Modeling the dishabituation hierarchy: The role of the primordial hippocampus

We present a neural model for the organization and neural dynamics of the medial pallium, the toad's homolog of mammalian hippocampus. A neural mechanism, called cumulative shrinking, is proposed for mapping temporal responses from the anterior thalamus into a form of population coding referenced by spatial positions. Synaptic plasticity is modeled as an interaction of two dynamic processes which simulates acquisition and both short-term and long-term forgetting. The structure of the medial pallium model plus the plasticity model allows us to provide an account of the neural mechanisms of habituation and dishabituation. Computer simulations demonstrate a remarkable match between the model performance and the original experimental data on which the dishabituation hierarchy was based. A set of model predictions is presented, concerning mechanisms of habituation and cellular organization of the medial palliumThe research described in this paper was supported in part by grant no. 1RO1 NS 24926 from the National Institutes of Health (M.A.A., Principal Investigator)     

How does the toad's visual system discriminate different worm-like stimuli?

Behavioral experiments show that toads exhibit stimulus- and locus-specific habituation. Different worm-like stimuli that toads can discriminate at a certain visual location form a dishabituation hierarchy. What is the neural mechanism which underlies these behaviors? This paper proposes that the toad discriminates visual objects based on temporal responses, and that discrimination is reflected in different average neuronal firing rates at some higher visual center, hypothetically anterior thalamus. This theory is developed through a large-scale neural simulation which includes retina, tectum and anterior thalamus. The neural model based on this theory predicts that retinal R2 cells play a primary role in the discrimination via tectal small pear cells (SP) and R3 cells refine the feature analysis by inhibition. The simulation demonstrates that the retinal response to the trailing edge of a stimulus is as crucial for pattern discrimination as the response to the leading edge. The new dishabituation hierarchies predicted by this model by reversing contrast and shrinking stimulus size need to be tested experimentally.     

Global convergence properties in multilocus viability selection models: the additive model and the Hardy-Weinberg law

A natural coordinate system is introduced for the analysis of the global stability of the Hardy-Weinberg (HW) polymorphism under the general multilocus additive viability model. A global convergence criterion is developed and used to prove that the HW polymorphism is globally stable when each of the loci is diallelic, provided the loci are overdominant and the multilocus recombination is positive. As a corollary the multilocus Hardy-Weinberg law for neutral selection is derived.Research supported in part by NIH grants GM 39907-01, GM 10452-26 and NSF Grant DMS 86-06244Research supported in part by a US-Israel Binational Science Foundation grant 85-00021 and NIH grant GM 28016     

Configurational pattern discrimination responsible for dishabituation in common toads Bufo bufo (L.): Behavioral tests of the predictions of a neural model

Summary Recently, a neural model of visual pattern discrimination for stimulus-specific habituation was developed, based on previous behavioral studies which demonstrated that toads exhibit a dishabituation hierarchy for different worm-like stimuli. The model suggests that visual objects are represented by temporal coding and predicts that the dishabituation hierarchy changes when the stimulus/background contrast direction is reversed or the stimulus size is varied. The behavioral experiments reported in this paper were designed to test these predictions, (1) For a pair of stimuli from the contrast reversal prediction, the experimental results validated the theory. (2) For a pair of stimuli from the size reduction prediction, the experimental results failed to validate the theory. Further experiments concerning size effects suggest that configurai visual pattern discrimination in toads exhibits size invariance. (3) Inspired by the Groves-Thompson account of habituation, we found that dishabituation by a second stimulus has a separate process from habituation to a first stimulus. This paper serves as an example of a fruitful dialogue between experimentation and modeling, crucial for understanding brain functions.Abbreviations a-h worm-like stimulus patterns - AT anterior thalamus - ERF excitatory receptive field - IRF inhibitory receptive field - RF receptive field - R2 to R4 retinal ganglion cell types - vMP posterior ventromedial pallium     

Transfer of habituation in Aplysia: contribution of heterosynaptic pathways in habituation of the gill-withdrawal reflex

