by Academician Mikhail OSTROVSKY, President of Pavlov Physiological Society, Laboratory Head of Emanuel Institute of Biochemical Physics, Russian Academy of Sciences

The brain science is universal. It includes not only physiology, but also virtually all biological and a number of medical disciplines, physics with its technological progress, chemistry with its potentialities of new drug synthesis, mathematics and informatics-as it is now time to systematize an enormous scope of accumulated data and create, at least tentatively, an information theory of the brain. And, no doubt, this science includes psychology and philosophy. Among the first who started to connect physiology and psychology are our great scientists Ivan Sechenov and Ivan Pavlov, who gave a powerful impetus to the development of Russian physiological school. Fortunately, it still exists. The progress of modern brain science is amazing. It leads to creation of grandious national projects, focused on human health, and of new information technologies (the USA and China are already starting to realize them). Russia should accept this challenge of time as well. We have the scientific potential for this. The only thing needed is potent support. What spheres of neurobiological studies are the most important for us? I suppose at least six important trends of studies of the brain should be distinguished. We shall discuss each of them.

EVOLUTION AND INDIVIDUAL DEVELOPMENT

It is impossible to understand the nature of human brain with its high mental abilities without understanding the nature of the evolution process. By the way, the term "evolutionary physiology" was suggested in 1914 by Alexei Severtsov, zoologist (Academician from 1920). The formation of this basic research trend is connected with Russian science, with the names of physiologists—Academician Leon Orbeli* and Corresponding Member of the USSR Academy of Sciences Khachatur Koshtoyants. In 1956, Orbeli organized an Institute of Evolutionary Physiology and Biochemistry in Leningrad and insisted that the Institute be named in honor of Ivan Sechenov. For more than half a century the scientists of this Institute are engaged in research in the sphere of evolutionary physiology. The living systems of different levels of complexity are studied there. According to the concept, developed by Academician Yuri Natochin and Corresponding Member of the Russian Academy of Sciences Nikolai Veselkin, the system of chemical regulation and signaling, which emerged at the earliest stages of evolutionary process in primitive unicellular organisms, proved to be no less essential for multi-cellular organisms, including primates and humans. It developed in the course of evolution into hormonal and specialized neuroendocrine systems. This latter supports homeostasis, regulates the priority functions of the brain and visceral systems.

Studies of the ontogenesis mechanism are an important trend of research in modern brain science. This problem is successfully developed by Academician Mikhail Ugryu-mov** at N. Koltsov Institute of Developmental Biology of the Russian Academy of Sciences in Moscow in collaboration with French neurobiologists.

Evolution of consciousness is one more important and interesting trend in modern neurobiology. Animals possess "primary consciousness", while humans—largely due to the language—possess its higher form. That is why it is impossible to understand the nature of human consciousness without understanding the genetic bases and evolution of the language development. It remains unclear how and when a language emerged. Two variants are discussed:

it is either a product of genetic "explosion" or a result of gradual natural selection of minor mutations. Irrespective of the answer, the specialists date the evolution tree of the primate order, Hominidae family, Homo sapiens species as follows: the neuroanatomical substrate of the tongue emerged in Homo erectus about 2 mln years ago; the proto-tongue emerged in Homo habilis about 1 mln years ago; and completely formed tongue emerged in Homo sapiens about 75 thous. years ago. Interesting neurolinguistic studies at the interface of physiology and linguistics are carried out at St. Petersburg University by Tatyana Chernigov-skaya, Dr. Sc. (Biol. & Philol.).

MOLECULAR PHYSIOLOGY

Adult human brain contains about 100 bln neurons and around 100 trln contacts between them, called synapses. When we speak about information processing in the brain, about "nerve networks", we should remember that these "networks" are a purely information notion. The nervous system is actually not a network (as it was assumed previously), but 100 bln of separate cells, contacting with each other.

