25-year development of the theory of functional systems at P K Anokhin Institute of Normal Physiology and the Department of Normal Physiology of I M Sechenov Moscow Medical Academy

New trends in the development of the theory of functional systems proposed by P.K. Anokhin in the scientific complex P.K. Anokhin Institute--Department of Normal Physiology during the last twenty five years are regarded. It has been shown that the functional systems represent an objective reality. Holographic and informational properties of the functional systems and general principles of their interrelations in the whole organism i.e. hierarchic domination, multiparametric and successive interaction have been disclosed. Some notions about "systemo-quanta" of vital activity as discrete units of dynamic activity of functional systems have been formulated. Further developments in the systemogenesis of behavioral acts also are presented. New ideas about pacemaker mechanism of dominant biological motivations, the role of oligopeptides in the system organization of behavioral acts have been formulated. The role of early genes in formation of behavioral reactions of animals and in the mechanisms of emotional stress is shown. The role of some oligopeptides in the mechanisms of resistance to emotional stress is stated. Some devices modeling the properties of functional systems and able to assess different organism's functional systems have been developed. Practical application of the theory of functional systems is also shown in the paper.     

Consequences of behavioral dynamics for the population dynamics of predator-prey systems with switching

This article explores how different mechanisms governing the rate of change of the predators preference alter the dynamics of predator-prey systems in which the predator exhibits positive frequency-dependent predation. The models assume that individuals of the predator species adaptively adjust a trait that determines their relative capture rates of each of two prey species. The resulting switching behavior does not instantaneously attain the optimum for current prey densities, but instead lags behind it. Several mechanisms producing such lags are discussed and modeled. In all cases examined, our question is whether a realistic behavioral lag can significantly change the dynamics of the system relative to an analogous case in which the predators switching is effectively instantaneous. We also explore whether increasing the rate parameters of dynamic models of behavior results in convergence to the population dynamics of analogous models with instantaneous switching, and whether different behavioral models produce similar population dynamics. The analysis concentrates on systems that undergo endogenously generated predator-prey cycles in the absence of switching behavior. The average densities and the nature of indirect interactions are often sensitive to the rate of behavioral change, and are often qualitatively different for different classes of behavioral models. Dynamics and average densities can be very sensitive to small changes in parameters of either the prey growth or predator switching functions. These differences suggest that an understanding of switching in natural systems will require research into the behavioral mechanisms that govern lags in the response of predator preference to changes in prey density.     

Neurons of the rabbit midbrain reticular formation during a defensive conditioned reflex]

Analysis of unit activity of the midbrain reticular formation was carried out on alert rabbits during defensive conditioning. Most of the examined neurones exhibited phasic responses corresponding in time to the components of the evoked potential (EP) recorded in the cortical visual area in response to the "indifferent" stimulus, and to the conditioned stimulus and electric cutaneous reinforcement. The data obtained are considered from the standpoint of the Anokhin functional systems theory. A conclusion has been made regarding the participation of reticular units in providing all the basic mechanisms of the functional system of the behavioral act. Discharges of one and the same neurone may correspond to different components of the EPs to conditioned and unconditioned stimuli. In different behavioral acts a neurone may apparently participate in different systemic mechanisms.     

Cellular bases of behavioral plasticity: establishing and modifying synaptic circuits in the Drosophila genetic system

Genetic malleability and amenability to behavioral assays make Drosophila an attractive model for dissecting the molecular mechanisms of complex behaviors, such as learning and memory. At a cellular level, Drosophila has contributed a wealth of information on the mechanisms regulating membrane excitability and synapse formation, function, and plasticity. Until recently, however, these studies have relied almost exclusively on analyses of the peripheral neuromuscular junction, with a smaller body of work on neurons grown in primary culture. These experimental systems are, by themselves, clearly inadequate for assessing neuronal function at the many levels necessary for an understanding of behavioral regulation. The pressing need is for access to physiologically relevant neuronal circuits as they develop and are modified throughout life. In the past few years, progress has been made in developing experimental approaches to examine functional properties of identified populations of Drosophila central neurons, both in cell culture and in vivo. This review focuses on these exciting developments, which promise to rapidly expand the frontiers of functional cellular neurobiology studies in Drosophila. We discuss here the technical advances that have begun to reveal the excitability and synaptic transmission properties of central neurons in flies, and discuss how these studies promise to substantially increase our understanding of neuronal mechanisms underlying behavioral plasticity.     