Habituation of the Aplysia gill-withdrawal reflex (and siphon-withdrawal reflex) has been attributed to low-frequency homosynaptic depression at central sensory-motor synapses. The recent demonstration that transfer of habituation between stimulation sites occurs in this model system has prompted the hypothesis that heterosynaptic inhibitory pathways also play a role in the mediation of habituation behavior. To test this hypothesis, the sites and mechanisms of neural plasticity which underlie transfer of habituation in Aplysia were examined. Transfer of habituation is a reduction in the reflex evoked at one stimulation site (siphon) due to repeated presentation of a stimulus to a second site (gill). Centrally mediated transfer of habituation, measured in a preparation lacking the siphon-gill peripheral nervous system (PNS), was associated with a reduced excitatory response in central motor neurons. Repeated tactile stimulation of the gill did not attenuate the gill response evoked by electrical stimulation of the branchial nerve nor the mechanoreceptor response recorded in LE sensory neurons. In contrast, repeated stimulation of siphon or gill at a site which was "off" the sensory field of a specific mechanoreceptor led to a diminution in synaptic transmission between that sensory neuron and its followers (motor neurons and inter-neurons). These data demonstrate that centrally mediated transfer of habituation results from heterosynaptic modulation of synaptic transmission at the sensory-motor (and sensory-interneuron) synapses. Therefore, habituation behavior in Aplysia is mediated through the conjoint action of homosynaptic and heterosynaptic inhibitory processes.     

Ultrastructural observations on some membranous cytoplasmic inclusion bodies in follicular cells of experimentally-induced goitres in tadpoles and toads of Xenopus laevis Daudin

Summary Tadpoles and young toads of Xenopus laevis were maintained in aqueous solutions of potassium perchlorate or thiourea (0.005% or 0.01% w/v) for up to 20 months. Metamorphosis of tadpoles was inhibited. Within a short time large well-vascularized goitres developed in both tadpoles and toads. An ultrastructural investigation of some of the follicular epithelial cells of these goitres revealed some unusual cytoplasmic membranous inclusions and a morphological account of these structures is presented. It is suggested that some of these complex membranous inclusions may give rise to cytosomes. The relationship between these complex cytoplasmic organelles is considered together with their possible significance and role in thyroid cell functioning.This work was carried out during the tenure by one of us (R.C.) of a Medical Research Council Scholarship and forms part of a programme of research in amphibian thyroid physiology supported by the Medical Research Council to whom we are indebted for their generous assistance.     

TGF-beta in neural stem cells and in tumors of the central nervous system

Mechanisms that regulate neural stem cell activity in the adult brain are tightly coordinated. They provide new neurons and glia in regions associated with high cellular and functional plasticity, after injury, or during neurodegeneration. Because of the proliferative and plastic potential of neural stem cells, they are currently thought to escape their physiological control mechanisms and transform to cancer stem cells. Signals provided by proteins of the transforming growth factor (TGF)-beta family might represent a system by which neural stem cells are controlled under physiological conditions but released from this control after transformation to cancer stem cells. TGF-beta is a multifunctional cytokine involved in various physiological and patho-physiological processes of the brain. It is induced in the adult brain after injury or hypoxia and during neurodegeneration when it modulates and dampens inflammatory responses. After injury, although TGF-beta is neuroprotective, it may limit the self-repair of the brain by inhibiting neural stem cell proliferation. Similar to its effect on neural stem cells, TGF-beta reveals anti-proliferative control on most cell types; however, paradoxically, many brain tumors escape from TGF-beta control. Moreover, brain tumors develop mechanisms that change the anti-proliferative influence of TGF-beta into oncogenic cues, mainly by orchestrating a multitude of TGF-beta-mediated effects upon matrix, migration and invasion, angiogenesis, and, most importantly, immune escape mechanisms. Thus, TGF-beta is involved in tumor progression. This review focuses on TGF-beta and its role in the regulation and control of neural and of brain-cancer stem cells. This work was supported by the German Federal Ministry of Education and Research (BMBF no. 01GA0510 and no. 0312134) and by the Bavarian State Ministry of Sciences, Research and the Arts, "Forneurocell grant".     

Transaminase reactions and glutamate dehydrogenase in gastropod hepatopancreas

Summary In toads,Bufo bufo L., ACTH (1 I.U.) causes a retardation of extinction compared with Ringer administration irrespective of whether the animals have received the ACTH injection before or at the end of acquisition. Treatment with ACTH 20 min prior to acquisition lowers the starting activity. Therefore, habituation is completed earlier than in Ringer controls. The effect of ACTH treatment is stimulus-specific, as toads habituated to a wormlike stripe show normal turning activity to a triangle even under the influence of ACTH.The conformity of these results with the ACTH effect on complex learning behaviour especially in rats may indicate an underlying common principle. It is concluded that ACTH and, possibly, related peptides elicite neuronal events which favour learning and memory processes even in lower vertebrates.We thank Prof. Dr. W. Hanke, Karlsruhe, for fruitful discussions.     

