Biology subjects

Jordan, C.

Publications and source records attributed to Jordan, C..

26 records · Page 2Linked to original sources

bioRxiv2020

FlyWire: Online community for whole-brain connectomics

Due to advances in automated image acquisition and analysis, new whole-brain connectomes beyond C. elegans are finally on the horizon. Proofreading of whole-brain automated reconstructions will require many person-years of effort, due to the huge volumes of data involved. Here we present FlyWire, an online community for proofreading neural circuits in a fly brain, and explain how its computational and social structures are organized to scale up to whole-brain connectomics. Browser-based 3D interactive segmentation by collaborative editing of a spatially chunked supervoxel graph makes it possible to distribute proofreading to individuals located virtually anywhere in the world. Information in the edit history is programmatically accessible for a variety of uses such as estimating proofreading accuracy or building incentive systems. An open community accelerates proofreading by recruiting more participants, and accelerates scientific discovery by requiring information sharing. We demonstrate how FlyWire enables circuit analysis by reconstructing and analysing the connectome of mechanosensory neurons.

neuroscience↗

bioRxiv2020

Chandelier cell anatomy and function reveal a variably distributed but common signal

The activity and connectivity of inhibitory cells has a profound impact on the operation of neuronal networks. While the average connectivity of many inhibitory cell types has been characterized, we still lack an understanding of how individual interneurons distribute their synapses onto their targets and how heterogeneous the inhibition is onto different individual excitatory neurons. Here, we use large-scale volumetric electron microscopy (EM) and functional imaging to address this question for chandelier cells in layer 2/3 of mouse visual cortex. Using dense morphological reconstructions from EM, we mapped the complete chandelier input onto 153 pyramidal neurons. We find that the number of input synapses is highly variable across the population, but the variability is correlated with structural features of the target neuron: soma depth, soma size, and the number of perisomatic synapses received. Functionally, we found that chandelier cell activity in vivo was highly correlated and tracks pupil diameter, a proxy for arousal state. We propose that chandelier cells provide a global signal whose strength is individually adjusted for each target neuron. This approach, combining comprehensive structural analysis with functional recordings of identified cell types, will be a powerful tool to uncover the wiring rules across the diversity of cortical cell types.

neuroscience↗

bioRxiv2020

The Neural Basis for a Persistent Internal State in Drosophila Females

Sustained changes in mood or action require persistent changes in neural activity, but it has been difficult to identify and characterize the neural circuit mechanisms that underlie persistent activity and contribute to long-lasting changes in behavior. Here, we focus on changes in the behavioral state of Drosophila females that persist for minutes following optogenetic activation of a single class of central brain neurons termed pC1. We find that female pC1 neurons drive a variety of persistent behaviors in the presence of males, including increased receptivity, shoving, and chasing. By reconstructing cells in a volume electron microscopic image of the female brain, we classify 7 different pC1 cell types and, using cell type specific driver lines, determine that one of these, pC1-Alpha, is responsible for driving persistent female shoving and chasing. Using calcium imaging, we locate sites of minutes-long persistent neural activity in the brain, which include pC1 neurons themselves. Finally, we exhaustively reconstruct all synaptic partners of a single pC1-Alpha neuron, and find recurrent connectivity that could support the persistent neural activity. Our work thus links minutes-long persistent changes in behavior with persistent neural activity and recurrent circuit architecture in the female brain.

neuroscience↗

bioRxiv2020

Acute Stress Reduces Reward-Related Neural Activity: Evidence from the Reward Positivity

Stress and blunted reward processing are risk factors for mood disorders, including Major Depressive Disorder (MDD). The experience of acute stress reduces fMRI correlates of reward-related neural activity; however, few studies have examined how acute stress impacts measures of reward derived from event-related potentials (ERPs). The current study examined the impact of an acute stressor on the Reward Positivity (RewP), an ERP that indexes reward sensitivity, in twenty-seven college students. Participants completed a monetary reward task while they placed their left hand in cold water set at 13 degrees Celsius (i.e., acute stress condition) and again while their hand was placed in room temperature water (i.e., control condition). These conditions were separated by one week and performed in a counter-balanced order across participants. The results revealed that the RewP amplitude was blunted in the acute stress condition compared to the control condition. Moreover, there was a trend toward this effect interacting with self-reported depressive symptoms: the RewP was only reduced among individuals who reported low depressive symptoms. The current study suggests that an acute stressor reduces the RewP, and that this effect might be moderated by current depressive symptoms. Future studies might examine the temporal association between reward processing and stress --and how they interact to predict depressive symptoms.