Information is transmitted from cell to cell by means of electrical and chemical signals. One of the key problems of molecular physiology is to understand, how an electrical signal (of course, we mean here not electric current, but ionic currents—positively charged potassium, sodium, and calcium ions, and negatively charged ions, for example, chlorine) propagates via long (axon) and short (dendrite) neuronal processes and how it is chemically transmitted at the site of the contact (in the synapse).

Ionic channel-membrane protein "inserted" in biological membrane-is a key molecular "chip" of a living cell.

* See: Ya.  Renkas, "The Orbeli Triad", Science in Russia, No. 6, 2002.-Ed.

** See: M. Ugryumov, "Compensatory Resources of the Brain", Science in Russia, No. 3, 2008.-Ed.

Reconstruction of the acetylcholine synapse between two neurons.

Low-molecular compounds, such as acetylcholine, glutamate, dopamine, and many others, serve as chemical transmission carriers (neurotransmitters or neuromediators).

The "element base" of a nerve cell includes the so-called "membranous proteins", as if "inserted" in the biological membrane. Of these proteins, incorporated in the membrane, let us speak about ionic channels (through which positively or negatively charged ions—cations or anions— are transmitted) and about receptors—membranous proteins, on which the neurotransmitter molecules "land" and with which they react. The protein receptors include the receptor part proper, "recognizing" the neurotransmitter molecule, and the channel part, through which the ions are transmitted. The "classical" ionic channels are regulated (are opened and closed) by means of modification of electric voltage on the membrane. The ionic channels provide propagation of an electric signal (nerve impulse) along the nerve cell processes. The information transmitted from neuron to neuron is coded for by a sequence of these impulses. In fact, the sequence of im-pulses is an information "language" of the brain.

The huge family of protein receptors includes the so-called G proteins. They are also called signal proteins, as they serve as universal mediators in intracellular transmission of photo-, chemical (taste, olfaction), nervous, hormonal signals to other proteins responsible for this or that specific function of a living cell. The best studied of the G-protein-binding receptor "superfamily" is rhodopsin, a photosensitive vision protein*.  Its primary structure

(amino acid sequence) was established at the beginning of the 1980s by Academician Yuri Ovchinnikov and his colleagues at the Moscow Institute of Organic Biochemistry of the Russian Academy of Sciences, now named after M. Shemyakin and Yu. Ovchinnikov.

A detailed description of three-dimensional structure of channels and receptors, understanding of peculiarities of their interaction with other proteins has now become an important problem of molecular physiology. It is quite obvious that only the knowledge of the "elementary base" of the cell will lead to understanding of the nature of its disorders. There is just no other way to clear out deep causes of diseases and their effective treatment, for creation of new drugs, including neuro- and psychotropic ones.

Of late for outstanding achievements in the studies of the structure and functions of ionic channels and receptor proteins we have been awarded Nobel Prize more than once. A lot of scientific schools, laboratories, and groups are engaged in these studies in Russia. For example, Academician Platon Kostyuk has made tremendous contribution to studies of ionic channels. His disciples now work in Russia, Ukraine, in many other countries. One of the bright representatives of this school is Oleg Kryshtal, Corresponding Member of the Russian Academy of Sciences and Academician of the National Academy of Sciences of Ukraine. His works, for example, studies of proton-sensitive ionic channels discovered by him, are published in the most respectable scientific journals. Scientific school of Boris Khodorov, Dr. Sc. (Med.), working at the Institute of Pathology and Pathophysiology of the Russian Academy of Medical Sciences, is well known. His works on ionic channels and neuron excitability have become the classics. Most

* See: M. Ostrovsky, "Paradox of Vision", Science in Russia, No. 5, 2006.-Ed.

