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Excitatory inputs to CA1 interneurons show selective synaptic dynamics.

The dynamic properties of synapses between neurons in the hippocampal CA1 area are important for the frequency-dependent signal transfer of the network. We have examined the synaptic dynamics of excitatory inputs to CA1 interneurons and pyramidal cells using whole cell voltage-clamp recordings. The CA1 network was activated using extracellular stimulation electrodes at the Schaffer collaterals (feedforward activation) or at the Alveus (activation of the feedback loop). The dynamic properties of input from the Schaffer collaterals to CA1 interneurons (basket and bistratified cells) were different from the synaptic dynamics of input from the Alveus. Synaptic input from the Schaffer collaterals to CA1 interneurons showed facilitation for most frequencies. After 10 stimuli the synaptic response reached a plateau level that was approximately 150% of the first response in the train. In contrast, the plateau levels of Alveus inputs to interneurons were not different from the first responses for frequencies <or=40 Hz. Paired-pulse facilitation of Schaffer input was stronger than for Alveus input. Cells in stratum oriens with horizontal dendritic trees appeared to be a special group of interneurons because Alveus input to these cells showed strong facilitation with plateau levels of 200% of the first responses. Schaffer input to CA1 basket and bistratified cells showed similar synaptic dynamics compared with Schaffer input to pyramidal cells for frequencies <or=80 Hz. The synaptic dynamics of Schaffer and Alveus input depended only weakly on the stimulus intensity. The difference between the dynamics of Alveus and Schaffer input to CA1 interneurons implies that the relative contribution of feedforward and -back inhibition to network activity depends on the frequency of the input signal at the afferent fibers, adding a level of complexity to transient responses.

Animals↗

Neuronal activity in the supplementary motor area of monkeys adapting to a new dynamic environment.

To execute visually guided reaching movements, the central nervous system (CNS) must transform a desired hand trajectory (kinematics) into appropriate muscle-related commands (dynamics). It has been suggested that the CNS might face this challenging computation by using internal forward models for the dynamics. Previous work in humans found that new internal models can be acquired through experience. In a series of studies in monkeys, we investigated how neurons in the motor areas of the frontal lobe reflect the movement dynamics and how their activity changes when monkeys learn a new internal model. Here we describe the results for the supplementary motor area (SMA-proper, or SMA). In the experiments, monkeys executed visually guided reaching movements and adapted to an external perturbing force field. The experimental design allowed dissociating the neuronal activity related to movement dynamics from that related to movement kinematics. It also allowed dissociating the changes related to motor learning from the activity related to motor performance (kinematics and dynamics). We show that neurons in SMA reflect the movement dynamics individually and as a population, and that their activity undergoes a variety of plastic changes when monkeys adapt to a new dynamic environment.

Action Potentials↗

Interlimb transfer of novel inertial dynamics is asymmetrical.

Mechanisms underlying interlimb transfer of adaptation to visuomotor rotations have recently been explored in depth. However, little data are available regarding interlimb transfer of adaptation to novel inertial dynamics. The present study thus investigated interlimb transfer of dynamics by examining the effect of initial training with one arm on subsequent performance with the other in adaptation to a 1.5-kg mass attached eccentrically to the forearm. Using inverse dynamic analysis, we examined the changes in torque strategies associated with adaptation to the extra mass, and with interlimb transfer of that adaptation. Following initial training with the dominant arm, nondominant arm performance improved substantially in terms of linearity and initial direction control as compared with naïve performance. However, initial training with the nondominant arm had no effect on subsequent performance with the dominant arm. Inverse dynamic analysis revealed that improvements in kinematics were implemented by increasing flexor muscle torques at the elbow to counter load-induced increases in extensor interaction torques as well as increasing flexor muscle torques at the shoulder to counter the extensor actions of elbow muscle torque. Following opposite arm adaptation, the nondominant arm adopted this dynamic strategy early in adaptation. These findings suggest that dominant arm adaptation to novel inertial dynamics leads to information that can be accessed and utilized by the opposite arm controller, but not vice versa. When compared with our previous findings on interlimb transfer of visuomotor rotations, our current findings suggest that adaptations to visuomotor and dynamic transformations are mediated by distinct neural mechanisms.

