by Academician Konstantin SUDAKOV, Director of P. K. Anokhin Institute of Normal Physiology, Russian Academy of Medical Sciences, and Konstantin ANOKHIN, Dr. Sc. (Medicine), head of the laboratory at the same institute

An astonishing finding from recent studies of the human and mouse genome is that probably as much as 50 percent of approximately 30-35 thousand mammalian genes are expressed in the nervous system. A question which still remains to be answered is how the massively complex functions of an organism, such as human behavior and cognition, are orchestrated by these thousands of genes.

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One of the answers to this complex question will require a synthesis of molecular genetics with the study of the systems mechanisms of behavior and mental activity Analysis of such mechanisms has been pioneered by I.P. Pavlov's student P.K. Anokhin (1898-1974) in the theory of functional systems.

Functional systems are dynamic self-organizing entities that involve elements from multiple tissues and organs so that all the elements cooperate with each other to achieve an adaptive result for an organism. An organism as a whole thus represents a well- organized aggregate of multiple functional systems at metabolic, homeostatic, behavioral, social and mental levels. Some of these functional systems maintain the stability of homeostatic parameters, while others are responsible for behavior and adaptation to the environment. Many functional systems are formed during embryonic development, whilst others are created during an individual's life and require learning.

According to the theory of functional systems, each behavioral act starts from a stage of afferent synthesis. This stage is responsible for neural integration of environmental information and memory resources with the internal needs of an organism. Afferent synthesis is then followed by sequential stages of decision-making, the formation of an anticipatory model of the required results- "acceptor of the results of action", efferent synthesis, and finally the action itself. This behavior is continuously evaluated by the acceptor of the results of action with the aid of "return afferentation" (reafferentation), until a final result that satisfies the original need of an organism is achieved.

Our studies have further developed this systemic approach by showing that the dynamics of behavioral continuum consist of "systemic quanta" spanning the emergence of a need to its accomplishment. Once an adaptive result has been achieved, the behavioral act is completed being reinforced by a positive emotion from correspondence between reafferentation and the anticipatory model of required result.

This brief outline suffices to illustrate that a systems approach to behavior raises new questions concerning the molecular genetic bases of these processes. What is the role played by the expression of different genes in systemic architecture of behavioral and mental acts? And what new rules are imposed on cellular regulation of gene expression in the conscious brain by a systems level of behavioral organization?

Of particular interest in the context of these questions are genes whose expression is regulated by neural activity Many of such genes like c-fos belong to the family of so-called "immediate early genes" (IEGs). They are known to be very rapidly activated in response to extracellular signals and encode transcription factors that play a role in regulation of cellular growth and differentiation during development.

However, our own studies showed that their expression of IEGs can be also robustly increased in the brain of adult animals during learning.

Their expression is also rapidly elevated in the nervous system if animals are placed into a novel environment or when they encounter difficulties in achieving the required behavioral outcome. We have found that such expression of IEGs in response to a novel situation and/or following learning occurs over many different brain regions and the patterns of their expression are determined by the context of the behavior and environment. IEGs expression is extinguished as the situation loses its novelty or when a behavior has been acquired and become automatic.

A direct test of the role of IEGs in learning and memory came from our experiments with selective inhibition of c-fos expression by antisense oligonu-cleotides. Administration of this short sequence-specific DNA fragments allows to selectively block the expression of targeted genes in the brain. These studies demonstrated that suppression of c-fos mRNA in the animal brain impaired long-term but not short-term memory in various learning tasks. Similar data were also obtained with other IEGs and the general num-

Central architectonics of a functional system on a behavioral level (by P.K. Anokhin).

EA-environmental afferentation, ТА- trigger afferentation.

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A sheme of "system-quantum" of behavior as a unit of organism system activity: n -> A -> B -> C -> D -> n- environmental events. R1-R6 - intermediate behavioral results helping (+) and blocking (-) the satisfaction of the initial need.

Expression of two early genes-C-FOS and C-JUN - in the cerebral cortex of mice learning to avoid skin irritation with electricity. The experimental animals could escape the electric shock by jumping onto a shelf (A). One group was trained to develop an automatic avoidance response (B). A gene expression maximum is observed after the first session of learning, but it wanes as the response becomes automatic (C).

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ber of candidate plasticity genes is currently estimated to be around 1,000.

These data, viewed in the framework of the functional systems theory, suggest that the expression of plasticity in the brain of awake behaving animals occurs under conditions of mismatch between the situational or motivational afferentations and one of the acceptor of the results of action for innate or acquired functional systems. This mismatch between previous experience and expectations of an animal and the actual situation is defined through psychological category of "novelty". Thus, by definition, IEG expression, involving as it does, a subjective assessment of previous experience, must depend on more than just molecular and cellular rules of control. Rather, a systems level approach, like one taken in the theory of functional systems, is required to explain such cognitive-related activation.

Repeated reinforcement of biological motivations of an animal produces a significant change in the properties of neuronal gene expression. For example, when food-deprived animals are allowed to reach and obtain a food, the protein synthesis inhibitors, such as cycloheximide, acquire the ability to completely suppress this feeding behavior for a prolonged period of time. The same picture is observed in animals that were allowed to avoid the site of experimental chamber where they received electric stimulation of the "fear centre" of the ventromedial hypothalamus. In these animals, protein synthesis inhibitors also start to prominently disrupt the acquired place-avoidance behavior.

These experiments demonstrate that new proteins are expressed in the brain as a consequence of repeated reinforcements and that these molecules participate in the organization of certain forms of animal goal-directed behavior.

What are these new proteins? Our experiments suggest that some of them might be neuropeptides. For instance, administration of the neuropeptide pentagastrin into the lateral ventricules of cycloheximide-treated animals can restore their inhibited food reaction. In a similar manner the defence reactions blocked by cycloheximide can be restored by intracerebroventricular administration of bradykinin neuropeptide.

Another group of targets for IEGs products might be genes of cell adhesion molecules, such as N-CAM or Ng-CAM. They are expressed on cell membrane surface and regulate aggregation and disaggregation of cells during neural development. However, our and other data show that antibodies to cell adhesion molecules are able to produce an amnesia in animals if administered within a strictly limited post-learning time period when the target genes for IEG products are activated.

Therefore, one might envision the following succession of molecular and genetic events during learning of new behavior. At the beginning, novelty, expressed as the mismatch of the existing situation with the previously acquired experience initiates activation of the immediate early gene cascade in the cell populations that mediate these behavioral and cognitive processes. The products of immediate early genes, in turn, trigger the expression of the late genes that are also known to participate in the processes of morphogenesis during embryonic development. The genomic response of neuronal cells to learning thus resembles reactions of other cells to growth factors. It is a two-phase response-at the beginning expression of IEGs is induced and later on reinforcement in conjunction with lEG- encoded transcription factors makes possible the expression of target "late" genes.

The English version of the article prepared by the authors

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