Объявление

Свернуть
Пока нет объявлений.

Публикации

Свернуть
  • Фильтр
  • Время
  • Показать
Очистить всё
новые сообщения

  • Программа 8-й международной конференции СТРЕСС И ПОВЕДЕНИЕ

    Программа 8-й международной конференции СТРЕСС И ПОВЕДЕНИЕ

    Мы приводим научную программу конференции "Стресс и Поведение", которая состоится в С.-Петербурге, Россия. 17-19 мая 2004.

    Понедельник, 17 мая 2004 Институт Экспериментальной медицины РАМН (ул. Акад. Павлова, 12) 8.00-9.00 Регистрация участников 9.00-9.30 Открытие конференции Приветственное слово Председателя Оргкомитета конференции А.В. Калуева Приветственное слово Директора Института экспериментальной медицины РАМН, академика РАМН, Вице-президента РАМН Б.И. Ткаченко Приветственное слово Президента Российского общества биопсихиатрии проф. О.Г.Сыропятова Приветственное слово Председателя Программного комитета проф. В.М. Клименко 9.30-10.30 Пленарные лекции. Проф. Дж. Фелдон (Швейцария) Экспериментальные модели депрессии Проф. И.П. Лапин (Россия) Нейрокинуренины как ...
    Читать дальше | К сообщению

  • Не спешите их хоронить, или апология биологических механизмов эволюции мозга

    Автор: Николай Новицкий
    Издавался какой-то научный труд. Редактора насторожила такая фраза: "Со времен Аристотеля мозг человеческий не изменился". Может быть, редактор почувствовал обиду за современного человека. А может, его смутила излишняя категоричность. Короче, редактор внес исправление. Теперь фраза звучала следующим образом: "Со времен Аристотеля мозг человеческий ПОЧТИ не изменился".
    С. Довлатов «Соло на ундервуде»

    1. Определения и недоразумения
    ...
    Читать дальше | К сообщению

  • Научение и память: системная перспектива

    Научение и память: системная перспектива

    Автор: Ю.И. Александров (Лаборатория нейрофизиологических основ психики им. В.Б. Швыркова, Институт психологии РАН, Москва)

    Содержание


    Введение
    Детерминация активности нейрона
    От концепции нейрона сумматора и проводника возбуждения к концепции его интегративной деятельности
    Нейрон как «организм» в организме
    Объединение нейронов в систему как способ достижения результата на уровне целого организма и отдельной клетки
    «Действие» нейрона
    Множественность «нейротрансмиттеров»
    Научение как образование «следов» и как системогенез
    Системно-селекционная концепция научения
    Актуализация памяти при реализации поведения
    Неонейрогенез
    Консолидация памяти: от формирования и упрочения «следов» посредством повышения эффективности синапсов к системогенезу
    Реконсолидация при реактивации памяти и при научении
    Консолидация с системной точки зрения
    В начале формирования памяти: экспрессия «ранних» генов как показатель рассогласования
    От рассогласования через согласование к консолидации
    Элиминация нейронов как «альтруистичный суицид»
    Долговременная потенциация: полезный артефакт?
    Выдвижение и селекция гипотез при научении
    Индивидуальное развитие как последовательность системогенезов
    Заключение
    Благодарность
    Литература


    Введение...
    Читать дальше | К сообщению

  • Об уникальной фотографии из нашего архива

    Об уникальной фотографии из нашего архива

    Академик РАМН, Заслуженный деятель науки РФ Н.А.Агаджанян
    Многочисленные исследования ученых – представителей молодой науки “науковедение” позволяют увидеть в истории физиологии определенные периоды отличающиеся своей спецификой. Так, во времена Гиппократа внимание ученых концентрировалось на функциях целостного организма (лечить не болезнь, а больного). На протяжении последующих столетий с помощью прогрессирующих смежных наук – физики, химии (позже – биофизики и биохимии) успешно исследовались функции отдельных органов и систем, включая механизмы их клеточной активности.
    ...
    Читать дальше | К сообщению

  • ЭЭГ руководство (часть 1: Basic concepts)

    ЭЭГ руководство (часть 1: Basic concepts)

    The selected sections of Chapter 35 “Electroencephalography”. From Handbook: Modern techniques in neuroscience research. Ed. U.Windhorst. Springer-Verlag, 1999. By Ivanitsky A.M., Nikolaev A.R., Ivanitsky G.A.

    EEG Origin

    Generators of electric field which can be registered by scalp electrodes are groups of neurons with uniformly oriented dendrites. The neurons permanently receive impulses from other neurons. These signals affect dendritic synapses inducing excitatory and inhibitory postsynaptic potentials. Currents derived from synapses move through the dendrites and cell body to a trigger zone in the axon base and pass through the membrane to the extracellular space along the way. EEG is a result of summation of potentials derived from the mixture of extracellular currents generated by populations of neurons. Hereby the EEG depends on the cytoarchitectures of the neuronal populations, their connectivity, including the feedback loops, and the geometries of their extracellular fields (Freeman 1992). The main physical sources of the scalp potentials are the pyramidal cells of cortical layers III and V (Mitzdorf 1987).


    Figure. Neuronal oscillators inside the cortex, discharging with their intrinsic frequencies (f1, f2, f3), produce extracellular currents summed o...
    Читать дальше | К сообщению

  • ЭЭГ руководство (часть 2: Signal analysis)

    ЭЭГ руководство (часть 2: Signal analysis)

    The selected sections of Chapter 35 “Electroencephalography”. From Handbook: Modern techniques in neuroscience research. Ed. U.Windhorst. Springer-Verlag, 1999. By Ivanitsky A.M., Nikolaev A.R., Ivanitsky G.A.

