Subchronic-intermittent caffeine amplifies the motor effects of amphetamine in rats

Summary. Caffeine, the most widely consumed psychostimulant drug, acutely stimulates motor behaviour and enhances dopamine agonists actions whilst chronically it induces tolerance to either caffeine- or dopamine agonist-induced motor activating effects. The present study examined whether subchronic caffeine administration (15 mg/kg, on alternate days for 14 days) induces enduring modifications in caffeine- and amphetamine-mediated motor activity. To this end, motor activation and rotational behaviour stimulated by either caffeine or D-amphetamine (0.5, 2 mg/kg), given 3 days after the last caffeine administration, were evaluated in neurologically intact and unilaterally 6-hydroxydopamine-lesioned rats respectively. Subchronic caffeine resulted in an increase in caffeine-induced motor and turning behaviour. Furthermore, caffeine pretreatment potentiated the motor effects of amphetamine in both intact and 6-hydroxydopamine-lesioned rats. These results suggest that subchronic caffeine treatment results in an enhancement of its motor stimulant effects, rather than in tolerance, and induces neuroadaptive facilitatory changes in dopamine transmission.     

Some models for selection of biological macromolecules with time varying constraints

We consider some models for selection in self-reproducing macromolecular systems subject to time varying environmental constraints. We show that many of the results concerning selection obtained previously for stationary constraints may be generalized and that the over-all selective behaviour even in complex enzyme coupled systems is basically the same under the time varying external conditions as it is in the stationary case.     

Theories of rotary motors

The bacterial flagellar motor and the ATP-hydrolysing F1 portion of the F1Fo-ATPase are known to be rotary motors, and it seems highly probable that the H+-translocating Fo portion rotates too. The energy source in the case of Fo and the flagellar motor is the flow of ions, either H+ (protons) or Na+, down an electrochemical gradient across a membrane. The fact that ions flow in a particular direction through a well-defined structure in these motors invites the possibility of a type of mechanism based on geometric constraints between the rotor position and the paths of ions flowing through the motor. The two best-studied examples of such a mechanism are the ''turnstile'' model of Khan and Berg and the ''proton turbine'' model of Läuger or Berry. Models such as these are typically represented by a small number of kinetic states and certain allowed transitions between them. This allows the calculation of predictions of motor behaviour and establishes a dialogue between models and experimental results. In the near future structural data and observations of single-molecule events should help to determine the nature of the mechanism of rotary motors, while motor models must be developed that can adequately explain the measured relationships between torque and speed in the flagellar motor.     

Life history reaction norms to time constraints in a damselfly: differential effects on size and mass

Optimality models predict that, under a time constraint, organisms should accelerate development, and preferably so by increasing growth rate, to keep size at emergence constant. Unfortunately, most tests did neglect genetic constraints and interchanged mass with body size which may explain mixed support for some of the models' predictions. We imposed time constraints on full sibling larvae of the damselfly Enallagma cyathigerum by manipulating day length regimes. Under a time constraint, larval development and growth rate based on size indeed were faster. This made it possible to keep size at emergence constant, despite the shorter development time. Interestingly, under a time constraint, growth rate based on mass was not increased and larvae had a lower mass at emergence. We see two reasons for this difference between body mass and size. First, size is fixed at emergence, while mass can still increase in many insects. Secondly, genetic constraints may have contributed to different responses for size and mass. In general, our results strongly suggest discriminating between size and mass when testing life history responses.  © 2004 The Linnean Society of London, Biological Journal of the Linnean Society , 2004, 83 , 187–196.     

Mapping the complexity of ecological models

We propose to define the complexity of an ecological model as the statistical complexity of the output it produces. This allows for a direct comparison between data and model complexity. Working with univariate time series, we show that this measure ‘blindly’ discriminates among the different dynamical behaviours a model can exhibit. We then search a model parameter space in order to segment it into areas of different dynamical behaviour and calculate the maximum complexity a model can generate. Given a time series, and the problem of choosing among a number of ecological models to study it, we suggest that models whose maximum complexity is lower than the time series complexity should be disregarded because they are unable to reconstruct some of the structures contained in the data. Similar reasoning could be used to disregard models’ subdomains as well as areas of unnecessary high complexity. We suggest that model complexity so defined better captures the difficulty faced by a user in managing and understanding the behaviour of an ecological model than measures based on a model ‘size’.     

