Improved signaling as a result of randomness in synaptic vesicle release.

The probabilistic nature of neurotransmitter release in synapses is believed to be one of the most significant sources of noise in the central nervous system. We show how p0, the probability of release per docked vesicle when an action potential arrives, affects the dynamics of the rate of vesicle release in response to changes in the rate of arrival of action potentials. Furthermore, we examine the theoretical capability of a synapse in the estimation of desired signals using information from the stochastic vesicle release events under the framework of optimal linear filter theory. We find that a small p0, such as 0.1, reduces the error in the reconstruction of the input, or in the reconstruction of the time derivative of the input, from the time series of vesicle release events. Our results imply that the probabilistic nature of synaptic vesicle release plays a direct functional role in synaptic transmission.

Robust phase-waves in chains of half-center oscillators.

Many neuronal circuits driving coordinated locomotion are composed of chains of half-center oscillators (HCOs) of various lengths. The HCO is a common motif in central pattern generating circuits (CPGs); an HCO consists of two neurons, or two neuronal populations, connected by reciprocal inhibition. To maintain appropriate motor coordination for effective locomotion over a broad range of frequencies, chains of CPGs must produce approximately constant phase-differences in a robust manner. In this article, we study phase-locking in chains of nearest-neighbor coupled HCOs and examine how the circuit architecture can promote phase-constancy, i.e., inter-HCO phase-differences that are frequency-invariant. We use two models with different levels of abstraction: (1) a conductance-based model in which each neuron is modeled by the Morris-Lecar equations (the ML-HCO model); and (2) a coupled phase model in which the state of each HCO is captured by its phase (the phase-HCO model). We show that one of four phase-waves with inter-HCO phase-differences at approximately 0, 25, 50 or 75 % arises robustly as a result of the inter-HCO connection topology, and its robust existence is not affected by the number of HCOs in the chain, the difference in strength between the ascending and descending nearest-neighbor connections, or the number of nearest-neighbor connections. Our results show that the internal anti-phase structure of the HCO and an appropriate inter-HCO connection topology together can provide a mechanism for robust (i.e., frequency-independent) limb coordination in segmented animals, such as the 50 % interlimb phase-differences in the tripod gate of stick insects and cockroaches, and the 25 % interlimb phase-differences in crayfish and other long-tailed crustaceans during forward swimming.

Neural mechanism of optimal limb coordination in crustacean swimming.

A fundamental challenge in neuroscience is to understand how biologically salient motor behaviors emerge from properties of the underlying neural circuits. Crayfish, krill, prawns, lobsters, and other long-tailed crustaceans swim by rhythmically moving limbs called swimmerets. Over the entire biological range of animal size and paddling frequency, movements of adjacent swimmerets maintain an approximate quarter-period phase difference with the more posterior limbs leading the cycle. We use a computational fluid dynamics model to show that this frequency-invariant stroke pattern is the most effective and mechanically efficient paddling rhythm across the full range of biologically relevant Reynolds numbers in crustacean swimming. We then show that the organization of the neural circuit underlying swimmeret coordination provides a robust mechanism for generating this stroke pattern. Specifically, the wave-like limb coordination emerges robustly from a combination of the half-center structure of the local central pattern generating circuits (CPGs) that drive the movements of each limb, the asymmetric network topology of the connections between local CPGs, and the phase response properties of the local CPGs, which we measure experimentally. Thus, the crustacean swimmeret system serves as a concrete example in which the architecture of a neural circuit leads to optimal behavior in a robust manner. Furthermore, we consider all possible connection topologies between local CPGs and show that the natural connectivity pattern generates the biomechanically optimal stroke pattern most robustly. Given the high metabolic cost of crustacean swimming, our results suggest that natural selection has pushed the swimmeret neural circuit toward a connection topology that produces optimal behavior.

Impact of 2009 American Recovery and Reinvestment Act (ARRA) health center investments on disadvantaged neighborhoods after recession.

