Biology subjects

Dwulet, J. M.

Publications and source records attributed to Dwulet, J. M..

7 recordsLinked to original sources

bioRxiv2024

Correlated spontaneous activity sets up multi-sensory integration in the developing higher-order cortex

To perceive and navigate complex sensory environments, animals combine sensory information from multiple modalities in specialized brain circuits. Known as multisensory integration, this process typically depends on the existence of co-aligned topographic connections from several sensory areas to downstream circuits exhibiting multimodal representations. How such topographically co-aligned connectivity necessary for multisensory integration gets set up in early stages of development is still unknown. Inspired by the role of spontaneous activity in refining topographic connectivity between early sensory circuits, here we investigated the potential of such spontaneous activity to also guide the co-alignment of multiple sensory modalities in RL, a higher-order associative cortical area rostro-lateral to V1. Analyzing spontaneous activity simultaneously recorded in primary visual and somatosensory cortex and area RL at different developmental ages before sensory experience, we identify candidate features of this activity to guide the emergence of co-aligned topographic multisensory projections with somatosensory leading the visual projection. We confirm this hypothesis using a computational model of activity-dependent circuit refinement, and show that the correlation of spontaneous activity between the visual and somatosensory primary cortex can establish an optimal fraction of multisensory neurons in RL for stimulus decoding. Our model provides an exciting new computational perspective of the role of spontaneous activity in the emergence of topographically co-aligned multimodal sensory representations in downstream circuits, specialized for the processing of rich sensory environments.

neuroscience↗

bioRxiv2022

What do Functional Synchronization Networks Indicate About Underlying Structure and System Dynamics? A network theory study in the islet

Diabetes is caused by dysfunction of electrically coupled heterogeneous {beta}-cells within the pancreatic islet. Functional networks have been used to represent cellular synchronization and study {beta}-cells subpopulations, which play an important role in driving dynamics. The mechanism by which highly synchronized {beta}-cell subpopulations drive islet function is not clear. We used experimental and computational techniques to investigate the relationship between functional networks, structural (gap-junction) networks, and underlying {beta}-cell dynamics. Highly synchronized subpopulations in the functional network were differentiated by metabolic dynamics rather than structural coupling. Consistent with this, metabolic similarities were more predictive of edges in the islet functional network. Finally, removal of gap junctions, as occurs in diabetes, caused decreases in the efficiency and clustering of the functional network. These results indicate that metabolism rather than structure drives connections in the function network, deepening our interpretation of functional networks and the formation of functional sub-populations in dynamic tissues such as the islet.

biophysics↗

bioRxiv2020

Functional architecture of the pancreatic islets: First responder cells drive the first-phase response

Insulin-secreting {beta}-cells are functionally heterogeneous. Whether there exist cells driving the first-phase calcium response in individual islets, has not been examined. We examine first responder cells, defined by the earliest [Ca2+] response during first-phase [Ca2+] elevation, distinct from previously identified "hub" and "leader" cells. First responder cells showed characteristics of high membrane excitability and lower electrical coupling to their neighbors. The first-phase response time of {beta}-cells in the islet was spatially organized, dependent on the cells distance to the first responder cell, and consistent over time up to [~]24 h. When first responder cells were laser ablated, the first-phase [Ca2+] was slowed down, diminished, and discoordinated compared to random cell ablation. Cells that were next earliest to respond often took over the role of the first responder upon ablation. In summary, we discover and characterize a distinct first responder {beta}-cell state, critical for the islet first-phase response to glucose.

biophysics↗

bioRxiv2020

Small subpopulations of β-cells do not drive islet oscillatory dynamics via gap junction communication