Vegetation responses to past climatic variation

Vegetation responses to climatic change can be studied retrospectively by utilizing the Quaternary fossil record. There has been controversy over the extent to which major changes in vegetation patterns at the continental scale lag behind the climatic changes that drive them, and to what extent vegetation can ever be said to be in equilibrium with climate. The equilibrium question has no single answer. The predominant mode of vegetation response to climatic change depends on the space and time frame and resolution of the data set in which the response is observed.Vegetation (as observed on particular space and time scales) can be in dynamic equilibrium with climate if its response time is sufficiently fast in relation to the rate of climatic change to which it is observed to be responding. Several processes can be involved in the response: successional, migrational, edaphic, and evolutionary. Successional response times can be deduced from forest succession models. The other processes are less well understood and different ideas exist concerning their rates. According to one hypothesis, migrational lags caused delays of thousands of years in the postglacial dynamics of forest composition. The alternative hypothesis explains these changes as dynamic equilibrium responses to changes in climatic seasonality and climatic anomaly patterns. Neither hypothesis need be universally true; gradient analysis and forest succession models are among the techniques that can be used in inferential tests of these hypotheses for particular space-time regions.Dynamic equilibrium may often be a reasonable approximation for the responses of the broadest continental-scale forest patterns to orbitally induced climatic changes. But as spatial and temporal frames of observation are diminished and resolution increased, biotic processes must eventually come to dominate. At sufficiently fine scales the main observable phenomena are successional responses to natural disturbance events. The late-Quaternary record of vegetation change allows a choice of observation scales and thus provides a continuum of possibilities for study, ranging from long-term dynamic bioclimatology to more conventional vegetation dynamics.I thank Margaret Davis, Honor Prentice, Jim Ritchie, Al Solomon, Geoff Spaulding and Tom Webb for their reviews of earlier drafts. Research supported by a US Department of Energy, Carbon Dioxide Research Division, grant to Brown University and a Swedish Natural Science Research Council grant to the project SlsSimulation of Natural Forest Dynamics.I thank Margaret Davis, Honor Prentice, Jim Ritchie, Al Solomon, Geoff Spaulding and Tom Webb for their reviews of earlier drafts. Research supported by a US Department of Energy, Carbon Dioxide Research Division, grant to Brown University and a Swedish Natural Science Research Council grant to the project SlsSimulation of Natural Forest Dynamics.     

Decoding of a motor command vector from distributed activity in superior colliculus

 Several alternative methods for decoding the desired motor command vector from neural networks containing distributed, place-coded information have been suggested. The two most widely discussed candidate mechanisms are vector summation (VS) and a center-of-mass (CM) computation. The latter mechanism has also been called vector averaging. The present paper compares the operation of these two methods in a model of an experimentally well-studied neural structure, the superior colliculus (SC). The SC is one structure that has been shown to be responsible for generating saccadic command vectors in the form of distributed neural activity that is topologically arranged across its surface. It has been suggested that the pattern of eye-movement errors obtained following the placement of a collicular lesion can distinguish between these two mechanisms. As a result of this suggestion, the pattern of saccadic errors produced by lesions in the SC have been widely cited to support the CM hypothesis. In the present paper the placement of a discrete lesion is simulated in a recurrent (dynamic) neural network model of the SC. These dynamic connections in the model SC network produce a systematic shift of the locus of distributed activity away from the site of the lesion. The spatiotemporal shift in the location of SC activity then produces a pattern of saccadic errors that appear to support the CM hypothesis, even though ensemble activity in our model colliculus is decoded by VS. This result demonstrates that, when ensemble activity on the SC motor map is dynamically modulated over space and time by intrinsic collicular circuitry, an explicit CM computation is not needed to reproduce the pattern of physiological results that follow focal SC lesions. Received: 19 December 2000 / Accepted in revised form: 27 September 2001     

Cystic fibrosis: Demonstration of an abnormality in mucopolysaccharides in cultured lymphoid lines