Left:

schematic image of the eye, retina, visual cell of the rod and photoreceptor membrane with "inserted" photosensitive membranous protein rhodopsin. Right:

three-dimensional organization in the bilayer photoreceptor membrane of rhodopsin molecule, surrounded by molecules of lipids.

sophisticated research in this sphere of molecular physiology is carried out by Galina Mozhaeva, Corresponding Member of the Russian Academy of Sciences, and her colleagues at the Institute of Cytology of the Russian Academy of Sciences (St. Petersburg).

A very important trend is study of model systems—artificial membranes and ionic channels "inserted" in them. This research is carried out at the world level by Yuri Chizmadzhev, Corresponding Member of the Russian Academy of Sciences, and his scientific school at A. Frum-kin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, in Moscow.

And now a little more details about synaptic receptors, "recognizing" and reacting with neurotransmitter molecules. As we have already mentioned, there are about 100 trln synaptic contacts in the brain. However, a synapse is not just a contact. A synapse is intricate molecular "machinery". All processes, leading to the main types of brain activity—perception, movement, training, behavior, and memory—take place in the synapse. A synapse is such an important structure, that its studies have resulted in a special branch of neuroscience—synaptology, in which Russian scientists play an adequate role.

In 1946, Khachatur Koshtoyants (mentioned above) and Tigran Turpaev (Academician since 1992) published in the Nature journal a pioneer article, in which they for the first time presented the results proving the protein nature of the synaptic receptor for acetylcholine (neurotransmitter). From the 1960s till the beginning of the 1980s, world class works on spinal synapses and evolution of synaptic transmission were headed by Alexander Shapovalov,

Corresponding Member of the USSR Academy of Sciences (I. Sechenov Institute of Evolutionary Physiology and Biochemistry).

Recently scientists from this Institute—Lev Magazanik, Corresponding Member of the Russian Academy of Sciences, and his disciple Denis Tikhonov, Dr. Sc. (Biol.), published an article about evolution of glutamate receptors, an important class of protein receptors of the central nervous system and the brain.

Glutamate is a key stimulatory neurotransmitter, while its receptor is, as was found, one of the most ancient receptors by origin: its precursors were found even in plants and prokaryotes (primitive unicellular nucleus-free organisms). Due to the knowledge of spatial organization and molecular physiology of these receptors, scientists at Magazanik's laboratory carry out an intelligent target-oriented search for new neuro- and psychotropic drugs. Some of them are already tried on animals.

One more example of the achievements in understanding of the evolution, structure, and function of a protein receptor are studies of an acetylcholine receptor. Like glutamate, acetylcholine is a key neurotransmitter. Priority studies in this "hot" sphere of synaptology are carried out by Viktor Tsetlin and Yevgeny Grishin, Corresponding Members of the Russian Academy of Sciences, at M. Shemyakin and Yu. Ovchinnikov Institute of Organic Biochemistry.

An original and at the same time traditional trend of synaptology is a study of the synapse between nerve and muscle cells. It is effectively developed by Yevgeny Nikolsky, Corresponding Member of the Russian Acade-

my of Sciences, and Andrei Zefirov, Corresponding Member of the Russian Academy of Medical Sciences, at Kazan Institute of Biochemistry and Biophysics of the Russian Academy of Sciences and Kazan State Medical University.

1 should like to repeat that a synapse is a complex molecular mechanism. Its disorders underlie the nervous and mental disorders; the entire neuro- and psychopharmacol-ogy of the present and future time is linked with the synapse.

PHYSIOLOGY OF SENSORY SYSTEMS

It is a traditionally potent trend of research in our country. It was founded by academicians Leon Orbeli (physiologist) and Sergei Vavilov (physicist). In the 1930s they gave a powerful impetus to studies of physiology of vision, which was followed by research in the field of physiology of hearing and other sensory modalities. Three main stages can be distinguished in the work of any sensory system. Stage 1 is reception (perception) and transformation of an external stimulus energy: optic (vision), mechanical (taction, hearing) or chemical (taste, olfaction) energy into a physiological signal. Stage 2 is transmission and information processing of the signal at all levels of the sensory system, from receptor to specialized subcortical and cortical compartments of the brain. Stage 3 is formation of a subjective image of the objective external world in the cerebral cortex. Each stage is an object of studies of specialists in various spheres.