Functional genomics of neural and behavioral plasticity

How does the environment, particularly the social environment, influence brain and behavior and what are the underlying physiologic, molecular, and genetic mechanisms? Adaptations of brain and behavior to changes in the social or physical environment are common in the animal world, either as short-term (i.e., modulatory) or as long-term modifications (e.g., via gene expression changes) in behavioral or physiologic properties. The study of the mechanisms and constraints underlying these dynamic changes requires model systems that offer plastic phenotypes as well as a sufficient level of quantifiable behavioral complexity while being accessible at the physiological and molecular level. In this article, I explore how the new field of functional genomics can contribute to an understanding of the complex relationship between genome and environment that results in highly plastic phenotypes. This approach will lead to the discovery of genes under environmental control and provide the basis for the study of the interrelationship between an individual's gene expression profile and its social phenotype in a given environmental context.     

The Formation Of A Behavioral Act: The Problem Of Intrasystemic Heterochronicity

Among the timely questions facing contemporary physiology, study of the laws of formation of new behavioral acts in learning by human beings and animals is one of the most important. The general theory of functional systems has made a substantial contribution to resolution of this problem [1-6]. According to this theory, human and animal behavior are based on the formation of special physiological integrations, selectively uniting central and peripheral components of the organism to achieve an overall adaptative result. It was found that such functional systems, despite the considerable variability in their component composition, always have an invariable internal operational architectonics [5]. Their functioning always involves the same sequence of key mechanisms: processes of afferent synthesis and the system of the acceptor of the result of an action (ARA), the realization of an "executive act," the accomplishment of an adaptative result, and evaluation of its parameters.     

Epigenetics and memory: causes,consequences and treatments for post‐traumatic stress disorder and addiction

Understanding the interaction between fear and reward at the circuit and molecular levels has implications for basic scientific approaches to memory and for understanding the etiology of psychiatric disorders. Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress‐related psychiatric disorder. Converging evidence suggests that similar behavioral, neurobiological and molecular mechanisms control the extinction of learned fear and drug‐seeking responses. This may, in part, account for the fact that individuals with post‐traumatic stress disorder have a significantly elevated risk of developing a substance use disorder and have high rates of relapse to drugs of abuse, even after long periods of abstinence. At the behavioral level, a major challenge in treatments is that extinguished behavior is often not persistent, returning with changes in context, the passage of time or exposure to mild stressors. A common goal of treatments is therefore to weaken the ability of stressors to induce relapse. With the discovery of epigenetic mechanisms that create persistent molecular signals, recent work on extinction has focused on how modulating these epigenetic targets can create lasting extinction of fear or drug‐seeking behavior. Here, we review recent evidence pointing to common behavioral, systems and epigenetic mechanisms in the regulation of fear and drug seeking. We suggest that targeting these mechanisms in combination with behavioral therapy may promote treatment and weaken stress‐induced relapse.     

Acceptor of action results as a structural functional basis of dynamic stereotype activities of the brain

The system mechanisms of brain dynamic stereotypes formation are considered. The brain dynamic stereotypes are shown to be formed on the structures of acceptor of action results by dominating motivations and reinforcements. Acceptors of action results are widely spread in brain structures. They are presented in functional systems which form behavioral acts of animals with spreading neural excitations in collaterals of axons of pyramidal tract. Reinforcing excitations form specific architectonic of acceptors of action results, which include brain structures corresponding to modalities of parameters of reinforcements. Dominating motivations, which predict future events, excite molecular engrams of action results which were formed by previous reinforcements.     

Single Medial Prefrontal Neurons Cope with Error

Learning from mistakes is a key feature of human behavior. However, the mechanisms underlying short-term adaptation to erroneous action are still poorly understood. One possibility relies on the modulation of attentional systems after an error. To explore this possibility, we have designed a Stroop-like visuo-motor task in monkeys that favors incorrect action. Using this task, we previously found that single neurons recorded from the anterior cingulate cortex (ACC) were closely tuned to behavioral performance and, more particularly, that the activity of most neurons was biased towards the evaluation of erroneous action. Here we describe single neurons engaged in both error detection and response alertness processing, whose activation is closely associated with the improvement of subsequent behavioral performance. Specifically, we show that the effect of a warning stimulus on neuronal firing is enhanced after an erroneous response rather than a successful one and that this outcome is correlated with an error rate decrease. Our results suggest that the anterior cingulate cortex, which exhibits this activity, serves as a powerful computational locus for rapid behavioral adaptation.     