Adolescent↗

Dynamic range of neural rate responses in the ventral cochlear nucleus of awake cats.

1. Response thresholds and dynamic range properties of neurons in the ventral cochlear nucleus (VCN) of awake cats were measured by fitting a computational model to rate-level functions for best frequency (BF) tone bursts and for bursts of broad-band noise. Dynamic range measurements were performed in quiet and in the presence of continuous background noise. 2. The sample of neurons obtained in the VCN of awake cats exhibited a variety of peristimulus histograms (PSTHs) and thresholds. All PSTH response types previously described in the VCN of anesthetized cats were found in awake cats. The lowest thresholds for neural responses were observed at sound pressure levels that were equivalent to behavioral thresholds of absolute auditory sensitivity. 3. When responses to BF tones or bursts of broad-band noise were recorded in quiet backgrounds, the dynamic range properties of most units in the VCN of awake cats were not significantly different from dynamic range properties of auditory nerve fibers (ANFs) in anesthetized cats or VCN units in decerebrate cats. All auditory units showed a larger dynamic range for noise bursts than for tone bursts, but VCN units with primary-like and onset PSTHs showed larger dynamic ranges for responses to noise bursts than that of ANFs and VCN chopper units. 4. When tests were performed in the presence of continuous noise, rate-level functions for BF tone bursts shifted to higher tone levels and showed a more compressed range of driven rates in comparison with data obtained in quiet. Compression of the rate-level function in noise resulted from an increase in driven rate at low tone levels and a decrease in rate at high tone levels. These changes in the rate-level function suggest that noise may reduce the range of BF tone levels that are potentially encoded by a unit's rate responses. By exhibiting larger shifts and less compression in background noise, VCN units in awake cats better preserved the dynamic range of their rate responses to BF tones than ANFs in anesthetized cats or VCN units in decerebrate cats. 5. Rate-level functions were obtained from a small sample of VCN units not only with the cat performing the behavioral task but also with the cat awake and sitting quietly in the testing apparatus. No differences in noise-induced shift or compression were noted between the two testing conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Acoustic Stimulation↗

Dynamic and static conditioning pressures evoke equivalent rapid resetting in rat aortic baroreceptors.

A recent study suggested that exposure of carotid sinus baroreceptors to pulsatile pressures for a period of minutes can decrease the static threshold pressure at which they begin to discharge; that is, the exposure can sensitize baroreceptors. Another study found that the rapid resetting of carotid sinus baroreceptors to elevated conditioning pressures was reduced or eliminated by pulsatile conditioning. In the present study, we tested the responses of aortic baroreceptors in an in vitro preparation to a range of static and dynamic conditioning pressures lasting 15 minutes. Slow test ramps of increasing pressure were used to assess static discharge properties (threshold and gain). To be accepted for analysis (n = 12), each baroreceptor had to successfully complete static and dynamic test sequences for at least three different conditioning mean arterial pressure levels. We measured aortic diameter simultaneously with pressure and baroreceptor discharge. Generally, we found no significant difference between the static pressure threshold measured before and after dynamic conditioning. The static pressure threshold was linearly related to the mean level of the conditioning pressure, and no differences in the slopes of these relations (a measure of the ability of a baroreceptor to rapidly reset) were found between static and dynamic conditioning. After dynamic conditioning, discharge rates returned to near control levels in all cases within a few seconds of the return to static conditioning. Two baroreceptors exposed to the vasodilator nitroprusside throughout the experiment showed similar results. Diameter measurements indicated no role of vessel diameter changes during dynamic or static conditioning. In conclusion, we found no evidence of a long-lasting sensitization of aortic baroreceptors by dynamic pressure inputs.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

Differential inspiratory muscle pressure contributions to breathing during dynamic hyperinflation.