运动过程的网络逻辑——从离子通道到动物行为

为了揭示神经网络在脊椎动物运动中所行使的内在功能,作者开发了七鳃鳗这种低等脊椎动物模型。在这套系统中,不仅可以了解到运动模式生成网络以及激活此网络的命令系统,同时还可以在运动中研究方向控制系统和变向控制系统。七鳃鳗的神经系统有较少的神经元,而且运动行为中的不同运动模式可以由分离的神经系统所引发。模式生成神经网络包括同侧的谷氨酸能中间神经元和对侧的抑制性甘氨酸能中间神经元。网络中的突触连接、细胞膜特性和神经递质都也已经被鉴定。运动是由脑干区域的网状脊髓神经元所引起,而这些神经元又是被问脑和中脑分离的一些运动命令神经元群所控制。因此,运动行为最初是由这两个“运动核心”所启动。而这两个运动核心被基底神经节调控,基底神经节即时地做出判断是否允许下游的运动程序启动。在静止情况下基底神经节的输出核团维持对下游不同运动核心的抑制作用,反之则去除抑制活化运动核心。纹状体和苍白球被认为是这个运动抉择系统的主要部件。根据“霍奇金一贺胥黎”模型神经元开发了这套网络模型,不同的细胞具有各自相应的不同亚型的钠、钾、钙离子通道和钙依赖的钾通道。每个模型神经元拥有86个不同区域模块以及其对应的生物学功能,例如频率控制、超极化等等。然后根据已有实验证据,利用突触将不同的模型神经元相连。而系统中的10000个神经元大致和生物学网络上的细胞数量相当。突触数量为760000。突触类型有AMPA、NMDA、glycine型。有了这样大规模的模型,不仅可以模拟肌节与肌节之间的神经网络,还可以模拟到由基底神经节开始的行为起始部分。此外,这些网络模拟还被用于一个神经机械学模型来模拟包含有推进和方向控制部分的真实运动。     

Temperature change and complex dynamics

Density-dependent factors, such as population growth rate and migration, influence dynamic behaviour in ecological models. Temperature, an abiotic and density-independent factor, is also an important determinant of insect population growth. We investigated the endogenous dynamics of a density-dependent response-surface model that included temperature, based on time series for two aphid species. We investigated the effects of temperature and random noise on the model dynamics. In most cases, an increase in temperature resulted in a higher predicted equilibrium density; it could induce complex dynamics. Noise at the level of the natural variation in temperature resulted in extinctions in some models. Our results from these models indicate that aphid populations might become more abundant, and less stable in some circumstances, if there is climate warming. Received: 25 November 1996 / Accepted: 30 June 1997     

Effect of nitric oxide synthase inhibition on the manipulative behaviour of Sepia officinalis

Nitric oxide (NO), produced by nitric oxide synthase (NOS) in brain tissue, is essential for a variety of kinds of learning in vertebrates. In invertebrates, there are clear examples of an association between NO signalling and olfaction, feeding behaviour and learning. The role of NO as a neurotransmitter in the manipulative behaviour of Sepia officinalis was tested. Manipulative behaviour requires extensive chemotactile sensory processing, fine motor control and probably motor learning processes. NADPH-diaphorase activity (a reliable histochemical marker for nitric oxide synthase) was found in sensory epithelia and in the axial nerve cord of the arms. NOS inhibitor injections (L-NAME) produced an increase in the latency of prey paralysis. By placing mechanical constraints on the base of the fifth periopods of the crab, we prevented the cuttlefish from injecting cephalotoxin and, thus, forced it to change injection sites. We showed that L-NAME pretreatment did not affect the flexibility of the manipulative behaviour. The implications of the involvement of NO in the acquisition of chemo-tactile information and in the programming of the motor skills of the manipulative behaviour is discussed.     