The islets of Langerhans exist as a multicellular network that is important for the regulation of blood glucose levels. The majority of cells in the islet are insulin-producing {beta}-cells, which are excitable cells that are electrically coupled via gap junction channels. {beta}-cells have long been known to display heterogeneous functionality. However, due to gap junction electrical coupling, {beta}-cells show coordinated [Ca2+] oscillations when stimulated with glucose, and global quiescence when unstimulated. Small subpopulations of highly functional {beta}-cells have been suggested to control the dynamics of [Ca2+] and insulin release across the islet. In this study, we investigated the theoretical basis of whether small subpopulations of {beta}-cells can disproportionality control islet [Ca2+] dynamics. Using a multicellular model of the islet, we generated continuous or bimodal distributions of {beta}-cell heterogeneity and examined how islet [Ca2+] dynamics depended on the presence of cells with increased excitability or increased oscillation frequency. We found that the islet was susceptible to marked suppression of [Ca2+] when a [~]10% population of cells with high metabolic activity was hyperpolarized; where hyperpolarizing cells with normal metabolic activity had little effect. However, when these highly metabolic cells were removed from the islet model, near normal [Ca2+] remained. Similarly, when [~]10% of cells with either the highest frequency or earliest elevations in [Ca2+] were removed from the islet, the [Ca2+] oscillation frequency remained largely unchanged. Overall these results indicate that small populations of {beta}-cells with either increased excitability or increased frequency, or signatures of [Ca2+] dynamics that suggest such properties, are unable to disproportionately control islet-wide [Ca2+] via gap junction coupling. As such, we need to reconsider the physiological basis for such small {beta}-cell populations or the mechanism by which they may be acting to control normal islet function. Author summaryMany biological systems can be studied using network theory. How heterogeneous cell subpopulations come together to create complex multicellular behavior is of great value in understanding function and dysfunction in tissues. The pancreatic islet of Langerhans is a highly coupled structure that is important for maintaining blood glucose homeostasis. {beta}-cell electrical activity is coordinated via gap junction communication. The function of the insulin-producing {beta}-cell within the islet is disrupted in diabetes. As such, to understand the causes of islet dysfunction we need to understand how different cells within the islet contribute to its overall function via gap junction coupling. Using a computational model of {beta}-cell electrophysiology, we investigated how small highly functional {beta}-cell populations within the islet contribute to its function. We found that when small populations with greater functionality were introduced into the islet, they displayed signatures of this enhanced functionality. However, when these cells were removed, the islet, retained near-normal function. Thus, in a highly coupled system, such as an islet, the heterogeneity of cells allows small subpopulations to be dispensable, and thus their absence is unable to disrupt the larger cellular network. These findings can be applied to other electrical systems that have heterogeneous cell populations.

biophysics↗

bioRxiv2020

Caloric Restriction recovers impaired β-cell-β-cell coupling, calcium oscillation coordination and insulin secretion in prediabetic mice

Caloric restriction has been shown to decrease the incidence of metabolic diseases such as obesity and type 2 diabetes mellitus (T2DM). The mechanisms underlying the benefits of caloric restriction involved in insulin secretion and glucose homeostasis and are not fully understood. Intercellular communication within the islets of Langerhans, mediated by Connexin36 (Cx36) gap junctions, regulates insulin secretion dynamics and glucose homeostasis. The goal of this study was to determine if caloric restriction can protect against decreases in Cx36 gap junction coupling and altered islet function induced in models of obesity and prediabetes. C57BL6 mice were fed with a high fat diet (HFD), showing indications of prediabetes after 2 months, including weight gain, insulin resistance, and elevated fasting glucose and insulin levels. Subsequently, mice were submitted to one month of 40% caloric restriction (2g/day of HFD). Mice under 40% caloric restriction showed reversal in weight gain and recovered insulin sensitivity, fasting glucose and insulin levels. In islets of mice fed the HFD, caloric restriction protected against obesity-induced decreases in gap junction coupling and preserved glucose-stimulated calcium signaling, including Ca2+ oscillation coordination and oscillation amplitude. Caloric restriction also promoted a slight increase in glucose metabolism, as measured by increased NAD(P)H autofluorescence, as well as recovering glucose-stimulated insulin secretion. We conclude that declines in Cx36 gap junction coupling that occur in obesity can be completely recovered by caloric restriction and obesity reversal, improving Ca2+ dynamics and insulin secretion regulation. This suggests a critical role for caloric restriction in the context of obesity to prevent islet dysfunction.

