plasma ghrelin levels, we hypothesized that peripheral leptin administration and/or antagonism of ghrelin receptors in fasted rats would rescue the ability of CCK to activate GLP-1 neurons and a caudal subset of A2 neurons that coexpress prolactin-releasing peptide (PrRP). To test this, cFos expression was examined in ad libitum-fed and overnight food-deprived (DEP) rats after intraperitoneal CCK, after coadministration of leptin and CCK, or after intraperitoneal injection of a ghrelin receptor antagonist (GRA) before CCK. In fed rats, CCK activated cFos in ~60% of GLP-1 and PrRP neurons. Few or no GLP-1 or PrRP neurons expressed cFos in DEP rats treated with CCK alone, CCK combined with leptin, or GRA alone. However, GRA pretreatment increased the ability of CCK to activate GLP-1 and PrRP neurons and also enhanced the hypophagic effect of CCK in DEP rats. Considered together, these new findings suggest that reduced behavioral sensitivity to CCK in fasted rats is at least partially due to ghrelin-mediated suppression of hindbrain GLP-1 and PrRP neural responsiveness to CCK.
Reduced small world brain connectivity in probands with a family history of epilepsy.
European journal of neurology, 2016

The role of inheritance in ascertaining susceptibility to epilepsy is well established, although the pathogenetic mechanisms are still not very clear. Interviewing for a positive family history is a popular epidemiological tool in the understanding of this susceptibility. Our aim was to visualize and localize network abnormalities that could be associated with a positive family history in a group of patients with hot water epilepsy (HWE) using resting-state functional magnetic resonance imaging (rsfMRI).
Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria.
Human molecular genetics, 2012

A proline-to-serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB; VAPBP56S) causes some dominantly inherited familial forms of motor neuron disease, including amyotrophic lateral sclerosis (ALS) type-8. Here, we show that expression of ALS mutant VAPBP56S but not wild-type VAPB in neurons selectively disrupts anterograde axonal transport of mitochondria. VAPBP56S-induced disruption of mitochondrial transport involved reductions in the frequency, velocity and persistence of anterograde mitochondrial movement. Anterograde axonal transport of mitochondria is mediated by the microtubule-based molecular motor kinesin-1. Attachment of kinesin-1 to mitochondria involves the outer mitochondrial membrane protein mitochondrial Rho GTPase-1 (Miro1) which acts as a sensor for cytosolic calcium levels ([Ca(2+)]c); elevated [Ca(2+)]c disrupts mitochondrial transport via an effect on Miro1. To gain insight into the mechanisms underlying the VAPBP56S effect on mitochondrial transport, we monitored [Ca(2+)]c levels in VAPBP56S-expressing neurons. Expression of VAPBP56S but not VAPB increased resting [Ca(2+)]c and this was associated with a reduction in the amounts of tubulin but not kinesin-1 that were associated with Miro1. Moreover, expression of a Ca(2+) insensitive mutant of Miro1 rescued defective mitochondrial axonal transport and restored the amounts of tubulin associated with the Miro1/kinesin-1 complex to normal in VAPBP56S-expressing cells. Our results suggest that ALS mutant VAPBP56S perturbs anterograde mitochondrial axonal transport by disrupting Ca(2+) homeostasis and effecting the Miro1/kinesin-1 interaction with tubulin.
Translating the evidence for gene association with depression into mouse models of depression-relevant behaviour: current limitations and future potential.
Neuroscience and biobehavioral reviews, 2013

Depression is characterised by high prevalence and complex, heterogeneous psychopathology. At the level of aetio-pathology, considerable research effort has been invested to identify specific gene polymorphisms associated with increased depression prevalence. Genome-wide association studies have not identified any risk polymorphisms, and candidate gene case-control studies have identified a small number of risk polymorphisms. It is increasingly recognised that interaction between genotype and environmental factors (G×E), notably stressful life events, is the more realistic unit of depression aetio-pathology, with G×E evidence described for a small number of risk polymorphisms. An important complementary approach has been to describe genes exhibiting brain region-specific expression changes in depression. Mouse models of depression informed by the human evidence allow for the study of causality, but to-date have also yielded limited insights into depression aetio-pathology. This review of the translational evidence integrates human and mouse research approaches and evidence. It also makes specific recommendations in terms of how future research in human and mouse should be designed in order to deliver evidence for depression aetio-pathology and thereby to inform the development of novel and improved antidepressant treatments.
Facilitation of fear extinction by novelty is modulated by β-adrenergic and 5-HT
Neurobiology of learning and memory, 2019