Intracellular mechanisms of adaptation and self-regulation in self-organizing networks: The role of chemical transducers

This paper describes mechanisms of intracellular and intercellular adaptation that are due to spatial or temporal factors. The spatial mechanisms support self-regulating pattern formation that is capable of directing self-organization in a large class of systems, including examples of directed intercellular growth, transmitter production, and intracellular conductance changes. A balance between intracellular flows and counterflows causes adaptation. This balance can be shifted by environmental inputs. The decrease in Ca²⁺-modulated outward K⁺ conductance in certain molluscan nerve cells is a likely example. Examples wherein Ca²⁺ acts as a second messenger that shunts receptor sensitivity can also be discussed from this perspective. The systems differ in basic ways from recent diffusion models. Chemical transducers driven by membrane-bound intracellular signals can establish long-range intercellular interactions that compensate for variable intercellular distances and are invariant under developmental size changes; diffusional signals do not. The intracellular adaptational mechanisms are formally analogous to intercellular mechanisms that include cellular properties which are omitted in recent reaction-diffusion models of pattern formation. The cellular models use these properties to compute size-invariant properties despite wide variations in their intercellular signals. Mechanisms of temporal adaptation can be derived from the simplest laws of chemical transduction by using a correspondence principle. These mechanisms lead to such properties of intercellular signals as transient overshoot, antagonistic rebound, and an inverted U in sensitivity as intracellular signals or adaptation levels shift. Such effects are implicated in studies of behavioral, reinforcement, motor control, and cognitive coding. Supported in part by the National Science Foundation (NSF MCS 77-02958).     

Spontaneous duplications in diploid Saccharomyces cerevisiae cells

The duplication of DNA sequences is a powerful determinant of genomic plasticity and is known to be one of the key factors responsible for evolution. Recent genomic sequence data demonstrate the abundance of duplicated genes in all surveyed organisms. Over the past years, experimental systems were adequately designed to explore the molecular mechanisms involved in their formation in haploid Saccharomyces cerevisiae strains. To obtain a more global and accurate view of the events leading to DNA sequence duplications, we have selected and characterized duplication occurrences in diploid S. cerevisiae cells. The molecular analysis showed that two other predominant ways lead to duplication in this context: formation of extra chimeric chromosomes and non-reciprocal translocation events. Moreover, we demonstrated that these two types of rearrangements are RAD52 independent and therefore that homologous recombination plays no part in their formation. Finally, our results show the multiplicity of mechanisms involved in duplication events and provide the first experimental evidence that these mechanisms might be ploidy dependent.     

网络成瘾者奖赏系统和认知控制系统的神经机制

网络成瘾作为一种行为成瘾,已成为严重影响人们心理健康的全球性问题.根据大脑发育的神经生物模型,揭示网络成瘾者奖赏和认知控制系统的神经机制是解决网络成瘾问题的关键,也是心理学研究的重大问题.行为研究探讨了网络成瘾具有高奖赏寻求和低认知控制特征;神经机制研究揭示了奖赏和认知控制系统的缺陷是网络成瘾行为的高风险因素;与药物成瘾的比较研究发现,网络成瘾有着独特的奖赏机制.这些研究深化了对网络成瘾心理和神经机制的理解,但仍存在网络成瘾筛查和入组标准不科学、分型笼统、因果研究匮乏、干预和治疗效果具有争议、研究范式存在漏洞等一些急需解决的问题.     

Seeking a spotless mind: extinction, deconsolidation, and erasure of fear memory

Learning to contend with threats in the environment is essential to survival, but dysregulation of memories for traumatic events can lead to disabling psychopathology. Recent years have witnessed an impressive growth in our understanding of the neural systems and synaptic mechanisms underlying emotional memory formation. As a consequence, interest has emerged in developing strategies for suppressing, if not eliminating, fear memories. Here, I review recent work employing sophisticated behavioral, pharmacological, and molecular tools to target fear memories, placing these memories firmly behind the crosshairs of neurobiologically informed interventions.     

Neuroendocrine-immune circuits,phenotypes, and interactions

Multidirectional interactions among the immune, endocrine, and nervous systems have been demonstrated in humans and non-human animal models for many decades by the biomedical community, but ecological and evolutionary perspectives are lacking. Neuroendocrine-immune interactions can be conceptualized using a series of feedback loops, which culminate into distinct neuroendocrine-immune phenotypes. Behavior can exert profound influences on these phenotypes, which can in turn reciprocally modulate behavior. For example, the behavioral aspects of reproduction, including courtship, aggression, mate selection and parental behaviors can impinge upon neuroendocrine-immune interactions. One classic example is the immunocompetence handicap hypothesis (ICHH), which proposes that steroid hormones act as mediators of traits important for female choice while suppressing the immune system. Reciprocally, neuroendocrine-immune pathways can promote the development of altered behavioral states, such as sickness behavior. Understanding the energetic signals that mediate neuroendocrine-immune crosstalk is an active area of research. Although the field of psychoneuroimmunology (PNI) has begun to explore this crosstalk from a biomedical standpoint, the neuroendocrine-immune-behavior nexus has been relatively underappreciated in comparative species. The field of ecoimmunology, while traditionally emphasizing the study of non-model systems from an ecological evolutionary perspective, often under natural conditions, has focused less on the physiological mechanisms underlying behavioral responses. This review summarizes neuroendocrine-immune interactions using a comparative framework to understand the ecological and evolutionary forces that shape these complex physiological interactions.     