    Fourier Transform The Fourier transform (FT) is a method to uncover the rhythmic structure of EEG. It is based on a mathematical fact that any signal defined in a given time interval can be decomposed into a sum of sinusoidal waves of different frequencies, amplitudes and phases. The FT is a method for signal’s frequency spectrum estimation. Mathematically, any signal in a given time interval can be decomposed into a sum of mutually orthogonal sinusoidal waves of different frequencies, amplitudes and phases. The FT is a complex function of frequency that describes these components’ amplitudes and phases. The FT is thus a way to obtain a spectrum of a signal. If some rhythms are present in an analyzed segment of EEG, these could be recognized as peaks on a spectrum obtained via FT. There are certain subtle points with the FT application. The first one is that FT is a complex function that can n...
    Читать дальше | К сообщению

  • ЭЭГ руководство (часть 3: Other issues)

    ЭЭГ руководство (часть 3: Other issues)

    The selected sections of Chapter 35 “Electroencephalography”. From Handbook: Modern techniques in neuroscience research. Ed. U.Windhorst. Springer-Verlag, 1999. By Ivanitsky A.M., Nikolaev A.R., Ivanitsky G.A.
    EEG Classification Using Artificial Neural Networks
    • Artificial neural networks (ANNs) is a convenient instrument to reveal EEG features pertinent to certain mental functions, and to perform classification of EEG based on these features.
    Each EEG component is caused by some brain process, whose nature, however, is in many cases unknown. This idea is linked to the problem of the normal subject's EEG classification. Since the EEG is a complicated and a multicomponent process, it is usually difficult to decide w...
    Читать дальше | К сообщению

