A guide to the BRAIN Initiative Cell Census Network data ecosystem.

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain.

A Model of Binocular Motion Integration in MT Neurons.

UNLABELLED: Primate cortical area MT plays a central role in visual motion perception, but models of this area have largely overlooked the binocular integration of motion signals. Recent electrophysiological studies tested binocular integration in MT and found surprisingly that MT neurons lose their hallmark "pattern motion" selectivity when stimuli are presented dichoptically and that many neurons are selective for motion-in-depth (MID). By unifying these novel observations with insights from monocular, frontoparallel motion studies concurrently in a binocular MT motion model, we generated clear, testable predictions about the circuitry and mechanisms underlying visual motion processing. We built binocular models in which signals from left- and right-eye streams could be integrated at various stages from V1 to MT, attempting to create the simplest plausible circuits that accounted for the physiological range of pattern motion selectivity, that explained changes across this range for dichoptic stimulus presentation, and that spanned the spectrum of MID selectivity observed in MT. Our successful models predict that motion-opponent suppression is the key mechanism to account for the striking loss of pattern motion sensitivity with dichoptic plaids, that opponent suppression precedes binocular integration, and that opponent suppression will be stronger in inputs to pattern cells than to component cells. We also found an unexpected connection between circuits for pattern motion selectivity and MID selectivity, suggesting that these two separately studied phenomena could be related. These results also hold in models that include binocular disparity computations, providing a platform for future exploration of binocular response properties in MT. SIGNIFICANCE STATEMENT: The neural pathways underlying our sense of visual motion are among the most studied and well-understood parts of the primate cerebral cortex. Nevertheless, our understanding is incomplete because electrophysiological research has focused mainly on motion in the 2D frontoparallel plane, even though real-world motion often occurs in three dimensions, involving a change in distance from the viewer. Recent studies have revealed a specialization for sensing 3D motion in area MT, the cortical area most tightly linked to the processing and perception of visual motion. Our study provides the first model to explain how 3D motion sensitivity can arise in MT neurons and predicts how essential features of 2D motion integration may relate to 3D motion processing.

Mechanisms for Rapid Adaptive Control of Motion Processing in Macaque Visual Cortex.

A key feature of neural networks is their ability to rapidly adjust their function, including signal gain and temporal dynamics, in response to changes in sensory inputs. These adjustments are thought to be important for optimizing the sensitivity of the system, yet their mechanisms remain poorly understood. We studied adaptive changes in temporal integration in direction-selective cells in macaque primary visual cortex, where specific hypotheses have been proposed to account for rapid adaptation. By independently stimulating direction-specific channels, we found that the control of temporal integration of motion at one direction was independent of motion signals driven at the orthogonal direction. We also found that individual neurons can simultaneously support two different profiles of temporal integration for motion in orthogonal directions. These findings rule out a broad range of adaptive mechanisms as being key to the control of temporal integration, including untuned normalization and nonlinearities of spike generation and somatic adaptation in the recorded direction-selective cells. Such mechanisms are too broadly tuned, or occur too far downstream, to explain the channel-specific and multiplexed temporal integration that we observe in single neurons. Instead, we are compelled to conclude that parallel processing pathways are involved, and we demonstrate one such circuit using a computer model. This solution allows processing in different direction/orientation channels to be separately optimized and is sensible given that, under typical motion conditions (e.g., translation or looming), speed on the retina is a function of the orientation of image components. SIGNIFICANCE STATEMENT: Many neurons in visual cortex are understood in terms of their spatial and temporal receptive fields. It is now known that the spatiotemporal integration underlying visual responses is not fixed but depends on the visual input. For example, neurons that respond selectively to motion direction integrate signals over a shorter time window when visual motion is fast and a longer window when motion is slow. We investigated the mechanisms underlying this useful adaptation by recording from neurons as they responded to stimuli moving in two different directions at different speeds. Computer simulations of our results enabled us to rule out several candidate theories in favor of a model that integrates across multiple parallel channels that operate at different time scales.

Monocyte activity is linked with abdominal aortic aneurysm diameter.