neuroscience↗

bioRxiv2019

Binary and analog variation of synapses between cortical pyramidal neurons

Learning from experience depends at least in part on changes in neuronal connections. We present the largest map of connectivity to date between cortical neurons of a defined type (L2/3 pyramidal cells), which was enabled by automated analysis of serial section electron microscopy images with improved handling of image defects. We used the map to identify constraints on the learning algorithms employed by the cortex. Previous cortical studies modeled a continuum of synapse sizes (Arellano et al. 2007) by a log-normal distribution (Loewenstein, Kuras, and Rumpel 2011; de Vivo et al. 2017; Santuy et al. 2018). A continuum is consistent with most neural network models of learning, in which synaptic strength is a continuously graded analog variable. Here we show that synapse size, when restricted to synapses between L2/3 pyramidal cells, is well-modeled by the sum of a binary variable and an analog variable drawn from a log-normal distribution. Two synapses sharing the same presynaptic and postsynaptic cells are known to be correlated in size (Sorra and Harris 1993; Koester and Johnston 2005; Bartol et al. 2015; Kasthuri et al. 2015; Dvorkin and Ziv 2016; Bloss et al. 2018; Motta et al. 2019). We show that the binary variables of the two synapses are highly correlated, while the analog variables are not. Binary variation could be the outcome of a Hebbian or other synaptic plasticity rule depending on activity signals that are relatively uniform across neuronal arbors, while analog variation may be dominated by other influences. We discuss the implications for the stability-plasticity dilemma.

neuroscience↗

bioRxiv2019

Cultivation and characterization of human midbrain organoids in sensor integrated microfluidic chips

1.With its ability to emulate microarchitectures and functional characteristics of native organs in vitro, induced pluripotent stem cell (iPSC) technology has enabled the generation of a plethora of organotypic constructs, including that of the human midbrain. However, reproducibly engineering and differentiating such human midbrain organoids (hMOs) under a biomimetic environment favorable for brain development still remains challenging. This study sets out to address this problem by combining the potential of iPSC technology with the advantages of microfluidics, namely its precise control over fluid flow combined with sensor integration. Here, we present a novel sensor-integrated platform for the long-term cultivation and non-invasive monitoring of hMOs under an interstitial flow regime. Our results show that dynamic cultivation of iPSC-derived hMOs maintains high cellular viabilities and dopaminergic neuron differentiation over prolonged cultivation periods of up to 50 days.

bioengineering↗

bioRxiv2019

The interoceptive hippocampus: mouse brain endocrine receptor expression highlights a dentate gyrus (DG)-cornu ammonis (CA) challenge-sufficiency axis

The primeval function of the mammalian hippocampus (HPC) remains uncertain. Implicated in learning and memory, spatial navigation, and neuropsychological disorders, evolutionary theory suggests that the HPC evolved from a primeval chemosensory epithelium. Internal sensing deficits in patients with HPC lesions argue that internal sensing may be conserved in higher vertebrates. We studied the expression of 250 endocrine receptors in mouse brain. Key findings are (i) the proportions and levels of endocrine receptor expression in the HPC are significantly higher than in all other comparable brain regions. (ii) Surprisingly, the distribution of endocrine receptor expression within mouse HPC was found to be highly structured: receptors signaling challenge are segregated in dentate gyrus (DG), whereas those signaling sufficiency are principally found in cornu ammonis (CA) regions. Selective expression of endocrine receptors in the HPC argues that internal sensing remains a core feature of hippocampal function. Further, we report that ligands of DG receptors predominantly inhibit both synaptic potentiation and neurogenesis, whereas CA receptor ligands conversely promote both synaptic potentiation and neurogenesis. These findings suggest that the hippocampus acts as an integrator of body status, extending its role in context-dependent memory encoding from where and when to how I feel. Implications for anxiety and depression are discussed.

neuroscience↗

bioRxiv2019

Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma

YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing Sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving EWSR1 gene, and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome.\n\nWe did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of RASSF1 locus -a regulator of Hippo pathway- was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the protumorigenic isoform RASSF1C promoting YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells, and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be partly explained by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS.

cancer biology↗