Phenotypic plasticity and optimal timing of metamorphosis under uncertain time constraints

Life-history theory suggests that optimal timing of metamorphosis should depend on growth conditions and time constraints under which individuals develop. Current models cannot make reliable predictions for species in ephemeral habitats where individuals often face an increasing mortality risk over time because these models assume time-invariant mortality rates (i.e., daily mortality rates remain constant) and fixed seasons. We examined the plasticity of growth, development, and body mass at metamorphosis in tadpoles of the tree-hole breeding frog Phrynobatrachus guineensis in relation to an unpredictable time constraint in the field and in controlled experiments along a fixed density and food gradient. Mean mass and age at metamorphosis of sibships were positively correlated with per capita food level. Based on our results, we developed a simple model of the optimal timing of metamorphosis under time-dependent mortality rates showing that development rates are not only adjusted to growth conditions but also to time-variant mortality rates. The increasing mortality rate represents a time constraint that favors a reduced larval period, but because it is based on probabilities of survival it allows a trade-off between development time and mass. We extend this model to different types of time constraints and show that it can predict the range of documented reaction norms. Differences between species in␣the correlation of age and mass at metamorphosis may have evolved due to differences in their time-variant mortality rates.     

A dopaminergic basis for the effects of amphetamine on a mouse "preadolescent hyperkinetic" model

Amphetamine significantly attenuated neural excitation, which was indexed by the onset of a myoclonic seizure, in young mice genetically predisposed to high levels of neural excitation and motor activity, whereas it increased excitation in mature mice of the same genetic stock. Apomorphine simulated the effects of amphetamine while clonidine did not. Consequently, it appears that a dopaminergic mechanism, which subsequently undergoes a developmental alteration, is mediating the paradoxical antiexcitatory effect of amphetamine.     

A novel method for predicting and using distance constraints of high accuracy for refining protein structure prediction

The principal bottleneck in protein structure prediction is the refinement of models from lower accuracies to the resolution observed by experiment. We developed a novel constraints‐based refinement method that identifies a high number of accurate input constraints from initial models and rebuilds them using restrained torsion angle dynamics (rTAD). We previously created a Bayesian statistics‐based residue‐specific all‐atom probability discriminatory function (RAPDF) to discriminate native‐like models by measuring the probability of accuracy for atom type distances within a given model. Here, we exploit RAPDF to score (i.e., filter) constraints from initial predictions that may or may not be close to a native‐like state, obtain consensus of top scoring constraints amongst five initial models, and compile sets with no redundant residue pair constraints. We find that this method consistently produces a large and highly accurate set of distance constraints from which to build refinement models. We further optimize the balance between accuracy and coverage of constraints by producing multiple structure sets using different constraint distance cutoffs, and note that the cutoff governs spatially near versus distant effects in model generation. This complete procedure of deriving distance constraints for rTAD simulations improves the quality of initial predictions significantly in all cases evaluated by us. Our procedure represents a significant step in solving the protein structure prediction and refinement problem, by enabling the use of consensus constraints, RAPDF, and rTAD for protein structure modeling and refinement. Proteins 2009. © 2009 Wiley‐Liss, Inc.     

Hyperactive behaviour in the mouse model of mucopolysaccharidosis IIIB in the open field and home cage environments

Mucopolysaccharidosis IIIB (MPS IIIB) is a lysosomal storage disorder characterized by severe behavioural disturbances and progressive loss of cognitive and motor function. There is no effective treatment, but behavioural testing is a valuable tool to assess neurodegeneration and the effect of novel therapies in mouse models of disease. Several groups have evaluated behaviour in this model, but the data are inconsistent, often conflicting with patient natural history. We hypothesize that this discrepancy could be due to differences in open field habituation and home cage behaviour. Eight-month-old wild-type and MPS IIIB mice were tested in a 1-h open field test, performed 1.5 h after lights on, and a 24-h home cage behaviour test performed after 24 h of acclimatization. In the 1-h test, MPS IIIB mice were hyperactive, with increased rapid exploratory behaviour and reduced immobility time. No differences in anxiety were seen. Over the course of the test, differences became more pronounced with maximal effects at 1 h. The 24-hour home cage test was less reliable. There was evidence of increased hyperactivity in MPS IIIB mice, however, immobility was also increased, suggesting a level of inconsistency in this test. Performance of open field analysis within 1-2 h after lights on is probably critical to achieving maximal success as MPS IIIB mice have a peak in activity around this time. The open field test effectively identifies hyperactive behaviour in MPS IIIB mice and is a significant tool for evaluating effects of therapy on neurodegeneration.     