  • Экспериментальное моделирование тревожности и депрессии

    Экспериментальное моделирование тревожности и депрессии

    Автор: А.В. Калуев, Медицинская школа Университета Тампере, Тампере, Финляндия
    Тревога и депрессия обладают огромный влиянием на поведение человека и животных. В настоящей лекции делается междисциплинарный обзор существующих экспериментальных моделей в области тревожно-депрессивного поведения с целью рассмотрения ряда важных аспектов биологической психиатрии данных патологий ЦНС. Понимание нейробиологических и поведенческих маркеров тревоги и депрессии у животных поможет специалистам-клиницистам лучше узнать нейробиологическую основу и пророду патогенеза. Ключевые слова: тревога, депрессия, биологическая психиатрия, экспериментальные модели. Abstract Anxiety and depression have dramatic impact on human and animal behaviours. We take an interdisciplinary approach and review the existing experimental models of anxiety and depression in order to promote further understanding of “biological” aspects in biological psychiatry of anxiety and depression. The present lecture provides a comprehensive overview of the existing neurobehavioural markers and models of anxiety and depression. Knowledge of neurobehavioural aspects and theories behind animal experimental disorders described in the present paper will assist health professionals to better understand the biological nature and causes of anxiety and depression. Key words: anxiety; depression; biological psychiatry; experimental models Introduction Stress is known to play the main role in pathogenesis of mental disorders including anxiety and depression [1-4]. According to McKinney [1], we use animal models as “experimental preparations developed in one species for the purposes of studying phenomena occurring in another species”. Over the past decades, there has been intensive study of a variety of neurobiological aspects of depression and anxiety and it is now widely recognized that anxiety and depression are associated with definite specific biological changes. Mice and humans share more then 90% of their genes, and animal models seem to be a useful tool in bio-medical sciences, as evidenced by a notable increase in the number of active laboratories working in the field. Animal models are particularly of help in cases where the impact of stress cannot be studied in humans because of ethical and other like reasons. However, the choice of which biological correlates to study is not easy. Problems with animal models of human psychic disorders include i) the difference between human’s and non-human’s nervous systems, ii) the difficulty in determining analogous behaviours among species and iii) the need in extrapolation of results from animals to humans. Such problems most likely reflect a significant difference in ethiology and complexity of anxious or depressive behaviours. In addition, the data derived from animal models are of value only to the extend that the models are valid [2], and the level of the disorder in animals may not be the level of the disorder in humans we want to model. Today our understanding of how anxiety and depression occur in the brain is still quite limited despite the tremendous progress made in this field since 1950s. In order to further promote cooperation between basic and clinical science, here we focus on a comprehensive and systematic approach to the existing neurobehavioural markers and experimental models of anxiety and depression. General concepts Behavioural repertoire of animals has long been used to detect effects on, and impact of, anxiety and depression [1, 3, 4]. A number of models, based on animal emotional reactivity, have been designed and proven to be bidirectionally sensitive to stressful manipulations, including those of anxiety and depression [5], see Tables 1 and 2. Many of these models have been successfully used to test new anxiolytics or antidepressants and understand the underlying neural mechanisms [2, 3, 4] by simple, rapid and inexpensive ways of evaluating an animal’s condition (Table 3). Substantial progress has been made in our understanding which stressors may affect behaviour and how. However, there are several key questions in this field we still have to answer. Can we really distinguish animal anxiety and depression? Do we have reliable neurobehavioural tools to assess anxiety and depression in animals? And, finally, do we always provide correct interpretations of behavioural changes seen in experiments? The paper will review the traditional animal models of, and discuss neurobehavioural approaches to, experimental anxiety and depression. Classification of experimental animal anxiety and depression is a difficult task. Animal anxiety and depression taxonomy can be based on the nature and type of stressors employed (Tables 1, 2), with the continuum of animal models used in psychiatric research ranging from “basic” animal assays to sophisticated homologous models [6]. The former are based on animal behaviours that do not need to be similar to human symptoms while the latter share some functional similarity with human behaviour. Depending on the aim of research, on can use simple models that utilize relatively primitive manipulations, complex models which incorporate both neurobehavioural and behavioural/cognitive aspects, or hybridic models that mechanically combine two working simple models in one new [7, 8], see also an example in [9]. Experimental anxiety and depression can be acute, sub-chronic and chronic (the latter is crucially important, for example, for modelling depression where behavioural symptoms persist for a period of weeks [2]). The models can be inducing pathology (e.g. by drugs, targeted gene mutations, brain lesions/stimulation or stressful external factors) and measuring pathology (in terms of behavioural and physiological reactions). Other classification considers the models as state or trait, as well as those based on unconditioned or conditioned response [10, 11]. Some authors [12] suggest that anxiety models can be based on: i) exploratory behaviours, ii) social behaviours, iii) defensive behaviours, iv) novelty responses, v) conditioning (active/passive avoidance), vi) suppression of hedonic behaviour, vii) conditioned fear. In addition, there are numerous models of anxiety and depression based on prenatal and neonatal manipulations, including acute and chronic exposure to various stressors or different psychotropic drugs (see [6] for a detailed and updated review). As expected, such experience resulted in long-term behavioural and neurobiological changes similar to those seen in humans having early life stress. Models of anxiety and depression can be “natural” (based on measuring natural animal behaviours) or “artificial” (utilizing behaviours not normally seen in natural conditions), Tables 1 and 2 [8, 10]. Natural animal models aim to reproduce behavioural and pathological aspect of the disorder, to investigate the neurobiological mechanisms that are not easily amendable to study in humans, and allow a reliable evaluation of a number of external factors including pharmacological agents [11]. Such ethologically based paradigms are more sensitive to stress compared to “artificial” animal conditioned behaviour models which usually use strong and often painful stressors (Table 4). Clearly, the stressfulness of the test has to be taken into account when analysing the behaviour, as it may significantly affect behavioural performance. Since extreme stressors suppress general activity and result in non-specific alterations in animal performance [7, 8], our paper will now focus on the first group of models, more relevant to assess the nature of anxiety and depression. Principal methodological issues Papers dealing with modification, validation or refinement of the existing models and introducing the new experimental paradigms are reported with astonishing frequency. Are animal anxiety and depression a good approximation of human disorders? Which tests are good models of anxiety or depression? Which particular subtypes of anxiety of depression they model? - these questions are relatively rarely asked, but are fundamentally important. The use of nearly all animal models from all groups has been extensively critisized in the literature. First, one has to keep in mind