During dynamic hyperinflation, the ventilatory pump is facing increased demand because it must overcome the intrinsic positive end-expiratory pressure (PEEPi) and decreased capacity since it must operate at a dynamically increased end-expiratory lung volume (EELV). The aim of this study was to evaluate the relative pressure contribution by the diaphragm and inspiratory rib cage muscles (RCMs) during dynamic hyperinflation. In six healthy subjects, dynamic hyperinflation was induced by limiting expiratory flow. The global inspiratory muscle pressure (delta Pmus,i) and transdiaphragmatic pressure (delta Pdi) were partitioned into the portion used to overcome PEEPi and the portion used to inflate the respiratory system. The delta Pdi/delta Pmus,i ratio was used to estimate the pressure contribution of RCMs relative to that of the diaphragm. Our results suggest that (1) with increasing severity of dynamic hyperinflation, there is a significant increase in the inspiratory pressure contribution of RCMs relative to that of the diaphragm for inflating the respiratory system; (2) during dynamic hyperinflation, especially at high EELV, the major pressure contribution of the diaphragm is to overcome the PEEPi-imposed inspiratory threshold load, whereas the inspiratory pressure needed for the subsequent task of inflating the respiratory system is largely contributed by RCMs. This arrangement is consistent with the change in mechanical advantages of RCMs and the diaphragm during the development of dynamic hyperinflation.

Humans↗

Ventilator-induced overdistension in children: dynamic versus low-flow inflation volume-pressure curves.

We applied to 20 paralyzed ventilated children (0.15 to 14.3 yr, six with acute respiratory distress syndrome [ARDS]) the low-flow inflation (LFI) technique providing quasi-static volume-pressure (V-P) curves and compared the assessment of overdistension (OD) on dynamic and LFI (reference) inspiratory V-P curves. Dynamic curves were obtained at the airway opening during regular constant flow ventilation (Servo 300). Then LFI curves were obtained. Two analyses were performed: First, the nonlinear coefficient c of a second order polynomial equation (SOPE) fitted to dynamic data obtained during constant flow was compared with the c of SOPE fitted to LFI curve (within tidal volume [VT]). Second, the dynamic C20/C (ratio of compliance of the last 20% of the curve (C20) to total compliance [C]) was compared with the determination of the upper inflection point (UIP) on the LFI curve. OD was defined as a negative value of c, a C20/C < 0.80, an UIP included within the VT range for that child during regular ventilation. Using LFI V-P curves as reference, SOPE offered a better detection of OD than dynamic C20/C or the determination of the UIP by graphical means. Indeed the first analysis showed a substantial agreement (kappa 0.75) between dynamic c and LFI c detection of OD whereas the second analysis showed a poor agreement (kappa 0.22) between C20/ C and LFI detection of the UIP. In conclusion, quasi-static V-P curves can easily be obtained in children with the LFI technique. SOPE offers a good detection of OD on dynamic and LFI V-P curves but the C20/C index seems to be an inadequate measure of OD.

Adolescent↗

Effects of pharmacologically manipulated amplitude and starting point on edinger-westphal-stimulated accommodative dynamics in rhesus monkeys.

PURPOSE: The aim of this study was to determine whether pharmacologically manipulated resting refraction, amplitude, and starting point affect accommodative and disaccommodative dynamics in anesthetized adolescent rhesus monkeys. METHODS: Pilocarpine and atropine were applied topically to manipulate resting refraction, accommodative amplitude, starting point, and end point in two monkeys with permanent electrodes in the Edinger-Westphal nucleus. Accommodation was centrally stimulated with submaximal and maximal current amplitudes. Dynamic accommodative responses were measured with infrared photorefraction before and during the course of action of the drugs. Accommodative and disaccommodative dynamics were analyzed in terms of peak velocity as a function of amplitude, starting point, and end point. RESULTS: Pilocarpine caused a myopic shift in resting refraction of 11.62 +/- 1.17 D. Centrally stimulated accommodative amplitude was 10.08 +/- 1.15 D before pilocarpine and 0.68 +/- 0.29 D after pilocarpine. Changes were found in accommodative dynamics as a function of starting point and in disaccommodative dynamics as a function of amplitude and end point. Accommodative amplitude was 11.25 +/- 0.18 D before atropine administration and 0.52 +/- 0.11 D after atropine administration. Accommodative dynamics as a function of amplitude were not substantially altered during the course of pilocarpine-induced accommodation or atropine-induced cycloplegia. CONCLUSIONS: Accommodative response amplitude is reduced with pilocarpine by shifting the eye to a more myopic state and with atropine by cycloplegia. Pharmacologic manipulations showed that accommodative and disaccommodative dynamics in anesthetized monkeys depend on amplitude, starting point, and end point of the response and on the contributions of neural and receptor activity.