Cultured lymphoid cells of both homozygotes and heterozygotes for cystic fibrosis could be distinguished from those of normals by (1) growth pattern, gross clumping, and (2) a relative increase in dermatan sulfate, with a normal total mucopolysaccharide content. Lines derived from the genetic mucopolysaccharidoses also had these characteristics, but their total mucopolysaccharide content was markedly increased. These observations support the hypothesis that the cellular disturbance in cystic fibrosis resides in those cellular regions whose functions would be altered by mucopolysaccharide composition.This research was made possible through a grant from The National Foundation-March of Dimes and, in part, supported by The Cystic Fibrosis Children's Fund and The National Cystic Fibrosis Research Foundation.Career Scientist of the Health Research Council of New York City (I-797).     

Genetic and population studies of quantitative levels of adenosine triphosphate in human erythrocytes

The mean content of ATP in red cells of American Negroes is significantly less than the mean level in American Caucasians. This is compatible with the hypothesis that the quantitative level of ATP in red cells may be involved in selective processes related to falciparum malaria. There is no evidence of a sex effect on levels of ATP in either population. Family studies conducted in both populations indicate that the quantitative level of red cell ATP is at least partially inherited. Studies of a number of biochemical characteristics of red cells have been conducted in an effort to elucidate the mechanism of genetic and biochemical control of quantitative levels of erythrocytic ATP. These studies have been negative. Although other studies have demonstrated that thalassemia trait influences the level of red cell ATP, the presence of sickle cell trait or G-6-PD deficiency, the other two systems postulated to be involved in malaria protection, did not result in significant differences in mean red cell ATP content.The work reported in this paper was supported in part by the Research and Development Command, Office of the Surgeon General, Department of the Army, under contract DA-49-193-MD-2855 with the Department of Medicine, University of Michigan. With respect to this support, it is contribution number 167 from the Army Research Program on Malaria. The work was also supported in part by USPHS grant AM 09381 and USPHS Career Development Award 1-K3-AM 7959.     

Heterogeneous selection in subdivided populations

The dynamics of allele frequencies changing under migration and heterogeneous selection in a subdivided population are investigated. Using perturbation techniques, a stationary state is obtained when migration and selection are both small. Heterogeneous selection leads to a positive correlation between values of F-statistics and heterozygosities when these are compared among sets of subdivided populations. This contrasts with a negative value of the correlation obtained under Wright's classical model of homogeneous selection, and with the absence of correlation in the completely neutral situation.Research supported in part by NIH grants GM 28016 and GM 10452 and a grant from the John D. and Catherine T. MacArthur Foundation     

Factors in visual acuity: I. Neural inhibition and the visual perception of contours

Interpretations of the mechanisms of perception of contours or of Mach bands have stressed either the role of various spatial derivatives of light intensity at the retina or the importance of various forms of inhibitory effects between neighboring retinal elements. Evidence is presented here in support of the latter type of interpretation. It is considered that the brightness contrast and perceived contours arise from neural elements, each of which is stimulated in proportion to the intensity of photo-receptor excitation at a point of the retina and inhibited in proportion to the mean intensity in some neighborhood of that point. The role of the spatial derivatives is best seen as a particular manifestation of the inhibitory mechanism. Predictions based upon this hypothesis appear to be consistent with experimentally observed evidence. This research was supported by the United States Air Force through the Air Force Office of Scientific Research of the Air Research and Development Command under Contract No. AF 18(600)-1454. Reproduction in while or in part is permitted for any purpose of the United States Government.     

The prey localisation Model: A stability analysis

This paper analyzes the Prey localisation Model (House 1984), for animals that are unable to verge their eyes. The Prey localisation Model selects a single point or a portion of the scene in its visual space. In particular it imitates the behaviour of frogs and toads of selecting the closer target when two equally attractive prey are presented to it. The model achieves its goal by tightly coupling two prey selection processes, one for each eye, with lens accommodation. In this paper we offer a stability analysis of the model, and show how lens accommodation, i.e. adjustment in the focal length of the lens, biases the selection of the proximal target. We examine the properties of the model that are responsible for its behaviour and derive a set of conditions which guarantees the localisation of the correct target.Preparation of this paper was supported in part by grant number 1 R01 NS24926 from the NINCDS of NIH     