BACKGROUND: Systemic inflammation and increased matrix metalloproteinase (MMP) cause elastin degradation leading to abdominal aortic aneurysm (AAA) expansion. Several prospective studies report that statin therapy can reduce AAA expansion through anti-inflammation. We hypothesize that monocyte activity plays a pivotal role in this AAA development and this study examines patient peripheral blood monocyte cell adhesion, transendothelial migration, and MMP concentrations between AAA and non-AAA patients. MATERIALS AND METHODS: Peripheral blood was collected and monocytes isolated from control (n=15) and AAA (n=13) patients. Monocyte adhesion, transmigration, and permeability assays were assessed. Luminex assays determined MMP-9 and tissue inhibitor of metalloproteinase-4 (TIMP-4) concentrations from cell culture supernatant and patient serum. RESULTS: AAA patient monocytes showed increased adhesion to the endothelium relative fluorescence units (RFU, 0.33±0.17) versus controls (RFU, 0.13±0.04; P=0.005). Monocyte transmigration was also increased in AAA patients (RFU, 0.33±0.11) compared with controls (RFU, 0.25±0.04, P=0.01). Greater numbers of adhesive (R2=0.66) and transmigratory (R2=0.86) monocytes were directly proportional to the AAA diameter. Significantly higher serum levels of MMP-9 (2149.14±947 pg/mL) were found in AAA patients compared with controls (1189.2±293; P=0.01). TIMP-4 concentrations were significantly lower in AAA patients (826.7±100 pg/mL) compared with controls (1233±222 pg/mL; P=0.02). Cell culture supernatant concentrations of MMP and TIMP from cocultures were higher than monocyte-only cultures. CONCLUSIONS: Monocytes from AAA patients have greater adhesion and transmigration through the endothelium in vitro, leading to elevated MMP-9 levels and the appropriate decrease in TIMP-4 levels. The ability to modulate monocyte activity may lead to novel medical therapies to decrease AAA expansion.

Inter-neuronal correlation distinguishes mechanisms of direction selectivity in cortical circuit models.

Direction selectivity is a fundamental physiological property that arises from primary visual cortex (V1) circuitry, yet basic questions of how direction-selective (DS) receptive fields are constructed remain unanswered. We built a set of simple, plausible neuronal circuits that produce DS cells via different mechanisms and tested these circuits to determine how they can be distinguished experimentally. Our models consisted of populations of spiking units representing physiological cell classes ranging from LGN cells to V1 complex DS cells. They differed in network architecture and DS mechanism, including linear summation of non-DS simple-cell inputs or nonlinear pairwise combinations of non-DS inputs. The circuits also varied in the location of the DS time delay and whether the DS interaction was facilitatory or suppressive. We tested the models with visual stimuli often used experimentally, including sinusoidal gratings and flashed bars, and computed shuffle-corrected cross-correlograms (CCGs) of spike trains from pairs of units that would be accessible to extracellular recording. We found that CCGs revealed fundamental features of the DS models, including the location of signal delays in the DS circuit and the sign (facilitatory or suppressive) of DS interactions. We also found that correlation was strongly stimulus-dependent, changing with direction and temporal frequency in a manner that generalized across model architectures. Our models make specific predictions for designing, optimizing, and interpreting electrophysiology experiments aimed at resolving DS circuitry and provide new insights into mechanisms that could underlie stimulus-dependent correlation. The models are available and easy to explore at www.imodel.org.

Localized DNA cleavage secondary to genotoxic exposure adjacent to an Alu inverted repeat.

Radiation is a potent inducer of DNA damage leading to both random DNA loss and mutation. As part of a study focused on the mechanism whereby cells undergo loss of heterozygosity (LOH), a region of common LOH telomeric termination at 11q24 was observed in clones of H292 mucoepidermoid cells established after irradiation (IR). A 10-kbp region including the telomeric extent of LOH termination was analyzed after IR using six sets of ligation-mediated polymerase chain reaction (PCR) primers to detect the presence of DNA breaks. A cluster of DNA breaks was detected that closely mapped to the telomeric extent of LOH and which were observed up to 8 hr after IR. Repeating the experiment in the presence of the inhibitor of apoptosis, zVAD.fmk, did not change the location or amount of cleavage. A similar distribution of breaks was also seen in the MCF-10A breast cancer cell line after IR. Further inspection of the involved region showed that 22/32 and 7/7 DNA breaks found in H292 and MCF-10A cells, respectively, were located either in or immediately adjacent to an AluSx1 sequence, itself ≈ 1 kbp 5' to an AluSq2 that was in an inverted orientation to the AluSx1. The region between the inverted Alu repeats was notable for both DNAse hypersensitivity and an open chromatin conformation inferred from histone modification data. These factors may contribute to genomic instability at this location.