that many clinically important symptoms, especially cognitive-based, of anxiety and depression can not be directly modeled in animals. Second, it appears that serious modelling problem is that the measures are confounded and reflect changes in general activity, exploration and anxiety-depression levels [16, 17, 18, 19]. Sometimes poor correlation between different behavioural measures taken in the same test, or the same measures taken in several different tests, is another problem [8]. For example, demonstrate that anxiety-like behaviour detected by using the plus-maze test is not detectable by using the two compartment exploratory test or the inner segment ambulation scoring in the open field-test. Furthermore, grooming and defecation can often be seen as the only behaviours that change in the tests designed to measure anxiety behaviours, not grooming, urinations and defecations [20, 21]. Scoring of defecation (for years used as “emotionality index”) often fails to correlate with any of the parameters in rodent anxiety models [8]. The simplest task – distinguishing between horizontal exploration and locomotion in the open field, often mistakenly used synonymously in the literature - is also open for further elaboration [22]. Thus, since it is difficult to interpret a subjective anxiety or depression level based on a single behavioural measure, proper understanding of animal state is only possible through assessment of interaction between behavioural and physiological variables in the multivariate analysis [23]. Also importantly, various forms of psychopathologies in animals and humans can be characterized as context-regulation disorders. This means that subjects may sometimes produce “normal” behaviour in inappropriate contexts. As such, a special research on behavioural contexts may be needed in the field of animal anxiety or depression biological psychiatry. It is important to remember that animal emotional behaviour is not just “plus” or “minus”. It is composed of several dimensions including anxiety, exploration, locomotion, risk assessment, general arousal and coping [24]. These dimensions interact with each other and cognitions, giving us a mosaic picture of animal or human behaviour. That is why traditional quantitative behavioural methods (i.e. latency, frequency and duration parameters and their spatial, temporal or sequential patterns) of animal stress are now combined with sophisticated analysis to assess “not just the presence or absence of these behaviours, but also whether or not the … acts, postures and gestures are fully developed in intensity, latency and patterning” [25]. In this context, trivial rather than relevant relationships among certain behaviour indices taken from the same test and common low correlations among variables apparently measuring the same phenomena in different models of anxiety or depression [26] . Because not all significant and robust behavioural changes are, in fact, meaningful parameters for assessment of animal anxiety and depression, there is a need for clear-cut measures that will be resistant to experimental conditions or apparatus design of particular laboratories but show reliable and predictable changes following experimental manipulations affecting anxiety and depression states (Table 4). However, here appears a new cluster of issues. First, can one model different subtypes of anxiety and depression? Distinct subtypes of anxiety can be modeled in the same test as suggested in [27] for the elevated plus maze (single vs. repeated testings). Second, although depression and anxiety are considered to be separate entities according to current diagnostic classifications, in clinical practice these two conditions are often seen to co-exist. “Ideal” modeling of anxiety or depression in animals presumes that in order to achieve better results we model either pathology separately. The important problem now is whether animals may possibly have comorbidity of depression and anxiety. Theoretically we see no reasons for excluding such cases, and they indeed may represent certain interest for the researchers. Relatively few studies of that kind have been conducted and there is a great need in developing specialized models which will allow to detect and study putative comorbidity states in animals. This can be an important and fruitful direction for future studies in biological psychiatry. Another key question to be asked here is whether we need a single model to be differentially sensitive to anxiety and depression. In other words, can we model several pathologies that develop one by one, in the same experimental test? From neurobehavioural perspective, such “combinational” models can be extremely useful and require future elaboration, and some promising approaches already come from neurogenetics. For example, Wistar-Kyoto rats have been recently suggested as an animal model of anxiety and depression [28] since they demonstrate frequent anxiety-like freezing and also depressive-like swim immobility. Gass et al. [29] suggested that mice with targeted mutations of gluco/mineralocorticoid receptors are the model of anxiety and depression. Perhaps, encouraging can be recent results obtained in high-anxiety HAB rats [24], considered to be a reliable model of trait anxiety and depression. Thus far, measuring comorbidity of anxiety or depression with other pathologies (addiction, etc), or measuring these states occurring consequently, may present an important field of research. It is, however, critical to ensure that all such models are being thoroughly validated. Validity and reliability of the models The discussion focusing on different aspect of animal models validity is key in biological psychiatry. Validation is defined as the process by which the reliability and relevance of a method are established for specific purposes. Reliability is characterized by the reproducibility of a test within and between laboratories and over time. Since numerous differences exist between laboratories, good reproducibility at least between the same laboratory has to be established [24]. At present, three principal and some additional validity criteria have been formulated and substantiated for animal models of anxiety and depression, including predictive, construct, concurrent or convergent, discriminant, ethiological and face validity [7, 30], see also Table 5. In addition, genetical validation based on behavioural phenotyping approach, is becoming increasingly important [15]. A “behavioural phenotype” refers to the specific and characteristic behavioural repertoire exhibited by animals with a specific genetic/chromosomal disorder [15]. As such, finding sets of “anxiety” or “depression” chromosomes involved in traditional experimental models in some cases will assist in genetical validation of novel putative models of anxiety or depression. However, the question as for whether certain behaviours shall be a part of behavioural phenotype, is far from being clearly understood. In animal models, as in the clinic, an association between behaviour and syndrome, and between the syndrome and the gene, is not always clear-cut and linear. On validity basis, animal models can be classified as correlational (based on predictive validity), isomorphic (based on face validity) and homologous (based on construct validity). A model shall fulfill all 3 criteria in order to be good model [42, 43] which means to be correlational, isomorphic and homologous at the same time. However, this situation is not seen in animal modeling very often. For example, traditional models of depression such as Porsolt’s swim and tail suspension tests lack face and construct validity but are extremely good at predictive validity [43]. Despite the fact that some animal models have poor construct and predictive validity, and there is a disconnect between predictive validity and face validity [11], construct validity seems to be the most important for the animal model of anxiety and depression. Conclusion As it was mentioned earlier, all animal models are generally seen as an attempt to reproduce a psychiatric disorder in a laboratory animal [1]. However, since the symptoms of psychiatric disorders are often being revised and their pathogenesis revisited [30, 44, 45], some caution is needed before claiming or using an animal model of anxiety or depression. With this in mind, we shall always remember that, as McKiney [46] incredibly timely and rightly notes, generating the perfect animal model does not represent a separate goal of research in biological psychiatry, rather the model and its constant evolution represents an integral part of biological psychiatry. And, of course, modelling proceeds most effectively when psychiatrists who are experts in the phenomena in question join forces with neuroscientists who know and understand available modelling tools [47]. Today, with the growing number of medical professionals being involved in basic research, and neuroscientists being heavily involved in clinically-oriented studies, an interdisciplinary view of anxiety and depression research, linking human data to animal experimentation, is becoming extremely important. References: 1. McKinney W.T. Animal models of depression: an overview // Psychiatry. - 1984. - Vol. 2. - P. 77-96. 