Network structure determines patterns of network reorganization during adult neurogenesis

New cells are generated throughout life and integrate into the hippocampus via the process of adult neurogenesis. Epileptogenic brain injury induces many structural changes in the hippocampus, including the death of interneurons and altered connectivity patterns. The pathological neurogenic niche is associated with aberrant neurogenesis, though the role of the network-level changes in development of epilepsy is not well understood. In this paper, we use computational simulations to investigate the effect of network environment on structural and functional outcomes of neurogenesis. We find that small-world networks with external stimulus are able to be augmented by activity-seeking neurons in a manner that enhances activity at the stimulated sites without altering the network as a whole. However, when inhibition is decreased or connectivity patterns are changed, new cells are both less responsive to stimulus and the new cells are more likely to drive the network into bursting dynamics. Our results suggest that network-level changes caused by epileptogenic injury can create an environment where neurogenic reorganization can induce or intensify epileptic dynamics and abnormal integration of new cells.Comment: 28 pages, 10 figure

From network structure to network reorganization: implications for adult neurogenesis

Networks can be dynamical systems that undergo functional and structural reorganization. One example of such a process is adult hippocampal neurogenesis, in which new cells are continuously born and incorporate into the existing network of the dentate gyrus region of the hippocampus. Many of these introduced cells mature and become indistinguishable from established neurons, joining the existing network. Activity in the network environment is known to promote birth, survival and incorporation of new cells. However, after epileptogenic injury, changes to the connectivity structure around the neurogenic niche are known to correlate with aberrant neurogenesis. The possible role of network-level changes in the development of epilepsy is not well understood. In this paper, we use a computational model to investigate how the structural and functional outcomes of network reorganization, driven by addition of new cells during neurogenesis, depend on the original network structure. We find that there is a stable network topology that allows the network to incorporate new neurons in a manner that enhances activity of the persistently active region, but maintains global network properties. In networks having other connectivity structures, new cells can greatly alter the distribution of firing activity and destroy the initial activity patterns. We thus find that new cells are able to provide focused enhancement of network only for small-world networks with sufficient inhibition. Network-level deviations from this topology, such as those caused by epileptogenic injury, can set the network down a path that develops toward pathological dynamics and aberrant structural integration of new cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85406/1/ph10_4_046008.pd

Race–Gender Differences in the Impact of History of Heavy Drinking on Current Alcohol Consumption during the Transition to Adulthood

American youth transitioning to adulthood consume more alcohol than in any other period of the life course. This high level of consumption can result in serious consequences, including lost productivity, death and disability, sexual assault, and addiction. Nevertheless, relatively little is known, especially by race and gender, about how prior history of heavy drinking (e.g., in late adolescence) impacts drinking in young adulthood. Utilizing data from the National Longitudinal Survey of Youth (1994-2004) for African Americans, Latinos, and Whites (N = 2,300), we found that Whites and Latinos drink more than African Americans, and men report drinking more than women. However, accounting for a history of heavy drinking introduces considerable variation in current drinking patterns by race–gender status. A history of heavy drinking more than doubles the number of drinks consumed by African American women, putting their drinking levels on par with African American men and White women and raising their level of drinking above Latinas. Further, African American women\u27s probability of heavy drinking becomes indistinguishable from that of African American men and White women, once accounting for a prior history of binge drinking. For Latinas with a history of heavy drinking, the probability of being a current binge drinker is equal to Latinos and White men and higher than African Americans and White women

Pattern Formation of Glioma Cells: Effects of Adhesion

We investigate clustering of malignant glioma cells. \emph{In vitro} experiments in collagen gels identified a cell line that formed clusters in a region of low cell density, whereas a very similar cell line (which lacks an important mutation) did not cluster significantly. We hypothesize that the mutation affects the strength of cell-cell adhesion. We investigate this effect in a new experiment, which follows the clustering dynamics of glioma cells on a surface. We interpret our results in terms of a stochastic model and identify two mechanisms of clustering. First, there is a critical value of the strength of adhesion; above the threshold, large clusters grow from a homogeneous suspension of cells; below it, the system remains homogeneous, similarly to the ordinary phase separation. Second, when cells form a cluster, we have evidence that they increase their proliferation rate. We have successfully reproduced the experimental findings and found that both mechanisms are crucial for cluster formation and growth.Comment: 6 pages, 6 figure