The carcinogenic effect of H. pylori on the gastric epithelial cell.

The recent demonstration in animal models that H. pylori alone may be capable of inducing intestinal-type gastric cancer, and that H. felis can accelerate gastrin-induced gastric neoplasia has stimulated research on examining the mechanisms of H. pylori-associated carcinogenesis in humans. Several mechanisms are currently under investigation, including the dysregulation of the gastric epithelial cell cycle, the formation of DNA adducts, the generation of free radicals, alterations in growth factor secretion and cytokines, and the effects of decreased gastric acid secretion. This review will examine the relevant evidence acquired from human tissue studies, animal models and cell culture systems in an attempt to explore these pathways, and to evaluate the mechanisms by which H. pylori may cause gastric cancer.     

Self-organized protein patterns: The MinCDE and ParABS systems

Self-organized protein patterns are of tremendous importance for biological decision-making processes. Protein patterns have been shown to identify the site of future cell division, establish cell polarity, and organize faithful DNA segregation. Intriguingly, several key concepts of pattern formation and regulation apply to a variety of different protein systems. Herein, we explore recent advances in the understanding of two prokaryotic pattern-forming systems: the MinCDE system, positioning the FtsZ ring precisely at the midcell, and the ParABS system, distributing newly synthesized DNA along with the cell. Despite differences in biological functionality, these two systems have remarkably similar molecular components, mechanisms, and strategies to achieve biological robustness.     

Why are behavioral and immune traits linked?

Through behavior, animals interact with a world where parasites abound. It is easy to understand how behavioral traits can thus have a differential effect on pathogen exposure. Harder to understand is why we observe behavioral traits to be linked to immune defense traits. Is variation in immune traits a consequence of behavior-induced variation in immunological experiences? Or is variation in behavioral traits a function of immune capabilities? Is our immune system a much bigger driver of personality than anticipated? In this review, I provide examples of how behavioral and immune traits co-vary. I then explore the different routes linking behavioral and immune traits, emphasizing on the physiological/hormonal mechanisms that could lead to immune control of behavior. Finally, I discuss why we should aim at understanding more about the mechanisms connecting these phenotypic traits.     

Evaluation of the role of the adaptive result in the theory of the functional systems

The fundamental of the theory of the functional systems, i.e., the concept of the useful adaptive result as a universal system-forming factor is considered. It is suggested that the adaptive result is not system-forming in behaviors actualized exclusively due to activity of systems developed earlier. It is argued that positive mutations may serve as the system-forming factor for hereditary determined behavioral forms. In all other cases of goal-directed behavior (except conditioning) the aim of performance as a model of the future result plays the decisive role. Only in conditioning the classical concept of the system-forming role of the adaptive result seems to be undeniable. The refined ideas about the mechanisms of formation of the functional systems may be useful in analysis of a number of animal and human functions (learning, emotional stress, neuroses, etc.).     

A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans

The activities of many neuronal proteins are modulated by ethanol, but the fundamental mechanisms underlying behavioral effects of ethanol remain unclear. To identify mechanisms responsible for intoxication, we screened for Caenorhabditis elegans mutants with altered behavioral responses to ethanol. We found that slo-1 mutants, which were previously recognized as having slightly uncoordinated movement, are highly resistant to ethanol in two behavioral assays. Numerous loss-of-function slo-1 alleles emerged from our screens, indicating that slo-1 has a central role in ethanol responses. slo-1 encodes the BK potassium channel. Electrophysiological analysis shows that ethanol activates the channel in vivo, which would inhibit neuronal activity. Moreover, behaviors of slo-1 gain-of-function mutants resemble those of ethanol-intoxicated animals. These results demonstrate that selective activation of BK channels is responsible for acute intoxicating effects of ethanol in C. elegans. BK channel activation may explain a variety of behavioral responses to ethanol in invertebrate and vertebrate systems.     

Are shy individuals less behaviorally variable? Insights from a captive population of mouse lemurs

Increasingly, individual variation in personality has become a focus of behavioral research in animal systems. Boldness and shyness, often quantified as the tendency to explore novel situations, are seen as personality traits important to the fitness landscape of individuals. Here we tested for individual differences within and across contexts in behavioral responses of captive mouse lemurs (Microcebus murinus) to novel objects, novel foods, and handling. We report consistent differences in behavioral responses for objects and handling. We also found that the responses to handling and novel objects were correlated and repeatable. Lastly, we show that shyer individuals may show less variability in their behavioral responses. This study provides new information on the potential for behavioral syndromes in this species and highlights differences in the degree to which behavioral types (e.g., shy/bold) vary in their behavioral responses.