2. Willner P. Validity, reliability and utility of chronic mild stress model of depression: a 10-year review and evaluation // Psychopharmacol. - 1997. - Vol. 134. - P. 319-329. 3. Arborelius L., Owens M.J., Plotsky P.M., Nemeroff C.B. The role of corticotropin-releasing factor in depression and anxiety disorders // J. Endocrinol. - 1999. - Vol. 160. - P. 1-12. 4. Paterson A., Whitting P.J., Gray J.A. et al. Lack of consistent behavioural effects of Maudsley reactive and non-reactive rats in a number of animal tests of anxiety and activity // Psychopharmacol. - 2001. - Vol. 154. - P. 336-342. 5. Espejo E.F. Structure of the mouse behaviour on the elevated plus-maze test of anxiety // Behav. Brain Res. - 1997. - Vol. 86. - P. 105-112. 6. Newport D.J., Stowe Z.N., Nemeroff C.B. Parental depression: animal models of an adverse life event // Am. J. Psychiatry. - 2002. - Vol. 159. - P. 1265-1283. 7. Sarter M., Bruno J.P. Biological psychiatry // Animal models in biological psychiatry / D’haenen H., den Boer J.A., Willner P., New York, John Willey and Sons, 2002. 8. Kalueff A.V. Today and tomorrow of anxiety research // Stress Behav. - 2003. - Vol. 8. - P. 145-147. 9. Dere E., Topic B., De Souza M.A. The graded anxiety test: a novel test of murine unconditioned anxiety based on the principles of the elevated plus-maze and light-dark test // J. Neurosci. Meth. - 2002. - Vol. 122. - P. 65-73. 10. King J.A., Messenger T., Ferris C.F. Seed finding in golden hamsters: a potential animal model for screening anxiolytic drugs // Neuropsychobiol. - 2002. - Vol. 45. - P. 150-155. 11. Overall K.L. Natural animal models of human psychiatry conditions: assessment of mechanisms and validity // Prog. Neuropsychopharm. Biol. Psychiatry - 2000. - Vol. 24. - P. 727-776. 12. Wall P.M., Messier C. Methodological and conceptual issues in the use of the elevated plus-maze as a psychological measurement instrument of animal // Neurosci. Biobehav. Revs - 2001. - Vol. 25. - P. 275-286. 13. Makarchuk N.E., Kalueff A.V. Olfaction and behavior. Kiev: KSF, 2000. 14. Rezvani A.H., Parsian A., Overstreet D.H. The Fawn-Hooded (FH/Wjd) rat: a genetic animal model of comorbid depression and alcoholism // Psychiatr. Genet. - 2002. - Vol. 12. - P. 1-16. 15. Flint J. Animal models of anxiety and their molecular dissection // Sem. Cell Devel. Biol. - 2003. - Vol. 14. - P. 37-42. 16. Rodgers R.J., Cole J.C. Ethological Pharmacology // The elevated plus maze: pharmacology, methodology and ethology / Cooper S.J., Hendrie C.A. New York: Willey, 1994. 17. Lapin I.P. Models of anxiety in mice: experimental verification and critical methodology. // Exp. Clin. Pharm. - 2000. - Vol. 63. - P. 58-62. 18. Belzung C., Griebel G. Measuring normal and pathological anxiety-like behaviour in mice: a review // Behav. Brain Res. - 2001. - Vol. 125. - P. 141-149. 19. File S.E. Factors controlling measures of anxiety and responses to novelty in the mouse // Behav. Brain Res. - 2001. - Vol. 125. - P. 151-157. 20. Kalueff A.V., Makarchuk N.E., Samohvalov V.P., Deryagina M.A. Urination and behavior. Kiev: KSF, 2001. 21. Kalueff A.V. Grooming and stress. M: Avix, 2002. 22. Choleris E., Thomas A.W., Kavaliers M., Prato F.S. A detailed ethological analysis of the mouse open field test: effects of diazepam, chlordiazepoxide and an extremely low frequently pulsed magnetic field // Neurosci. Biobehav. Revs - 2001. - Vol. 25. - P. 235-260. 23. Calatayud F., Belzung C. Emotional reactivity in mice, a case of nongenetic heredity? // Physiol. Behav. – 2001. – Vol. 74. - P. 355-362. 24. Salome N., Viltart O., Darnaudery M. et al. Reliability of high and low anxiety-related behavuiour: influence of laboratory environment and multifactorial analysis // Behav. Brain Res. - 2002. - Vol. 136. - P. 227-37. 25. Barrett J.E., Miczek K.A. Psychopharmacology, the forth generation of the progress // Behavioral techniques in preclinical neuropsychopharmacology research / Bloom F.E., Kupfer D.J. New York: Raven Press, 2000. 26. Aguilar R., Gil L., Flint J. et al. Learned fear, emotional reactivity and fear of heights: a factor analytic map from a large F2 intercross of Roman rat strains // Brain Res. Bull. - 2002. - Vol. 57. - P. 17-26. 27. Holmes A., Rodgers R.J. Prior exposure to the elevated plus-maze sensitizes mice to the acute behavioral effects of fluoxetine and phenelzine // Eur. J. Pharmacol. - 2001. - Vol. 459. - P. 221-230. 28. Tejani-Butt S., Kluczynski J., Pare W.P. Strain-dependent modification of behavior following antidepressant treatment // Prog. Neuropsychopharmacol. Biol. Psychiatry - 2003. - Vol.27. - P. 7-14. 29. Gass P., Reichardt H.M., Strekalova T. et al. Mice with targeted mutations of glucocorticoid and mineralocorticoid receptors: models for depression and anxiety? // Physiol. Behav. - 2001. - Vol.73. - P. 811-825. 30. Geyer M., Markou A. Psychopharmacology, the forth generation of the progress // Animal models in psychiatric disorders / Bloom F.E., Kupfer D.J. New York: Raven Press, 2000. 31. Kalueff A.V. Problems of the study of stress-related behavior. Kiev: KSF, 1999. 32. Moyano A., Eguibar J.R., Diaz J.L. Induced grooming transitions and open field behavior differ in high- and low-yawning sublines of Sprague-Dawley rats // Animal Behav. - 1995. - Vol. 50. - P. 61-72. 33. Andrade M.M., Tome M.F., Santiago E.S. et al. Longitudinal study of daily variation of rats’ behavior in the elevated plus maze // Physiol. Behav. - 2003. - Vol. 78. - P. 125-133. 34. Belzung C. Handbook of Molecular genetics for brain and behavior research // Measuring rodent exploratory behavior / Cruzio W.E., Gerlai R.T. New York: Elsevier, 1999. 35. Chapillon P., Manneche C., Belzung C., Caston J. Rearing environment enrichment in two inbred strains of mice: 1. Effect of emotional reactivity // Behav. Genet. - 1999. - Vol. 29. - P. 41-46. 36. Magalhaes A., Tavares M.A., De Sousa L. Postnatal cocaine: effects on behavior of rats in forced swim test // Ann. N.Y. Acad. Sci. - 2002. - Vol. 965. - P. 529-534. 37. Kelly J.P., Wrynn A.S., Leonard B.E. The olfactory bulbectomized rat as a model of depression: an update // Pharmacol. Ther. - 1997. - Vol. 74. - P. 299-316. 38. Mayorga AJ, Lucki I. Limitation on the use of C57BL/6 mouse in the tail suspension test. Psychopharmacol 2001. - Vol. 155. - P. 110-112. 39. Fundarro A. Pinch-induced catalepsy in mice: a useful model to investigate antidepressant or anxiolytic drugs // Progr. Neuropsychopharmacol. Biol. Psychiatry - 1998. - Vol. 22. - P. 147-158. 40. Chen S.W., Xin Q., Kong W.X. et al. Anxiolytic-like effect of succinic acid in mice // Life Sci. - 2003. - Vol. 73. - P. 3257-3264. 41. Bouwknecht J.A., Hijzen T.H., van der Gugten J. et al. Stress-induced hyperthermia in mice: effects of flesinoxan on heart rate and body temperature // Eur. J. Pharmacol. - 2000. - Vol. 400. - P. 59-66. 42. Clement E.Y., Calatayd F., Belzumg C. Genetic basis of anxiety-like behaviour: a critical review // Brain Res. Bull. - 2002. - Vol. 57. - P. 57-71. 43. Bai F., Li X., Clay M. et al. Intra- and interstrain differences in models of "behavioral despair" // Pharmacol. Biochem. Behav. - 2001. - Vol. 70. - P. 187-192. 44. Boyer P. Do anxiety and depression have a common pathophysiological mechanism? // Acta Psychiatr. Scand. Suppl. - 2000. - Vol. 406. - P. 24-29. 