physiology↗

bioRxiv2019

Islet architecture controls synchronous β cell response to glucose in the intact mouse pancreas in vivo

The spatial architecture of the islets of Langerhans is hypothesized to facilitate synchronized insulin secretion between {beta} cells, yet testing this in vivo in the intact pancreas is challenging. Robo {beta}KO mice, in which the genes Robo1 and Robo2 are deleted selectively in {beta} cells, provide a unique model of altered islet spatial architecture without loss of {beta} cell differentiation or islet damage from diabetes. Combining Robo {beta}KO mice with intravital microscopy, we show here that Robo {beta}KO islets lose synchronized intra-islet Ca2+ oscillations between {beta} cells in vivo. We provide evidence that this loss is not due to a {beta} cell-intrinsic function of Robo, loss of Connexin36 gap junctions, or changes in islet vascularization, suggesting that the islet architecture itself is required for synchronized Ca2+ oscillations. These results have implications for understanding structure-function relationships in the islets during progression to diabetes as well as engineering islets from stem cells.

developmental biology↗

bioRxiv2019

How heterogeneity in glucokinase and gap junction coupling determines the islet electrical response

Understanding how cell sub-populations in a tissue impact the function of the overall system is often challenging. There is extensive heterogeneity among insulin-secreting {beta}-cells within islets of Langerhans, including their insulin secretory response and gene expression profile; and this heterogeneity can be altered in diabetes. Several studies have identified variations in nutrient sensing between {beta}-cells, including glucokinase (GK) levels, mitochondrial function or expression of genes important for glucose metabolism. Sub-populations of {beta}-cells with defined electrical properties can disproportionately influence islet-wide free-calcium activity ([Ca2+]) and insulin secretion, via gap junction electrical coupling. However, it is poorly understood how sub-populations of {beta}-cells with altered glucose metabolism may impact islet function. To address this, we utilized a multicellular computational model of the islet in which a population of cells deficient in GK activity and glucose metabolism was imposed on the islet, or where {beta}-cells were heterogeneous in glucose metabolism and GK kinetics were altered. This included simulating Glucokinase gene (GCK) mutations that cause monogenic diabetes. We combined these approaches with experimental models in which gck was genetically deleted in a population of cells or GK was pharmacologically inhibited. In each case we modulated gap junction electrical coupling. Both the simulated islet and the experimental system required 30-50% of the cells to have near-normal glucose metabolism. Below this number, the islet lacked any glucose-stimulated [Ca2+] elevations. In the absence of electrical coupling the change in [Ca2+] was more gradual. As such, given heterogeneity in glucose metabolism, electrical coupling allows a large minority of cells with normal glucose metabolism to promote glucose-stimulated [Ca2+]. If insufficient numbers of cells are present, which we predict can be caused by a subset of GCK mutations that cause monogenic diabetes, electrical coupling exacerbates [Ca2+] suppression. This demonstrates precisely how heterogeneous {beta}-cell populations interact to impact islet function.\n\nSIGNIFICANCEBiological tissues contain heterogeneous populations of cells. Insulin-secreting {beta}-cells within the islets of Langerhans are critical for regulating blood glucose homeostasis. {beta}-cells are heterogeneous but it is unclear how the islet response is impacted by different cell populations and their interactions. We use a multicellular computational model and experimental systems to predict and quantify how cellular populations defined by varied glucose metabolism interact via electrical communication to impact islet function. When glucose metabolism is heterogeneous, electrical coupling is critical to promote electrical activity. However, when cells deficient in glucose metabolism are in the majority, electrical activity is completely suppressed. Thus modulating electrical communication can promotes islet electrical activity, following dysfunction caused by gene mutations that impact glucose metabolism.

biophysics↗