Neuronal responses during and after the presentation of static visual stimuli in macaque primary visual cortex.

Viewing static visual scenes for several seconds or longer can induce a wide variety of striking percepts, including negative afterimages, fading, and motion aftereffects. To characterize the neuronal bases of such phenomena and elucidate functional circuitry in the visual system, we recorded responses of neurons in primary visual cortex (V1) of anesthetized macaques during and after the presentation of prolonged static visual stimuli. We found that 72% of cells generated significant after-responses (ARs) that outlasted classical off-transients after the cessation of stimuli, and AR amplitude grew with stimulus duration. After the longest stimuli tested (32 s), the amplitude and the time course of the AR were on average comparable to, and correlated with, those of the maintained response evoked while stimuli were present. These observations generally held regardless of cell class: simple, complex, direction selective (DS) or non-DS. The average decay time constant of the AR for orientation-tuned cells was 0.65 s. This is strikingly shorter than time constants observed in the lateral geniculate nucleus, which were on the order of tens of seconds. Cells in V1 that lacked orientation tuning displayed an intermediate time course, with a mean time constant of 4.3 s. These results are consistent with a multistage model in which cells at successive stages adapt to their inputs with progressively shorter time constants. Our findings suggest that the perceptual phenomena of fading and afterimages are shaped by both cortical and subcortical dynamics and provide a physiological framework for the interpretation of recent and long-standing psychophysical observations.

11q21.1-11q23.3 Is a site of intrinsic genomic instability triggered by irradiation.

The chromosome location, 11q21-23, is linked to loss of heterozygosity (LOH) in multiple tumors including those of breast, lung, and head and neck. To examine the process of LOH induction, the H292 cell line (human muco-epidermoid carcinoma) was irradiated or treated with anti-CD95 antibody, and individual clones isolated through two rounds of cloning. Regions of LOH were determined by screening a suite of eight polymorphic microsatellite markers covering 11p15-11q24 using fluorescent primers and genetic analyzer peak discrimination. LOH induction was observed extending through 11q21.1-11q23.3 in 6/49 of clones surviving 4 Gy and 8/50 after 8 Gy. Analysis of selected clones by Affymetrix 6.0 single nucleotide polymorphism (SNP) arrays confirmed the initial assessment indicating a consistent 27.3-27.7 Mbp deletion in multiple clones. The telomeric border of LOH mapped to a 1 Mbp region of elevated recombination. Whole genome analysis of SNP data indicated that site-restricted LOH also occurred across multiple additional genomic locations. These data indicate that 11q21.1-11q23.3, and potentially other regions of this cell line are sites of intrinsic cell-specific instability leading to LOH after irradiation. Such deletions may subsequently be propagated by genetic selection and clonal expansion.

Disruption of coherent oscillations in inhibitory networks with anesthetics: role of GABA(A) receptor desensitization.

The effect of anesthetic drugs at central synapses can be described quantitatively by developing kinetic models of ligand-gated ion channels. Experiments have shown that the hypnotic propofol and the sedative benzodiazepine midazolam have similar effects on single inhibitory postsynaptic potentials (IPSPs) but very different effects on slow desensitization that are not revealed by examining single responses. Synchronous oscillatory activity in networks of interneurons connected by inhibitory synapses has been implicated in many hippocampal functions, and differences in the kinetics of the GABAergic response observed with anesthetics can affect this activity. Thus we have examined the effect of propofol and midazolam-enhanced IPSPs using mathematical models of self-inhibited one- and two-cell inhibitory networks. A detailed kinetic model of the GABA(A) channel incorporating receptor desensitization is used at synapses in our models. The most dramatic effect of propofol is the modulation of slow desensitization. This is only revealed when the network is driven at frequencies that are thought to be relevant to cognitive tasks performed in the hippocampus. The level of desensitization at synapses with propofol is significantly reduced compared to control synapses. In contrast, midazolam increases macroscopic desensitization at network synapses by altering receptor affinity without concurrently modifying desensitization rates. These differences in gating between the two drugs are shown to alter network activity in stereotypically different ways. Specifically, propofol dramatically increases the amount of excitatory drive necessary for synchronized behavior relative to control, which is not the case for midazolam. Moreover, the range of parameters for which synchrony occurs is larger for propofol but smaller for midazolam, relative to control. This is an important first step in linking alterations in channel kinetics with behavioral changes.