45. Borsini F., Podhorna J., Marazziti D. Do animal models of anxiety predict anxiolytic-like effects of antidepressants? // Psychopharmacol. - 2002. - Vol. 163. - P. 121-131. 46. McKinney W.T. Overview of the past contributions in animal models and their changing place in psychiatry // Sem. Clin. Psychiatry - 2001. - Vol. 6. - P. 68-78. 47. Davidson R.J., Lewis D.A., Alloy L.B. et al. Neural and behavioral substrates of mood and mood regulation // Biol. Psychiatry - 2002. - Vol. 52. - P. 478-502. Table 1. Animal models in the study of anxiety and depression I. Depression: Acute: 1) Pharmacologic: Reserpine- or clonidine-induced depression 2) Stress-evoked: Porsolt test (forced swimming) behavioural despair task, tail suspension test, inclined /vertical screen test Chronic: 3) Stress-evoked Learned helplessness (unsignalled inescapable shock) Vogel and Gellert tests 4) Social disruption: Maternal or peer separation, Social defeat, altered group hierarchy Reduced submissive behaviour 5) Chronic stress-evoked depression models (see also p. 7) 6) Sensory models: Olfactory bulbectomy Long-term ZnSO4-induced anosmia 7) Anhedonic models Willner’s test (sucroze consumption), Hedonic behaviour suppression [2]. II. Anxiety: Acute: 1) Pharmacologic: Convulsant- or stimulant-induced anxiety 2) Stress-evoked: “Forced” single-factor (novelty) or multi-factor tests (eg. novelty + aversion): elevated plus or zero-maze, light-dark box, holeboard, inclined or vertical screen test, seed seeking behaviour in hamsters, shock-probe defensive burying, etc. Free exploration paradigm 3) Social models: Social interaction (File’s) paradigm Chronic: 4) Stress-evoked: Learned anxiety (Geller conflict test), Chronic forced exposure to acute stressors 5) Social models: Chronic social defeat test* 6) Prenatal stress-evoked “state” anxiety models 7) Sensory models: Short-term ZnSO4-induced anosmia*, Exposure to novel or predator odors, Amputation of vibrissae 8) Innate anxiety: Selected “high-anxiety” strains III.Transitory models: Initially anxiety then depression Anosmia-induced anxiety-depressive symptoms [13], partition test IV.Combination models: Anxiety and depression states to be measured simultaneously ** V. Comorbidity models: Allows to model anxiety or depression in comorbidity with other psychiatric illnesses (eg. addiction, see [14] for details, epilepsy, etc) Comments: *See [8] for details. ** Porsolt’s swim and tail suspension depression tests are also sensitive to some anxiolytic actions. Table 2. Summary of animal conditioned response-based models [15] Two way avoidance conditioning test “Shuttle box” Rate of acquisition response Accoustic startle Contraction in response to loud noise Foot shock induced freezing Contraction in response to conditioned stimuli Fear-potentiated startle Contraction in response to loud noise in conjunction with loud noise Geller (Geller-Seifnert) conflict test Frequency of conditioned response coincidental to an electrical shock Vogel conflict test Frequency of conditioned licking coincidental to an electrical shock Table 3. Principal behavioural profiles in experimental models of anxiety and depression Behavioural indices Anxiety Depression General locomotion Exploration Self-grooming Immobility Defecation, urination Aggression Self-aggression Transitions between behaviours Risk assessment Some other “specific” behaviours Activated Decreased Activated (frequency) Activated (freezing) Activated Activated 0 Increased Increased or decreased *** Activated**** Inhibited * Decreased Activated (duration) Activated (despair)** ? Activated Activated Decreased Decreased 0 ? Comments: ? means unclear or inconsistent effects, 0 means no effects. *activated in the open field in olfactory bulbectomy model of depression. **in Porsolt’s swim and tail suspension tests. ***depending on the model. **** e.g. seed finding, shock-probe defensive burying, etc., see [10) for details. Table 4. Major behavioural measures in experimental models of anxiety and depression Tests Neurobehavioural parameters Anxiety Depres sion Ref. Open field (circular, square or rectangular open lit arenas) Defecations/urinations number and duration Total distance traveled or squares crossed Speed of movements Distance in the inner area Number of squares crossed in the inner area Distance in the outer area Self-grooming latency duration frequency % of interrupted (aborted) or incorrect groomings Average duration of a single grooming Stretch Attend postures Latency of the 1st and the 2nd visits to the central area Latency to leave the central area + - + - - - - + + + - + + + - + * - + + - +? ** + - ? ? [20, 26, 31, 32] Open field with novel objects Approach latency Number of contacts Duration of exploration of the novel object + - - 0 0 0 See [20] for a review Elevated plus maze (plus-shaped maze) Latency to leave the centre Total arms entries (4 paws criterion) Enclosed arms entries Open arms entries (4 paws) and rears (2 paws) Time spent in the open arms Time spent in the enclosed arms % Open arms entries % Time spent in the open arms Head dips Defecations, urinations Self-grooming latency duration frequency Central platform crossings and time spent + a + - - + - - - + + + + - - + - + - ? [17, 26, 31, 33) Hole board test (open field arena with “exploratory” holes in the floor) Head dipping (hole poking) latency number, duration Defecations, urinations, total distance traveled/squares crossed, distance/squares crossed in the inner area, distance in the outer area, self-grooming, rears. - + - as in the open field ? + - as in the open field [20, 26, 31] Light/dark box (two boxed interconnected with a sliding door) Light box entries number (4 paws criterion) Light box time spent Light box rears number (2 paws criterion) Duration of light box rears Latency of the first rear and entry Vertical activity in the light box (c) Urinations, defecations, grooming - - - - - + + - - - - - ? ? [21, 31] Exploration of novel objects Number of approached and contacts Duration of contacts Latency of the first approach/contact - - + - - + [31, 34] Free exploratory paradigm Number of entries to the novel compartment Time spent in the novel environment Latency to enter the novel compartment Stretch attention, rearing to the novel box - - + - ? ? ? ? [35] Porsolt’s swim test (water tank) Immobility latency (until first floating) Immobility duration in the water tank Swimming average speed and distance ? ? - - + - [24,31] Olfactory bulbectomy Behavioral hyperlocomotion in the open field Aggression - + + [37] Tail suspension test Immobility latency Immobility duration “Tail-climbing“ +? +? - + + - [31, 38] Inclined screen retention test Time spent on the screen (falling latency) Urinations, defecations - + - - (?) [31] Pinch-induced catalepsy Duration of catalepsy Required number of pinches +? +? +? +? [39] Stress-induced hyperthermia The amplitude of hyperthermia The duration of hyperthermia + + ? ? [40, 41] Hyponeophagia Latency to start eating + ? [15] Comments: + means activation of a behavioural pattern, - means inhibition of a behavioural pattern, ? means unclear or inconsistent effects. *in olfactory bulbectomy depression model. **Different effects of anxiety (shortening, reversals) and depression (prolonged, stereotypic). Table 5. Summary of validity of animal models of anxiety and depression Validity Impor tance Brief description Major Face Predictive Construct - + ++ Reflects phenomenological similarities (isomorphism) between the model and human pathology to be modeled Based on ability to predict drugs or manipulations effective in animal models to be effective in humans. May be limited to the drugs or manipulations it has been designed for. Based on similar theoretical rationale (homology) behind the pathology in animals and humans. May be limited to the extend of our knowledge of pathological mechanisms Additional Discriminant Convergent Ethiological Genetical - - - + Degree to which a test measures aspects of a phenomenon that are different from other aspects of the phenomenon that other tests assess Degree to which a test correlates with other tests to measure the same construct Degree of similarity of ethiology of animal and human states Degree of similarity of the genes involved in anxiety or depression induced in a particular test Comments: - not important, + important, ++ critically important....
    Читать дальше | К сообщению