Oscillations in a model of repression with external control

A mathematical model for control by repression by an extracellular substance is developed, including diffusion and time delays. The model examines how active transport of a nutrient can produce either oscillatory or stable responses depending on a variety of parameters, such as diffusivity, cell size, or nutrient concentration. The system of equations for the mathematical model is reduced to a system of delay differential equations and linear Volterra equations. After linearizing these equations and forming the limiting Volterra equations, the resulting linear system no longer has any spatial dependence. Local stability analysis of the radially symmetric model shows that the system of equations can undergo Hopf bifurcations for certain parameter values, while other ranges of the parameters guarantee asymptotic stability. One numerical study shows that the model can exhibit intracellular biochemical oscillations with increasing extracellular concentrations of the nutrient, which suggests a possible trigger mechanism for morphogenesis.The work of this author was supported in part by NSF grants DMS-8603787 and DMS-8807360The work of this author was supported under the REU program of NSF by grant DMS-8807360The work of this author was supported under the REU program of NSF by grant DMS-8807360     

Ultrastructural and immunohistological characterization of the sirc corneal cell line

Summary A widely utilized rabbit corneal cell line, SIRC, was characterized ultrastructurally and immunohistologically. Although SIRC cells are often described as being of epithelial origin, important ultrastructural and antigenic characteristics indicate that these cells are fibroblastic and not epithelial. SIRC cells lack desmosomes, cytoplasmic filaments, and cytokeratin—structures that are characteristic of corneal epithelial cells. By contrast, the dendritic morphology, presence of vimentin, and the extensive dense accumulations of ribosomes and rough endoplasmic reticulum are consistent with a fibroblastic phenotype. Collectively, the morphology, ultrastructural features, and antigenic composition favor the hypothesis that SIRC cells are fibroblastic cells (keratocytes) and not corneal epithelial cells. This work supported in part by grant EY 07641 from the National Institutes of Health, Bethesda, MD, and an unrestricted grant from Research to Prevent Blindness, Inc., New York.     

Minireview: Cholinergic and monoaminergic substrates of startle habituation

Research is reviewed arising from the proposition that behavioral habituation is mediated by brain mechanisms operated by the neurotransmitter, acetylcholine. Effects of cholinergic drugs on habituation of the startle response in rats fail to support involvement of acetylcholine. Likewise, serotonergic drug effects do not favor the more recent view that startle habituation depends on brain serotonin, nor is there sufficient evidence for an essential role of either dopamine or noradrenalin. Because of persistence of habituation following challenge with a variety of pharmacological agents, the phenomenon probably depends upon a complex interplay between a number of transmitters and behavioral processes. Contrary to earlier belief, no single transmitter should be seen as crucially responsible for startle habituation.     

An automata-theoretical model of the vegetative and flowering development of Hieracium murorum L.

By means of a computer model certain essential aspects of the vegetative and flowering development of Hieracium murorum have been successfully simulated. The model is based on local control mechanisms operating over a large number of units and is stated in terms of the theory of developmental systems and languages. The model is constructed as a table deterministic 1,1 L-system. The model is especially concerned with the correlation mechanisms between the various differentiating parts of the plant.This work has been supported by a grant from the Netherlands Organization for the Advancement of Pure Research (Z.W.O.)     

Habituation of an odorant-induced startle response in Drosophila

Habituation is a fundamental form of behavioral plasticity that permits organisms to ignore inconsequential stimuli. Here we describe the habituation of a locomotor response to ethanol and other odorants in Drosophila, measured by an automated high-throughput locomotor tracking system. Flies exhibit an immediate and transient startle response upon exposure to a novel odor. Surgical removal of the antennae, the fly's major olfactory organs, abolishes this startle response. With repeated discrete exposures to ethanol vapor, the startle response habituates. Habituation is reversible by a mechanical stimulus and is not due to the accumulation of ethanol in the organism, nor to non-specific mechanisms. Ablation or inactivation of the mushroom bodies, central brain structures involved in olfactory and courtship conditioning, results in decreased olfactory habituation. In addition, olfactory habituation to ethanol generalizes to odorants that activate separate olfactory receptors. Finally, habituation is impaired in rutabaga, an adenylyl cyclase mutant isolated based on a defect in olfactory associative learning. These data demonstrate that olfactory habituation operates, at least in part, through central mechanisms. This novel model of olfactory habituation in freely moving Drosophila provides a scalable method for studying the molecular and neural bases of this simple and ubiquitous form of learning.