Reduction of food intake by piribedil in the rat: relation to dopamine receptor stimulation

Piribedil, given either intraperitoneally or intracerebroventricularly to rats trained to eat 4 h a day, induced a dose- and time-related anorexia. In this context it was less potent than either amphetamine or fenfluramine.The anorectic effect of piribedil was selectively antagonized by blockade of dopamine (DA) receptors in the central nervous system but not either inhibition of catecholamine synthesis, blockade of α- or β-adrenoceptors or serotoninergic receptors. Also a blocker of “peripheral” DA receptors failed to antagonize piribedil-induced anorexia.Piribedil, as opposed to amphetamine, failed to increase locomotor activity or to induce stereotyped behaviour at doses lower than that required to cause an approximate 80% reduction of food intake.These findings indicate that stimulation of central DA receptors involved in feeding regulation is responsible for the anorexigenic effect of piribedil. This effect in most instances occurs at dose levels of the compound which fail to induce other central stimulant effects.     

Sport science for salmon and other species: ecological consequences of metabolic power constraints

For metabolically demanding behaviours, power supply (ATP resynthesis per unit time) is an important constraint on performance. Yet ecology as a discipline lacks a framework to account for these power constraints. We developed such a framework (borrowing concepts from sports science) and applied it to the upriver migration of anadromous fish. Our models demonstrate how metabolic power constraints alters optimal migratory behaviour; in response to strong counter flows, fish minimise cost of transport by alternating between rapid, anaerobically fuelled swimming and holding to restore spent fuels. Models ignoring power constraints underestimated the effect of elevated water temperature on migration speed and costs (by up to 60%). These differences were primarily due to a temperature‐mediated reduction in aerobic scope that impairs the ability of fish to rapidly migrate through warm waters. Our framework provides a mechanistic link between temperature‐induced reductions in aerobic scope and their ecological consequences for individuals, populations and communities.     

Thermal and digestive constraints to foraging behaviour in marine mammals

While foraging models of terrestrial mammals are concerned primarily with optimizing time/energy budgets, models of foraging behaviour in marine mammals have been primarily concerned with physiological constraints. This has historically centred on calculations of aerobic dive limits. However, other physiological limits are key to forming foraging behaviour, including digestive limitations to food intake and thermoregulation. The ability of an animal to consume sufficient prey to meet its energy requirements is partly determined by its ability to acquire prey (limited by available foraging time, diving capabilities and thermoregulatory costs) and process that prey (limited by maximum digestion capacity and the time devoted to digestion). Failure to consume sufficient prey will have feedback effects on foraging, thermoregulation and digestive capacity through several interacting avenues. Energy deficits will be met through catabolism of tissues, principally the hypodermal lipid layer. Depletion of this blubber layer can affect both buoyancy and gait, increasing the costs and decreasing the efficiency of subsequent foraging attempts. Depletion of the insulative blubber layer may also increase thermoregulatory costs, which will decrease the foraging abilities through higher metabolic overheads. Thus, an energy deficit may lead to a downward spiral of increased tissue catabolism to pay for increased energy costs. Conversely, the heat generated through digestion and foraging activity may help to offset thermoregulatory costs. Finally, the circulatory demands of diving, thermoregulation and digestion may be mutually incompatible. This may force animals to alter time budgets to balance these exclusive demands. Analysis of these interacting processes will lead to a greater understanding of the physiological constraints within which the foraging behaviour must operate.     

Using Data-Driven Model-Brain Mappings to Constrain Formal Models of Cognition

In this paper we propose a method to create data-driven mappings from components of cognitive models to brain regions. Cognitive models are notoriously hard to evaluate, especially based on behavioral measures alone. Neuroimaging data can provide additional constraints, but this requires a mapping from model components to brain regions. Although such mappings can be based on the experience of the modeler or on a reading of the literature, a formal method is preferred to prevent researcher-based biases. In this paper we used model-based fMRI analysis to create a data-driven model-brain mapping for five modules of the ACT-R cognitive architecture. We then validated this mapping by applying it to two new datasets with associated models. The new mapping was at least as powerful as an existing mapping that was based on the literature, and indicated where the models were supported by the data and where they have to be improved. We conclude that data-driven model-brain mappings can provide strong constraints on cognitive models, and that model-based fMRI is a suitable way to create such mappings.     