The role of cell-cell adhesion in wound healing

We present a stochastic model which describes fronts of cells invading a wound. In the model cells can move, proliferate, and experience cell-cell adhesion. We find several qualitatively different regimes of front motion and analyze the transitions between them. Above a critical value of adhesion and for small proliferation large isolated clusters are formed ahead of the front. This is mapped onto the well-known ferromagnetic phase transition in the Ising model. For large adhesion, and larger proliferation the clusters become connected (at some fixed time). For adhesion below the critical value the results are similar to our previous work which neglected adhesion. The results are compared with experiments, and possible directions of future work are proposed.Comment: to appear in Journal of Statistical Physic

Synaptic Cleft Segmentation in Non-Isotropic Volume Electron Microscopy of the Complete Drosophila Brain

Neural circuit reconstruction at single synapse resolution is increasingly recognized as crucially important to decipher the function of biological nervous systems. Volume electron microscopy in serial transmission or scanning mode has been demonstrated to provide the necessary resolution to segment or trace all neurites and to annotate all synaptic connections. Automatic annotation of synaptic connections has been done successfully in near isotropic electron microscopy of vertebrate model organisms. Results on non-isotropic data in insect models, however, are not yet on par with human annotation. We designed a new 3D-U-Net architecture to optimally represent isotropic fields of view in non-isotropic data. We used regression on a signed distance transform of manually annotated synaptic clefts of the CREMI challenge dataset to train this model and observed significant improvement over the state of the art. We developed open source software for optimized parallel prediction on very large volumetric datasets and applied our model to predict synaptic clefts in a 50 tera-voxels dataset of the complete Drosophila brain. Our model generalizes well to areas far away from where training data was available

Conserved neural circuit structure across Drosophila larval development revealed by comparative connectomics.

During postembryonic development, the nervous system must adapt to a growing body. How changes in neuronal structure and connectivity contribute to the maintenance of appropriate circuit function remains unclear. Previously , we measured the cellular neuroanatomy underlying synaptic connectivity in Drosophila (Schneider-Mizell et al., 2016). Here, we examined how neuronal morphology and connectivity change between first instar and third instar larval stages using serial section electron microscopy. We reconstructed nociceptive circuits in a larva of each stage and found consistent topographically arranged connectivity between identified neurons. Five-fold increases in each size, number of terminal dendritic branches, and total number of synaptic inputs were accompanied by cell type-specific connectivity changes that preserved the fraction of total synaptic input associated with each pre-synaptic partner. We propose that precise patterns of structural growth act to conserve the computational function of a circuit, for example determining the location of a dangerous stimulus

Unveiling the sensory and interneuronal pathways of the neuroendocrine connectome in Drosophila.

Neuroendocrine systems in animals maintain organismal homeostasis and regulate stress response. Although a great deal of work has been done on the neuropeptides and hormones that are released and act on target organs in the periphery, the synaptic inputs onto these neuroendocrine outputs in the brain are less well understood. Here, we use the transmission electron microscopy reconstruction of a whole central nervous system in the Drosophila larva to elucidate the sensory pathways and the interneurons that provide synaptic input to the neurosecretory cells projecting to the endocrine organs. Predicted by network modeling, we also identify a new carbon dioxide-responsive network that acts on a specific set of neurosecretory cells and that includes those expressing corazonin (Crz) and diuretic hormone 44 (Dh44) neuropeptides. Our analysis reveals a neuronal network architecture for combinatorial action based on sensory and interneuronal pathways that converge onto distinct combinations of neuroendocrine outputs