BACKGROUND: Federally qualified health centers (FQHCs) are integral to the U.S. healthcare safety net and uniquely situated in disadvantaged neighborhoods. The 2009 American Recovery and Reinvestment Act (ARRA) invested $2 billion in FQHC stimulus during the Great Recession; but it remains unknown whether this investment was associated with extended benefits for disadvantaged neighborhoods. METHODS: We used a propensity-score matched longitudinal design (2008-2012) to examine whether the 2009 ARRA FQHC investment was associated with local jobs and establishments recovery in FQHC neighborhoods. Job change data were obtained from the Longitudinal Employer-Household Dynamics (LEHD) survey and calculated as an annual rate per 1,000 population. Establishment change data were obtained from the National Neighborhood Data Archive (NaNDA) and calculated as an annual rate per 10,000 population. Establishment data included 4 establishment types: healthcare services, eating/drinking places, retail establishments, and grocery stores. Fixed effects were used to compare annual rates of jobs and establishments recovery between ARRA-funded FQHC census tracts and a matched control group. RESULTS: Of 50,381 tracts, 2,223 contained ≥ 1 FQHC that received ARRA funding. A higher proportion of FQHC tracts had an extreme poverty designation (11.6% vs. 5.4%), high unemployment rate (45.4% vs. 30.3%), and > 50% minority racial/ethnic composition (48.1% vs. 36.3%). On average, jobs grew at an annual rate of 3.84 jobs per 1,000 population (95% CI: 3.62,4.06). In propensity-score weighted models, jobs in ARRA-funded tracts grew at a higher annual rate of 4.34 per 1,000 (95% CI: 2.56,6.12) relative to those with similar social vulnerability. We observed persistent decline in non-healthcare establishments (-1.35 per 10,000; 95% CI: -1.68,-1.02); but did not observe decline in healthcare establishments. CONCLUSIONS: Direct funding to HCs may be an effective strategy to support healthcare establishments and some jobs recovery in disadvantaged neighborhoods during recession, reinforcing the important multidimensional roles HCs play in these communities. However, HCs may benefit from additional investments that target upstream determinants of health to mitigate uneven recovery and neighborhood decline.

Phase response properties of half-center oscillators.

We examine the phase response properties of half-center oscillators (HCOs) that are modeled by a pair of Morris-Lecar-type neurons connected by strong fast inhibitory synapses. We find that the two basic mechanisms for half-center oscillations, "release" and "escape", give rise to strikingly different phase response curves (PRCs). Release-type HCOs are most sensitive to perturbations delivered to cells at times when they are about to transition from the active to the suppressed state, and PRCs are dominated by a large negative peak (phase delays) at corresponding phases. On the other hand, escape-type HCOs are most sensitive to perturbations delivered to cells at times when they are about to transition from the suppressed to the active state, and PRCs are dominated by a large positive peak (phase advances) at corresponding phases. By analyzing the phase space structure of Morris-Lecar-type HCO models with fast synaptic dynamics, we identify the dynamical mechanisms underlying the shapes of the PRCs. To demonstrate the significance of the different shapes of the PRCs for the release-type and escape-type HCOs, we link the shapes of the PRCs to the different frequency modulation properties of release-type and escape-type HCOs, and we show that the different shapes of the PRCs for the release-type and escape-type HCOs can lead to fundamentally different phase-locking dynamics.

Hyperglycemia Associated With Raynaud Phenomenon and Liver Dysfunction After COVID-19 Vaccination in Type 1 Diabetes Mellitus.

Background/Objective: The association of COVID-19 vaccinations and the changes in glycemic control remains debatable. We report a case of a patient with type 1 diabetes mellitus (DM) with previously well-controlled glucose on a hybrid closed-loop insulin pump who developed significant glucose variation, new onset Raynaud phenomenon, and liver dysfunction after the vaccination. Case Report: A 33-year-old man with type 1 DM since the age of 5 years was on an insulin pump for 17 years. He had a reasonable controlled glucose level with a hemoglobin A1c level of 6.8% (51 mmol/mol). Three days after he received the COVID-19 vaccination, his glucose level started to fluctuate in the range of 46 to 378 mg/dL with 3.5 times higher total daily insulin requirement. The patient developed white-pale cold hands, weight gain, fatigue, and liver dysfunction. Computed tomography of the abdomen revealed mild hepatomegaly, and laboratory workup was negative for hepatitis. One month later, his glucose level became better controlled, and his liver function improved. Continuous glucose monitoring revealed that his glucose profile returned to baseline after 6 weeks. Discussion: COVID-19 vaccination resulted in significant glucose variation and fluctuations in this patient. It could be explained by the vaccine-induced immune response causing an increase in insulin resistance, such as in adipose tissue and muscle cells. Immune stimulation could have also caused the abnormal liver function and explain his new onset Raynaud phenomenon. Conclusion: We described, for the first time, the long-term continuous glucose monitoring glucose profile with a hybrid closed-loop system in type 1 DM after COVID-19 vaccination. Clinicians need to keep alert to glycemic excursion and side effects after immunization in type 1 DM.