The Role of the Dopamine Transporter in the Effects of Amphetamine on Sleep and Sleep Architecture in Drosophila

The dopamine transporter (DAT) mediates the inactivation of released dopamine (DA) through its reuptake, and thereby plays an important homeostatic role in dopaminergic neurotransmission. Amphetamines exert their stimulant effects by targeting DAT and inducing the reverse transport of DA, leading to a dramatic increase of extracellular DA. Animal models have proven critical to investigating the molecular and cellular mechanisms underlying transporter function and its modulation by psychostimulants such as amphetamine. Here we establish a behavioral model for amphetamine action using adult Drosophila melanogaster. We use it to characterize the effects of amphetamine on sleep and sleep architecture. Our data show that amphetamine induces hyperactivity and disrupts sleep in a DA-dependent manner. Flies that do not express a functional DAT (dDAT null mutants) have been shown to be hyperactive and to exhibit significantly reduced sleep at baseline. Our data show that, in contrast to its action in control flies, amphetamine decreases the locomotor activity of dDAT null mutants and restores their sleep by modulating distinct aspects of sleep structure. To begin to explore the circuitry involved in the actions of amphetamine on sleep, we also describe the localization of dDAT throughout the fly brain, particularly in neuropils known to regulate sleep. Together, our data establish Drosophila as a robust model for studying the regulatory mechanisms that govern DAT function and psychostimulant action.

     

Interaction between dopaminergic and cholinergic systems under conditions of deficiency of mesencephalo-striatal dopamine in rats

In chronic behavioral experiments on rats with a unilateral deficiency of mesencephalo-striatal dopamine, we studied the effect of the blocker of M-cholinoreceptors atropine on the rotational motor activity induced by systemic injections of dopamine agonists exerting direct (apomorphine) and indirect (amphetamine) actions. We found that premedication with atropine increased significantly the intensity of the rotational movements induced by both apomorphine and amphetamine. We conclude that the mesencephalo-striatal dopaminergic system exerts inhibitory effects on cholinergic neurons of the neostriatum. Neirofiziologiya/Neurophysiology, Vol. 37, Nos. 5/6, pp. 459–462, September–December, 2005.     

Foraging behaviour and fuel accumulation of capital breeders during spring migration as derived from a combination of satellite‐ and ground‐based observations

The migration strategy of many capital breeders is to garner body stores along the flyway at distinct stopover sites. The rate at which they can fuel is likely to be strongly influenced by a range of factors, such as physiology, food availability, time available for foraging and perceived predation. We analysed the foraging behaviour and fuel accumulation of pink‐footed geese, an Arctic capital breeder, at their mid‐flyway spring stopover site and evaluated to what extent their behaviour and fuelling were related to physiological and external factors and how it differed from other stopovers along the flyway. We found that fuel accumulation rates of geese at the mid‐flyway site were limited by habitat availability rather than by digestive constraints. However, as the time available for foraging increased over the stopover season, geese were able to keep constant fuelling rate. Putting this in perspective, geese increased their daily net energy intake along the flyway corresponding to the increase in time available for foraging. The net energy intake per hour of foraging remained the same. Geese showed differences in their reaction to predators/disturbance between the sites, taking higher risks particularly at the final stopover site. Hence, perceived predation along the flyway may force birds to postpone the final fuel accumulation to the last stopover along the flyway. Flexibility in behaviour appears to be an important trait to ensure fitness in this capital breeder. Our findings are based on a new, improved method for estimating fuel accumulation of animals foraging in heterogeneous landscapes based on data obtained from satellite telemetry and habitat specific intake rates.     

Buoyancy and its constraints on the underwater foraging behaviour of Reed Cormorants Phalacrocorax africanus and Darters Anhinga melanogaster

The effects of changing buoyancy on the diving and feeding behaviour of Reed Cormorants Phalacrocorax africanus and Darters Anhinga melanogaster was investigated at Lake Kariba, Zimbabwe. A qualitative model of the energetic constraints caused by buoyancy changes on the diving behaviour of these two birds is presented and the predictions from the model are tested. The buoyancy of both species declined exponentially at different rates with water depth. Reed Cormorants were neutrally buoyant at 5–6 m while Darters were neutrally buoyant at 2–4 m depth. Buoyancy changes affect underwater swimming speed, which for Reed Cormorants is twice as fast on the bottom than when commuting, and for the Darter is significantly slower when diving than at any other time. Cormorants feeding in water deeper then 6 m spent less time on the bottom and fed less successfully than those birds feeding in shallower water. This is because their bottom times were significantly reduced as a result of the energetic constraints caused by changes in their buoyancy.