Sensory photoreception is studied at several laboratories, including those headed by Viktor Govardovsky, Dr. Sc. (Biol.) at I. Sechenov Institute of Evolutionary Physiology and Biochemistry, Oleg Sineshchekov and Pavel Filippov at Lomonosov Moscow State University, the author of this article at N. Emanuel Institute of Biochemical Physics. Studies of gestatory reception are carried out at the laboratory headed by Stanislav Kolesnikov at the RAS Institute of Cell Biophysics in Pushchino.

The understanding of molecular mechanisms of sensory reception opens up new vistas for medicine and technology. For example, the results of studies of primary photochemical reactions in the molecule of rhodopsin (photosensitive visual protein) can be helpful in creation of fast response devices for information processing. The matter is that this photochemical reaction is realized in rhodopsin within ultrashort time—just 100-200 fs (1 femtosecond is equal to 10^-15 s). The recent joint work, carried out at the laboratory headed by Oleg Sarkisov, Dr. Sc. (Phys. & Math.), at N. Semyonov Institute of Chemical Physics, Academician Mikhail Kirpichnikov at M. Shemyakin and Yu. Ovchinnikov Institute of Organic Biochemistry, and the author of this paper, has shown that this reaction is not only superfast, but also photoreversible. This means that a molecular "photoswitch" or a "photochip", working in the femto- and picosecond time scales, can be created in the same way as rhodopsin.

Transmission and processing of sensory information, recognition and formation of a subjective image of the external world, evaluation of its biological and sense significance—these are objects of rapidly developing sensory physiology. Works in this sphere are carried out at laboratories of the RAS Institute of Higher Nervous Activity and Neurophysiology in Moscow, (headed by Academician Igor Shevelyov till his death in early 2010).* Yuri Shelepin, Dr. Sc. (Med.), Yakov Altman, Corresponding Member of the Russian Academy of Sciences, at Pavlov Institute of Physiology in St. Petersburg, and Alexander Supin, Dr. Sc. (Biol.), at A. Severtsov Institute of Problems of Ecology and Evolution in Moscow.

Superfast photoreversible rhodopsin reaction. Specters of its absorption and first product of photochemical transformation-photorhodopsin. Arrows show direct and inverse photoreactions.

PHYSIOLOGY OF MOVEMENT

Sechenov's words that "all external manifestations of the brain activity can be reduced to a muscle movement" are true even today. Modern physiology of movement is a domain of physiologists, mathematicians, and specialists in the management theory.

The feedback plays a key role in the organization of motor behavior. It helps evaluate the movement and its result, and correct them, if necessary. This was first realized in the 1930s-1940s by our outstanding physiologists Nikolai Bernstein, Corresponding Member of the USSR

* See: I. Shevelyov, "The Brain and Recognition of Visual Images", Science in Russia, No. 3, 2007.-Ed.

Memory systems in human brain. Its different types are "located" in its different areas. 1-8-input of visual information getting into the brain.

Academy of Medical Sciences, and Academician Pyotr Anokhin. Subsequent studies were carried out in the 1960s by Academician Viktor Gurfmkel (physiologist) and Israel Gelfand (mathematician) together with their disciples. Their works recognized as classical laid a foundation for creation of a walking robot, new methods for rehabilitation of patients with spinal injuries. One more classical work of scientists from the Institute of Information Transmission Problems (the USSR Academy of Sciences) Grigory Orlovsky, Fyodor Severin, and Mark Shik, was published in 1967. It described for the first time the spinal generator of walking movements.

