Behavioral adaptation is a prerequisite for survival in a constantly changing sensory environment, but the underlying strategies and relevant variables driving adaptive behavior are not well understood. Many learning models and neural theories consider probabilistic computations as an efficient way to solve a variety of tasks, especially if uncertainty is involved. Although this suggests a possible role for probabilistic inference and expectation in adaptive behaviors, there is little if any evidence of this relationship experimentally. Here, we investigated adaptive behavior in the rat model by using a well controlled behavioral paradigm within a psychophysical framework to predict and quantify changes in performance of animals trained on a simple whisker-based detection task. The sensory environment of the task was changed by transforming the probabilistic distribution of whisker deflection amplitudes systematically while measuring the animal's detection performance and corresponding rate of accumulated reward. We show that the psychometric function deviates significantly and reversibly depending on the probabilistic distribution of stimuli. This change in performance relates to accumulating a constant reward count across trials, yet it is exempt from changes in reward volume. Our simple model of reward accumulation captures the observed change in psychometric sensitivity and predicts a strategy seeking to maintain reward expectation across trials in the face of the changing stimulus distribution. We conclude that rats are able maintain a constant payoff under changing sensory conditions by flexibly adjusting their behavioral strategy. Our findings suggest the existence of an internal probabilistic model that facilitates behavioral adaptation when sensory demands change.The strategy animals use to deal with a complex and ever-changing world is a key to understanding natural behavior. This study provides evidence that rodent behavioral performance is highly flexible in the face of a changing stimulus distribution, consistent with a strategy to maintain a desired accumulation of reward.
Biochemical aspects of cellular process are well characterized, but more recently, it has been shown that cells dynamically sense and respond to biophysical cues such as substrate stiffness and geometrical constraints; physical cues even direct cell differentiation and stem cell lineage (Discher et al, Science, 2005). In hematology, we know that platelets are shear activated and attenuate force based on substrate stiffness, and that endothelial cells align with flow and are activated by shear stress. Blood cells pass through, and interact with, biological matrices such as fibrin clots and the vascular wall, but the physical and biochemical aspects of these interactions are indistinguishable from one another in vivo. As such, there is a gap in knowledge as to how blood cells respond to matrices as they transit through them. To decouple the physical and biochemical interactions of blood cells and biological matrices, we sought to recreate the physical geometry of a fibrin network in a controlled, non-biological, in vitro microfluidic system. To this end, we designed a two-part microfluidic device comprised of an array of micron sized pillars (~1 µm diameter, 3 µm height, and 2 µm gap between pillars) overlaid with a microfluidic channel (Fig 1). The dimensions of the pillars are on the order of the diameter of fibrin fibers and the mesh size of a fibrin gel (Okada et al, J. Biol. Chem, 1985), while channels of various dimensions can be bonded over the pillar array to represent various biological scenarios. Standard microfluidic processes cannot produce pillars with the feature sizes reported herein, so electron beam lithography was used to create the mold from which the elastomeric pillars are made. The biophysical interaction of platelets flowing through fibrin mesh (absent biological factors) was recreated by a pillar array oriented perpendicular to the direction of flow in a 6 µm tall channel. When washed platelets are perfused through the system, they adhere to the pillars, aggregate, and form an occlusive mass that extends to the edges of the array (Fig 2A). Platelet adhesion initiates exclusively at the pillars and aggregation propagates to the extents of the channel area perpendicular to flow, resulting in channel occlusion and flow cessation. These findings show that in the absence of platelet agonists and biological ligands, platelets are activated by the shear environment afforded by the presence of fibrin fibers. Thus, in addition to the biochemical players in clot formation, the geometry of the fibrin mesh plays a role in platelet adhesion, and clot propagation. As expected, passive adsorption of fibrinogen and collagen to the pillar surfaces enhances platelet aggregation, as evidenced by a decrease in time to channel occlusion from 10 min to 2 min and 6 min, respectively. With thus we see the synergistic effect of biophysical and biochemical factors in clot propagation. This novel microfluidic system both separates biophysical and biochemical aspects of clot formation and allows researchers to specify the precise location and extent of clot formation in vitro. Platelets are not the only blood cells to interact with and react to physical barriers. Red blood cell (RBC) deformation has been historically studied in single cell assays, SEM studies of fixed clots, and more recently after RBCs have passed through a filtration system comprised of either beads or long slits (Deplaine et al, Blood, 2010); however, real time visualization of RBC deformation in geometries representative of biological matrices has remained elusive. The deformation (and possible fragmentation) that RBCs undergo when passing through the physical challenges of a fibrin matrix or the interendothelial slits of the spleen can be visualized in our system: an array of pillars overlaid by a 3 µm channel. Our findings visually suggest that red blood cells are able to deform through the matrix with little effect on their membranes, and that exposure to high shear gradients alone does not cause cell fragmentation (Figure 2B). The ready deformation and transit of healthy RBCs in our system confirms recent computational studies of RBC filtration by the spleen (Pivkin et al, PNAS, 2016). Further studies will give insight into the deformation and transit of sickled cells and malaria infected RBCs in physical matrices. Overall, our microfluidic studies give novel insight into the biophysical aspect of blood cell interactions with biological matrices. Disclosures Lam: Sanguina, LLC: Equity Ownership.