Accommodation, Ocular↗

Dynamic measures of visual function and their relationship to self-report of visual functioning.

PURPOSE: The purpose of this analysis was to determine whether dynamic measures of vision, such as dynamic acuity and motion threshold, are independently associated with self-reported difficulty in activities involving vision. METHODS: Data were used from the third round of the Salisbury Eye Evaluation (n = 1198), a longitudinal, population-based study of older adults. Multiple measures of visual function were tested, including dynamic acuity, motion threshold, visual acuity, contrast sensitivity, visual fields, and stereoacuity. Difficulty was assessed using the Activities of Daily Vision Scale (ADVS). Polytomous logistic regression procedures were used to determine log odds ratios for the dynamic measures of vision while adjusting for demographic, health, and other measures of vision. RESULTS: In fully adjusted models including other vision variables, worse dynamic acuity was associated with greater difficulty on the near-vision ADVS subscale (beta = 0.68, P < 0.01), but not with the overall ADVS or the far-vision or night-driving subscales (P > 0.05). Motion threshold was not associated with the overall ADVS or any of the subscales after controlling for other vision variables, although it was associated when no other vision variables were in the models. CONCLUSIONS: Motion threshold was not independently associated with any ADVS difficulty. Dynamic acuity was independently associated with self-reported difficulty with near-vision tasks only. Other studies should confirm this association. If confirmed, strategies to improve dynamic acuity could be developed to try to reduce difficulty with tasks involving near vision.

Aged↗

Static and dynamic rigidities of normal and sickle erythrocytes. Major influence of cell hemoglobin concentration.

Static and dynamic deformabilities of erythrocytes are important determinants of microcirculatory blood flow. To determine the influence of increased cellular hemoglobin concentration on these properties, we quantitated static and dynamic deformabilities of isolated subpopulations of oxygenated normal and sickle erythrocytes with defined cell densities using micromechanical manipulations of individual cells. The rheological properties measured to characterize static deformability were membrane extensional rigidity and bending rigidity. To characterize dynamic deformability of the cells, we measured the time constants for rapid elastic recovery from extensional and bending deformations. The extensional rigidity of sickle cells increased with increasing cell hemoglobin concentration while that of normal cells was independent of the state of cell hydration. Moreover, sickle cells were found to exhibit inelastic behavior at much lower cell hemoglobin concentrations than normal cells. In contrast, the dynamic rigidity of both normal and sickle cells was increased to the same extent at elevated hemoglobin concentrations. Moreover, this increase in dynamic rigidity with increasing cellular dehydration was much more pronounced than that seen for static rigidity. Both the increased static and dynamic rigidities of the dehydrated sickle cells could be greatly improved by hydrating the cells. This suggests that increased bulk hemoglobin concentration, which is perhaps inordinately increased adjacent to the membrane, plays a major role in regulating the rigidity of sickle cells. In addition, irreversible membrane changes also appear to accompany cell dehydration in vivo, resulting in increased membrane shear rigidity and plastic flow. We expect that the marked increases in rigidity of dehydrated sickle cells observed here may have a major influence on the dynamics of their circulation in the microvasculature.

Anemia, Sickle Cell↗

Dynamic dead space in face masks used with noninvasive ventilators: a lung model study.

The aim of this study was to determine what the influence of different designs of face masks and different noninvasive ventilator modes would be upon total dynamic dead space. Using a spontaneous breathing model, total dynamic dead space was measured when using 19 commercially available face masks and a range of ventilators in various ventilation modes. Total dynamic dead space during spontaneous ventilation was increased above physiological dead space from 32% to 42% of tidal volume by using face masks. The use of noninvasive ventilation modes such as bilevel and continuous positive airway pressure, with continuous pressure throughout the expiratory phase, reduced total dynamic dead space to approach physiological dead space with most face masks. Pressure assist and pressure support ventilation decreased total dynamic dead space to a lesser degree, from 42% to 39% of tidal volume. Face masks with expiratory ports over the nasal bridge resulted in beneficial flow characteristics within the face mask and nasal cavity, so as to decrease total dynamic dead space to less than physiological dead space from 42% to 28.5% of tidal volume. Exhaust ports over the nasal bridge in face masks effect important decreases in dynamic dead space provided positive pressure throughout the expiratory phase is used.