  • Проблемы и перспективы экспериментального моделирования тревоги и депрессии

    Авторы: Калуев А.В., Туохимаа П.

    Проблемы и перспективы экспериментального моделирования тревоги и депрессии // Психофармакол. и биол. наркол. 2004. Медицинская школа и Университетсткий госпиталь, Университет Тампере, Тампере, Финляндия

    Тревога и депрессия являются многофакторными, крайне тяжелыми стрессорными расстройствами. Человек и животные имеют много общих патогенетических механизмов тревоги и депрессии. В настоящей статье рассмотрены экспериментальные подходы к моделированию тревоги и депрессии на животных и сделан подробный анализ существующих проблем и перспектив исследований в данной области биологической психиатрии, понимание которых поможет в поиске новых подходов терапии тревожно-депрессивных расстройств.
    Ключевые слова: тревога, депрессия, биологическая психиатрия, экспериментальные модели. Kalueff A.V., Tuohimaa P. Problems and perspectives of experimental modeling of anxiety and depression // Psihofarmakol. Biol. Narkol. 2004. Medical School, Tampere University Hospital, University of Tampere, Tampere, Finland Anxiety and depression are multifacetic debilitating stress-related behavioural disorders. Humans and animals share many pathogenic mechanisms of these disorders. Here we review the experimental modeling approaches to anxiety and depression in order to contribute to a better understanding of underlying biological aspects of these disorders. The present paper provides a comprehensive overview of the emerging problems and perspectives in the field of experimental biological psychiatry of anxiety and depression. Understanding the existing challenges, limitations and perspectives in the field of experimental modeling of stress-related disorders may assist in the search of novel biologically oriented approaches to the treatment of human anxiety and depression. Key words: anxiety; depression; biological psychiatry; experimental models Introduction In recent years a large body of evidence appear to link stressful life events with an increased vulnerability for anxiety and depression disorders [1]. Anxiety and depression have long been known to have dramatic impact on behaviour [2]. Numerous clinical data show that patients with anxiety and depression differ in their behavioural manifestations, although in many cases mild anxiety and mild depression are clinically very similar [3]. Despite human and animal depression or anxiety profiles differ in their cognitive-behavioural aspects, animals share the same “behavioural” problem since many findings show similar behavioural effects of animal anxiety and depression [4, 5]. Study of anxiety and depression is a rapidly developing field where all contemporary theories and paradigms are based on cross-disciplinary approaches and data coming from biology, medicine and psychology [5]. During the past decades, a remarkable link has been formed among psychiatry, physiology, molecular biology, and behavioural biology to demonstrate the striking parallel nature of animal and human anxiety/depression behaviours [1, 3]. Specific social behaviours in rodents are very sensitive to anxiety levels [6]. Homologous to human “social anxiety” state, it is a valuable behavioural model for testing putative anxiotropic manipulations [6]. Aggression is a common feature of many forms of anxiety and depression in humans [5], yet it is often seen as a measure of depressiveness in olfactory bulbectomised rodents [7]. While many forms of human anxiety are based on innate fears of natural dangers, exposure to a predator is known to be a useful model of “innate” animal anxiety [8]. Behavioral “despair” and anhedonia models of animal depression are based on similar behavioral symptoms often seen in human depression [2, 5]. There are numerous models of anxiety and depression based on prenatal and neonatal manipulations, including acute and chronic exposure to various stressors or psychotropic drugs [8]. As expected, such experience result in long-term behavioural and neurobiological changes similar to those seen in humans having early life stress [8]. Exploratory behaviour (walking, approaches, scanning, sniffing, rearing, wall leaning, etc) is most often studied in the laboratory, in forced (non-escapable) or free (free-choice) situations, as stress-sensitive behavioural parameter to assess anxiety and/or depression [9]. Similarly, exploratory drive is known to be severely affected by anxiety and depression in humans [5, 8]. In addition, a number of vetetative behaviours, both in animals and humans, are meaningful parameters that can be sensitive to the level of stress [10, 11, 12]. As such, changes in “additional” behaviours such as self-grooming, defecation, urination, and yawnings [5, 12, 13] may be useful ethological parameters in anxiety/depression research. One can agree that some of these parameters are useful markers of human anxiety or depression. Risk assessment is another important ethological domain in anxiety and depression research [14]. In animals, these “anxiety-defensive postures” include immobility (freezing), stretched attention (orientation) and “flatback” approach to the stimulus [14, 15, 16]. In humans, there is a set of surprisingly similar alarming reactions which, both in animals and humans, are particularly sensitive to stress and can be bidirectionally affected by neurotropic drugs including anxiolytics and, at a lesser extend, antidepressants [5, 11]. However, in experiments it is sometimes difficult to distinguish certain different meaningful behaviours. For example, novelty is often used in stress research as both anxiety-provoking and attractive. Therefore, approach to one stimulus (attraction) will be difficult to distinguish from avoidance of another (aversion) or the lack of motivation to interact (anhedonia) in depression. That is why a detailed analysis and correct terming and interpretation of behaviours are crucial issues for biological psychiatry of anxiety and depression. It must, however, be emphasized that we can not ask animals how they feel in a model or why they react in a certain way. Since the question remains open as to whether we can say that a laboratory animal is “anxious” or “depressed”, problems with data interpretations are well-documented in neurobehavioural studies [2, 5]. However, interpretation of the behaviour is critically important since it may be “more in the eye of the researcher than in the brain of the animal” [14] and, as we can add, “in the brain of the patient”. Pitfalls and problems of animal models Considerable attention has been focused on the pitfalls and weaknesses of anxiety and depression models. As we review these aspects in animals, one can see that many of them are equally important, and perhaps equally ignored, in the clinic. One of the major problems is that “different laboratories commonly employ their own idiosyncratic versions of behavioural tests apparatus and protocols, and any laboratory environment has many unique features” [17]. Can we say that psychiatric clinics too have “own idiosyncratic” views of treating their anxiety and depression patients? Lapin [18] listed other factors often neglected in experimental research of anxiety and depression: vehicle monitoring, handling control, false injection control, body temperature control, general activity control (false positives and negatives), injection effect, time of the day, light conditions, and pre-test manipulations. Ignoring them will almost certainly result in obtaining the data difficult to analyze. As more drugs become available and are used concominantly in different psychopharmacological assays, the potential for drug interaction increases and needs to be taken into consideration. Other significant test problems include: i) strains/species differences, ii) sex and age differences, iii) sensitivity to pretest manipulations (e.g. housing, transportation), iv) construction of apparatus, iv) conditions prior behavioural testing, iiv) scoring method (manual vs. automated), iiiv) acclimation before and after the testing. Variations between laboratories in any of these factors lead to conflicting results [17]. Previous housing regime (individual vs. grouped) is also an important biosocial factor able to affect anxiety and depression-related behaviours [19]. For example, isolated animals tend to be more active in the novel conditions and engage in more exploratory and escape-oriented behaviours [19, 20]. Since animals used in biomedical research are usually reared in small cages that lack key features of their natural habitat, it is now becoming evident that animals need to be reared in enriched conditions in order to be able to produce normal behaviours [20]. Rearing conditions may therefore, and in fact do so, affect behavioural reactions seen in animal models of anxiety and depression, also influencing memory, attention, agonistic behaviours and other important aspects of normal brain-behaviour interaction [17, 19, 20]. Timetable and intensity of the experiments are also key for obtaining correct and reliable experimental data. Since rodents are very sensitive to the rhythm of activity of the researchers and animal house staff (usually much higher from Mondays to Friday), after relatively “easy” weekend days animals will behave differently on Monday than on the rest of the week [21]; interestingly, can the same rule “work” in the clinic, say, to cause different therapeutical sensitivity on Friday and Monday? A significant amount of total variability of the experimental behavioural indexes could also be attributed to 24h variation [22]. All major behavioural parameters in rodents are largely affected by light/dark phases. Since behavioral scores are much higher during the dark time of the day, this shows the importance of standardization of all experimental procedures [22] especially in their timing aspect. The major challenge here, however, lies in determining which factors need to be standardized [23]. For example, the experimenter identity has extremely important role in animal behaviours and strikingly overweights all other factors (in the order of importance: season, cage density, time of the day, sex, humidity and the order of testing) [23]. As such, we can suggest that the important “therapeutic” role of the doctor-patient relations in the clinic [18] may, in fact, be homologous to these pre-clinical observations. Individual differences contribute significantly to the discrepancies and conflicting findings in the literature [24]. Further important problem arises when it became evident that anxiety and depression are heterogenous and each could be divided in various forms. Wehner et al. [25] note that heterogenity of anxiety reflects its polygenic regulation and many behavioural models are used to study its nature. Discussing possible evolutionary rationale, Marks and Nesse [26] write that for anxiety “subtypes exist because of the benefits of having responses specialized to deal with particular dangers or threats”, yet they agree that subtypes of anxiety are not completely distinct as multiple dangers and thereat are common. Various subtypes of anxiety and depression include state (inductive) and trait (consitutive), “male-like” and “female-like”, acute and chronic, innate and evoked, mild and severe subtypes [12, 15, 19, 27, 28]. It is now clear that all these forms are not only neuroethologically and physiologically different but also possess differential sensitivity to stressors. Importantly, a common behavioural factor does not emerge from numerous factor analytical studies and common animal models do not measure the same type of phenomena [29], and different str...
    Читать дальше | К сообщению