Blood cells circulate in a dynamic fluidic environment, and during hematologic processes such as hemostasis, thrombosis, and inflammation, blood cells interact biophysically with a myriad of vascular matrices-blood clots and the subendothelial matrix. While it is known that adherent cells physiologically respond to the mechanical properties of their underlying matrices, how blood cells interact with their mechanical microenvironment of vascular matrices remains poorly understood. To that end, we developed microfluidic systems that achieve high fidelity, high resolution, single-micron PDMS features that mimic the physical geometries of vascular matrices. With these electron beam lithography (EBL)-based microsystems, the physical interactions of individual blood cells with the mechanical properties of the matrices can be directly visualized. We observe that the physical presence of the matrix, in and of itself, mediates hematologic processes of the three major blood cell types: platelets, erythrocytes, and leukocytes. First, we find that the physical presence of single micron micropillars creates a shear microgradient that is sufficient to cause rapid, localized platelet adhesion and aggregation that leads to complete microchannel occlusion; this response is enhanced with the presence of fibrinogen or collagen on the micropillar surface. Second, we begin to describe the heretofore unknown biophysical parameters for the formation of schistocytes, pathologic erythrocyte fragments associated with various thrombotic microangiopathies (poorly understood, yet life-threatening blood disorders associated with microvascular thrombosis). Finally, we observe that the physical interactions with a vascular matrix is sufficient to cause neutrophils to form procoagulant neutrophil extracellular trap (NET)-like structures. By combining electron beam lithography (EBL), photolithography, and soft lithography, we thus create microfluidic devices that provide novel insight into the response of blood cells to the mechanical microenvironment of vascular matrices and have promise as research-enabling and diagnostic platforms.
Background: Regional anesthesia (“block”) is an important component of upper extremity (UE) surgery pain control. However, little is known about patient experience related to perioperative opioid use. This study assessed patient-reported pain control and satisfaction with UE blocks and evaluated how opioid consumption impacted these outcomes before the block “wore off.” Methods: A postoperative phone survey was administered to patients who underwent outpatient UE surgery at a surgery center for more than 16 months. It assessed pain scores (scale 1-10), satisfaction with block duration (scale 1-5), duration until return of UE function, and opioid consumption. Analyses used Mann-Whitney U tests, Fisher exact tests, and bivariate and multivariable linear and ordered logistic regressions to understand relationships between opioid use and outcomes. Results: A total of 509 patients (61%) completed the survey, and 441 (88%) were satisfied with block duration. Initial and final pain scores were significantly higher in patients who took opioids prior to the block wearing off (6 and 4.5, P = .04 and 3.5 and 2, P = .002, respectively). Although satisfaction with block duration was not different in group comparisons (ie, patients who premedicated vs those who did not), in a multivariable analysis, patients who premedicated with opioids had 78% increased odds of reporting the highest level of satisfaction compared with the lower 4 levels ( P = .03). Conclusions: Upper extremity blocks are associated with high overall patient satisfaction and postsurgical pain control. Premedicating before the block wears off may increase patient satisfaction with block duration even if pain is not notably impacted.
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