Equipment Design↗

A method for estimation of elasticities in metabolic networks using steady state and dynamic metabolomics data and linlog kinetics.

BACKGROUND: Dynamic modeling of metabolic reaction networks under in vivo conditions is a crucial step in order to obtain a better understanding of the (dis)functioning of living cells. So far dynamic metabolic models generally have been based on mechanistic rate equations which often contain so many parameters that their identifiability from experimental data forms a serious problem. Recently, approximative rate equations, based on the linear logarithmic (linlog) format have been proposed as a suitable alternative with fewer parameters. RESULTS: In this paper we present a method for estimation of the kinetic model parameters, which are equal to the elasticities defined in Metabolic Control Analysis, from metabolite data obtained from dynamic as well as steady state perturbations, using the linlog kinetic format. Additionally, we address the question of parameter identifiability from dynamic perturbation data in the presence of noise. The method is illustrated using metabolite data generated with a dynamic model of the glycolytic pathway of Saccharomyces cerevisiae based on mechanistic rate equations. Elasticities are estimated from the generated data, which define the complete linlog kinetic model of the glycolysis. The effect of data noise on the accuracy of the estimated elasticities is presented. Finally, identifiable subset of parameters is determined using information on the standard deviations of the estimated elasticities through Monte Carlo (MC) simulations. CONCLUSION: The parameter estimation within the linlog kinetic framework as presented here allows the determination of the elasticities directly from experimental data from typical dynamic and/or steady state experiments. These elasticities allow the reconstruction of the full kinetic model of Saccharomyces cerevisiae, and the determination of the control coefficients. MC simulations revealed that certain elasticities are potentially unidentifiable from dynamic data only. Addition of steady state perturbation of enzyme activities solved this problem.

Algorithms↗

Structure and evolution of protein interaction networks: a statistical model for link dynamics and gene duplications.

BACKGROUND: The structure of molecular networks derives from dynamical processes on evolutionary time scales. For protein interaction networks, global statistical features of their structure can now be inferred consistently from several large-throughput datasets. Understanding the underlying evolutionary dynamics is crucial for discerning random parts of the network from biologically important properties shaped by natural selection. RESULTS: We present a detailed statistical analysis of the protein interactions in Saccharomyces cerevisiae based on several large-throughput datasets. Protein pairs resulting from gene duplications are used as tracers into the evolutionary past of the network. From this analysis, we infer rate estimates for two key evolutionary processes shaping the network: (i) gene duplications and (ii) gain and loss of interactions through mutations in existing proteins, which are referred to as link dynamics. Importantly, the link dynamics is asymmetric, i.e., the evolutionary steps are mutations in just one of the binding parters. The link turnover is shown to be much faster than gene duplications. Both processes are assembled into an empirically grounded, quantitative model for the evolution of protein interaction networks. CONCLUSIONS: According to this model, the link dynamics is the dominant evolutionary force shaping the statistical structure of the network, while the slower gene duplication dynamics mainly affects its size. Specifically, the model predicts (i) a broad distribution of the connectivities (i.e., the number of binding partners of a protein) and (ii) correlations between the connectivities of interacting proteins, a specific consequence of the asymmetry of the link dynamics. Both features have been observed in the protein interaction network of S. cerevisiae.

Biological Evolution↗

Oxygen cost of dynamic or isometric exercise relative to recruited muscle mass.