  • Диффузная внесинаптическая нейропередача посредством глутамата и ГАМК

    Автор: А.В. Семьянов (Институт Неврологии, Лондон, Великобритания)
    Глутамат и ГАМК являются основными синаптическими нейропередатчиками в мозге. Однако их действие не ограничивается только локальным постсинаптическим участком. Эти аминокислоты способны высвобождаться во внесинаптическое пространство за счет обратного захвата глутамата и ГАМК, глиального экзоцитоза, при осмотическом шоке и спиловере (растекании из синаптической щели). Рецепторы глутамата и ГАМК также расположены на различных участках нейронов и глии. В зависимости от субклеточного распределения этих рецепторов, их субъединичной композиции и метаботропной/ионотропной функции эффект внеклеточного глутамата или ГАМК будет различным. В данном обзоре рассмотрен общий принцип организации диффузных глутамат- и ГАМКергической систем внесинаптической нейропередачи, взаимодействие этих систем с синаптической передачей и взаимодействие диффузных сигналов между собой преимущественно на примере гипокампа.Ключевые слова: спиловер, транспортеры, внесинаптические рецепторы, диффузия, глия. Глутамат является основным нейропередатчиком синаптического возбуждения во взрослом гиппокампе.  Другим основным синаптическим нейропередатчиком в гиппокампе является ГАМК (?-аминомасляная кислота). Долгое время считалось, что эта аминокислота исключительно связана с синаптическим торможением. Но оказалось, что на ранних этапах развития мозга ГАМК опосредует преимущественно синаптическое возбуждение. Во взрослом мозге возбуждающая функция ГАМК сохраняется лишь частично, уступая место синаптическому торможению [21, 22, 134]. Помимо глутамата и ГАМК в гиппокампе обнаружен ряд различных по химической природе нейропередатчиков (моноамины, ацетилхолин, пурины и др.), которые не вовлекаются непосредственно в синаптическое возбуждение или торможение, но оказывают на них модулирующее влияние [30, 35, 73, 144]. Сбалансированна...
    Читать дальше | К сообщению

  • Эгоизм и альтруизм нейрона

    Эгоизм и альтруизм нейрона

    Стенограмма передачи Гордона на НТВ

    Анохин Константин Владимирович - член-корреспондент РАМН, профессор, доктор медицинских наук, руководитель отдела системогенеза института нормальной физиологии им.П.К.Анохина РАМН

    Александров Юрий Иосифович...
    Читать дальше | К сообщению

  • Механизмы нейропротекторного действия витамина Д3

    Механизмы нейропротекторного действия витамина Д3

    Авторы: А.В. Калуев, К.О. Еремин, П.Туохимаа (e-mail: avkalueff@inbox.ru; Центр физиолого-биохимических проблем, Киев, Украина, НИИ фармакологии РАМН, Москва, Россия, Кафедра клинической химии, Медицинская школа Университета Тампере, Тампере, Финляндия)...
    Читать дальше | К сообщению
There are no articles in this category.
  • Фильтр
  • Время
  • Показать
Очистить всё
новые сообщения
Пожалуйста, войдите, используя своё имя пользователя, чтобы увидеть список сообщений из подписки.
Обработка...
X