Extinction is the learned inhibition of retrieval of a previously acquired memory and is a major component of exposure therapy, which has attracted much attention because of the use in the treatment of drug addiction, phobias and particularly fear disorders such as post-traumatic stress disorder (PTSD). Exposure to a novel environment before or after extinction training can enhance the extinction of contextual fear conditioning, however the cellular and molecular substrates are still unclear. Here, we investigated the participation of H2-histaminergic, β-adrenergic and 5-HT
Subliminally presented and stored objects capture spatial attention.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010

When objects disappear from view, we can still bring them to mind, at least for brief periods of time, because we can represent those objects in visual short-term memory (VSTM) (Sperling, 1960; Cowan, 2001). A defining characteristic of this representation is that it is topographic, that is, it preserves a spatial organization based on the original visual percept (Vogel and Machizawa, 2004; Astle et al., 2009; Kuo et al., 2009). Recent research has also shown that features or locations of visual items that match those being maintained in conscious VSTM automatically capture our attention (Awh and Jonides, 2001; Olivers et al., 2006; Soto et al., 2008). But do objects leave some trace that can guide spatial attention, even without participants intentionally remembering them? Furthermore, could subliminally presented objects leave a topographically arranged representation that can capture attention? We presented objects either supraliminally or subliminally and then 1 s later re-presented one of those objects in a new location, as a "probe" shape. As participants made an arbitrary perceptual judgment on the probe shape, their covert spatial attention was drawn to the original location of that shape, regardless of whether its initial presentation had been supraliminal or subliminal. We demonstrate this with neural and behavioral measures of memory-driven attentional capture. These findings reveal the existence of a topographically arranged store of "visual" objects, the content of which is beyond our explicit awareness but which nonetheless guides spatial attention.
An in vitro model of the inhibition of axon growth in the lesion scar formed after central nervous system injury.
Molecular and cellular neurosciences, 2010

After central nervous system (CNS) injury, meningeal fibroblasts migrate in the lesion center to form a fibrotic scar which is surrounded by end feet of reactive astrocytes. The fibrotic scar expresses various axonal growth-inhibitory molecules and creates a major impediment for axonal regeneration. We developed an in vitro model of the scar using coculture of cerebral astrocytes and meningeal fibroblasts by adding transforming growth factor-beta1 (TGF-beta1), a potent fibrogenic factor. Addition of TGF-beta1 to this coculture resulted in enhanced proliferation of fibroblasts and the formation of cell clusters which consisted of fibroblasts inside and surrounded by astrocytes. The cell cluster in culture densely accumulated the extracellular matrix molecules and axonal growth-inhibitory molecules similar to the fibrotic scar, and remarkably inhibited the neurite outgrowth of cerebellar neurons. Therefore, this culture system can be available to analyze the inhibitory property in the lesion site of CNS.
Descending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice.
Nature communications, 2019

Locomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways. Spinal cord injury (SCI) interrupts descending projections and denervates lumbar motor neurons (MNs). We previously reported that retrogradely transported neurotrophin-3 (NT-3) to lumbar MNs attenuated SCI-induced lumbar MN dendritic atrophy and enabled functional recovery after a rostral thoracic contusion. Here we functionally dissected the role of descending neural pathways in response to NT-3-mediated recovery after a T9 contusive SCI in mice. We find that residual projections to lumbar MNs are required to produce leg movements after SCI. Next, we show that the spared descending propriospinal pathway, rather than other pathways (including the corticospinal, rubrospinal, serotonergic, and dopaminergic pathways), accounts for NT-3-enhanced recovery. Lastly, we show that NT-3 induced propriospino-MN circuit reorganization after the T9 contusion via promotion of dendritic regrowth rather than prevention of dendritic atrophy.
PLD1 Negatively Regulates Dendritic Branching.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012

Neurons have characteristic dendritic arborization patterns that contribute to information processing. One essential component of dendritic arborization is the formation of a specific number of branches. Although intracellular pathways promoting dendritic growth and branching are being elucidated, the mechanisms that negatively regulate the branching of dendrites remain enigmatic. In this study, using gain-of-function and loss-of-function studies, we show that phospholipase D1 (PLD1) acts as a negative regulator of dendritic branching in cultured hippocampal neurons from embryonic day 18 rat embryos. Overexpression of wild-type PLD1 (WT-PLD1) decreases the complexity of dendrites, whereas knockdown or inhibition of PLD1 increases dendritic branching. We further demonstrated that PLD1 acts downstream of RhoA, one of the small Rho GTPases, to suppress dendritic branching. The restriction of dendritic branching by constitutively active RhoA (V14-RhoA) can be partially rescued by knockdown of PLD1. Moreover, the inhibition of dendritic branching by V14-RhoA and WT-PLD1 can be partially ameliorated by reducing the level of phosphatidic acid (PA), which is the enzymatic product of PLD1. Together, these results suggest that RhoA-PLD1-PA may represent a novel signaling pathway in the restriction of dendritic branching and may thus provide insight into the mechanisms of dendritic morphogenesis.