BACKGROUND: Oxygen cost of different muscle actions may be influenced by different recruitment and rate coding strategies. The purpose of this study was to account for these strategies by comparing the oxygen cost of dynamic and isometric muscle actions relative to the muscle mass recruited via surface electrical stimulation of the knee extensors. METHODS: Comparisons of whole body pulmonary delta VO2 were made in seven young healthy adults (1 female) during 3 minutes of dynamic or isometric knee extensions, both induced by surface electrical stimulation. Recruited mass was quantified in T2 weighted spin echo magnetic resonance images. RESULTS: The delta VO2 for dynamic muscle actions, 242 +/- 128 ml x min(-1) (mean +/- SD) was greater (p = 0.003) than that for isometric actions, 143 +/- 99 ml x min(-1). Recruited muscle mass was also greater (p = 0.004) for dynamic exercise, 0.716 +/- 282 versus 0.483 +/- 0.139 kg. The rate of oxygen consumption per unit of recruited muscle (VO2(RM)) was similar in dynamic and isometric exercise (346 +/- 162 versus 307 +/- 198 ml x kg(-1) x min(-1); p = 0.352), but the VO2(RM) calculated relative to initial knee extensor torque was significantly greater during dynamic exercise 5.1 +/- 1.5 versus 3.6 +/- 1.6 ml x kg(-1) x Nm(-1) x min(-1) (p = 0.019). CONCLUSION: These results are consistent with the view that oxygen cost of dynamic and isometric actions is determined by different circumstances of mechanical interaction between actin and myosin in the sarcomere, and that muscle recruitment has only a minor role.

Journal Article↗

The interplay between interpersonal dynamics, treatment barriers, and larger social forces: an exploratory study of drug-using couples in Hartford, CT.

BACKGROUND: The drug treatment field tends to place emphasis on the individual rather than the individual in social context. While there are a growing number of studies indicating that drug-using intimate partners are likely to play an important role in determining treatment options, little attention has been given to the experience and complex treatment needs of illicit drug-using (heroin, cocaine, crack) couples. METHODS: This exploratory study used in-depth interviews and ethnographic engagement to better understand the relationship between interpersonal dynamics and the treatment experience of ten relatively stable drug-using couples in Hartford, CT. Semi-structured and open-ended qualitative interviews were conducted with each couple and separately with each partner. Whenever possible, the day-to-day realities and contexts of risk were also observed via participant and non-participant observation of these couples in the community. A grounded theory approach was used to inductively code and analyze nearly 40 transcripts of 60-90 minute interviews as well as fieldnotes. RESULTS: This study builds on a concept of complex interpersonal dynamics among drug users. Interpersonal dynamics of care and collusion were identified: couples cared for each other and colluded to acquire and use drugs. Care and collusion operate at the micro level of the risk environment. Treatment barriers and inadequacies were identified as part of the risk environment at the meso or intermediate level of analysis, and larger social forces such as gender dynamics, poverty and the "War on Drugs" were identified at the macro level. Interpersonal dynamics posed problems for couples when one or both partners were interested in accessing treatment. Structural barriers presented additional obstacles with the denial of admittance of both partners to treatment programs which had a sole focus on the individual and avoided treating couples. CONCLUSION: Detoxification and treatment facilities need to recognize the complex interplay between interpersonal dynamics which shape the treatment experience of couples, and which are also shaped by larger structural dynamics, including barriers in the treatment system. Improvements to the treatment system in general will go a long way in improving treatment for couples. Couples-specific programming also needs to be developed.

Adult↗

Geometric mechanics and the dynamics of asteroid pairs.

The purpose of this paper is to describe the general setting for the application of techniques from geometric mechanics and dynamical systems to the problem of asteroid pairs. The paper also gives some preliminary results on transport calculations and the associated problem of calculating binary asteroid escape rates. The dynamics of an asteroid pair, consisting of two irregularly shaped asteroids interacting through their gravitational potential is an example of a full-body problem or FBP in which two or more extended bodies interact. One of the interesting features of the binary asteroid problem is that there is coupling between their translational and rotational degrees of freedom. General FBPs have a wide range of other interesting aspects as well, including the 6-DOF guidance, control, and dynamics of vehicles, the dynamics of interacting or ionizing molecules, the evolution of small body, planetary, or stellar systems, and almost any other problem in which distributed bodies interact with each other or with an external field. This paper focuses on the specific case of asteroid pairs using techniques that are generally applicable to many other FBPs. This particular full two-body problem (F2BP) concerns the dynamical evolution of two rigid bodies mutually interacting via a gravitational field. Motivation comes from planetary science, where these interactions play a key role in the evolution of asteroid rotation states and binary asteroid systems. The techniques that are applied to this problem fall into two main categories. The first is the use of geometric mechanics to obtain a description of the reduced phase space, which opens the door to a number of powerful techniques, such as the energy-momentum method for determining the stability of equilibria and the use of variational integrators for greater accuracy in simulation. Second, techniques from computational dynamic systems are used to determine phase space structures that are important for transport phenomena and dynamic evolution.

Journal Article↗

Tissue differences in estrogen receptor dynamics: nuclear retention, rate of replenishment, and transient receptor loss vary in hypothalamus, pituitary, and uterus of C57BL/6J mice.

Little is known about tissue differences in estrogen receptor (ER) dynamics, despite evidence that they could play a role in the tissue specificity of estrogen action. This study was designed to test the hypothesis that ER dynamics differ in uterus (UT), pituitary (PIT), and hypothalamus (HYPO), as measured by 1) duration of peak nuclear ER (ERn), 2) rate of replenishment of cytosolic ER (ERc), and 3) loss of total ER (ERt) after a bolus of estradiol (E2). Young adult mice were studied at two hormonally distinct stages of the cycle [days 2 or 3 (D2-3) and D5 (D1 = proestrus)]. Animals were injected with a dose of E2 (0.05 microgram/10 g BW) sufficient to achieve maximal ERn or with vehicle only, and ER was determined in nuclear and cytosolic fractions 1, 2, 4, 8, 12, and 24 h later. ERn peaked concomitantly with plasma E2 at 1 h in all tissues, but the duration of peak ERn varied among tissues: 4 h in HYPO compared to 1-2 h in UT and PIT. ERc replenishment was complete by 12 h in HYPO, but not until 24 h or more in PIT; replenishment in UT was intermediate (12-24 h). The transient loss of ERt after E2 injection was pronounced in UT and PIT, but was undetectable in HYPO. These tissue differences were maintained across cycle state, despite effects of cycle state on ER dynamics. The effects of cycle state on ER dynamics were also tissue specific; they were greatest in UT and absent in HYPO. On D2-3 in UT, ERn and ERt were lower, and replenishment of ERc was slower than on D5. Parallel effects of cycle state were seen in PIT, with the exception of ERn, which was unaffected. Because altered ER dynamics similar to those observed on D2-3 can be produced by progesterone pretreatment, the altered ER dynamics on D2-3 may be a consequence of recent exposure on D1 to the ovulatory surge of progesterone. Taken together, these results indicate that the mechanisms governing intracellular ER dynamics vary markedly among tissues and provide an impetus for further examination of their role in the tissue specificity of estrogen action.

Animals↗

Insights into cytoskeletal behavior from computational modeling of dynamic microtubules in a cell-like environment.

Microtubule dynamic instability plays a fundamental role in cell biology, enabling microtubules to find and interact with randomly distributed cargo and spatially localized signals. In vitro, microtubules transition between growth and shrinkage symmetrically, consistent with the theoretical understanding of the mechanism of dynamic instability. In vivo, however, microtubules commonly exhibit asymmetric dynamic instability, growing persistently in the cell interior and experiencing catastrophe near the cell edge. What is the origin of this behavior difference? One answer is that the cell edge causes the asymmetry by inducing catastrophe in persistently growing microtubules. However, the origin of the persistent growth itself is unclear. Using a simplified coarse-grained stochastic simulation of a system of dynamic microtubules, we provide evidence that persistent growth is a predictable property of a system of nucleated, dynamic, microtubules containing sufficient tubulin in a confined space--MAP activity is not required. Persistent growth occurs because cell-edge-induced catastrophe increases the concentration of free tubulin at steady-state. Our simulations indicate that other aspects of MT dynamics thought to require temporal or spatial changes in MAP activity are also predictable, perhaps unavoidable, outcomes of the "systems nature" of the cellular microtubule cytoskeleton. These include the mitotic increase in microtubule dynamics and the observation that defects in nucleation cause changes in the behavior of microtubule plus ends. These predictions are directly relevant to understanding of the microtubule cytoskeleton, but they are also attractive from an evolutionary standpoint because they provide evidence that apparently complex cellular behaviors can originate from simple interactions without a requirement for intricate regulatory machinery.

Cell Shape↗