Recently Yuri Gerasimenko, Dr. Sc. (Biol.), from the laboratory of physiology of movement, I. Pavlov Institute of Physiology, has proved in collaboration with American physiologists that electrical stimulation of the spinal cord in combination with drug treatment caused well-coordinated walking movements in rats, i.e. walking with proper support of body weight. (These results were published in Nature Neuroscience, a neurobiological scientific journal, in 2009.)

The results of experiments on animals suggest that thousands of paralyzed spinal patients can hope for at least partial rehabilitation.

Physiology of movement remains an object of intense studies for us.

Physiology of the motor system is an important constituent of gravitation physiology, to which our scientists have made an exceptionally great contribution. Due to studies under conditions of zero gravitation it became possible to evaluate the role of the brain systems, primarily sensory ones, in normal motor behavior. This trend is intensely developed at the laboratory headed by Inesa Kozlovskaya, Corresponding Member of the Russian Academy of Sciences, at the Institute of Biomedical Problems of the Russian Academy of Sciences.

Understanding of physiological mechanisms of movement is a basis of neurology. This important medical physiological sphere has been effectively developed at the laboratory headed by Marat Ioffe, Dr. Sc. (Med.), at the RAS Institute of Higher Nervous Activity and Neurophysiology.

PHYSIOLOGICAL BASES OF MENTAL FUNCTIONS

This trend is one of the most interesting and, we can say, revolutionary. Striking progress has been attained during recent years in this sphere and, which is presumably even more important, new problems have been formulated, which are to be solved. The "bridge", connecting physiology and psychology, built by Ivan Sechenov and Ivan Pavlov, has turned today into a general line of modern neuroscience.  Speaking about physiological mechanisms,

what are the priorities here? The fact that synapses and genes, cell-to-cell interactions and intracellular "machinery" are involved here. We cannot but mention in this connection the great Spanish histologist Ramon-y-Cajal. In 1894, he suggested that training was based on increasing the efficiency of the synapse work (now it is proved by fine modern methods). In addition, repeated activation results in greater efficiency.

An extremely important fact is electrophysiological study of mechanisms of training and memory. These studies are carried out, for example, at the laboratory headed by Vadim Skrebitsky, Corresponding Member of the Russian Academy of Sciences and Russian Academy of Medical Sciences (Research Center of Neurology of the Russian Academy of Medical Sciences); scientists here are working out drugs improving memory impaired due to cerebral diseases or old age.

Starting from the 1970s, the progress in studies of cellular and molecular mechanisms of memory is largely due to studies of the nervous systems of invertebrates. To begin with, they are convenient objects for experiments of different kind. In addition, they are extremely interesting from the viewpoints of evolution and comparative physiology. One of the first who studied synaptic transmission and a diversity of neurotransmitters in mollusks in the 1960s-1970s was Dmitry Sakharov, Dr. Sc. (Biol.), at N. Koltsov Institute of Development Biology. One of the leading scientific groups, studying mechanisms of training, memory, and behavior of invertebrates is the laboratory headed by Pavel Balaban, Dr. Sc. (Biol.), at the Institute of Higher Nervous Activity and Neurophysiology. Using modern electrophysiological and optical methods for registration of the activity of snail neurons, the scientists described the organization of nerve networks in primitive nervous systems. Accumulation of experimental data of this kind is extremely valuable for creating a future information theory of the brain.

As we have mentioned above, the synapses and intracellular "machines" are involved in the training and memory mechanisms. Short-term memory (from minutes to tens of minutes) depends on conformational changes of synaptic structures' protein molecules, while long-term memory (days and years) is determined by expression of genes, synthesis of new proteins, RNA molecules, and emergence of new synapses. The problem is—what kind of genes are activated in the course of training and what they do in the neurons? This trend is effectively developed at the laboratory headed by Konstantin Anokhin, Corresponding Member of the Russian Academy of Sciences and Russian Academy of Medical Sciences, at P. Anokhin Institute of Normal Physiology (Moscow).

Striking achievements are attained in understanding of localization of various memory types due to new methods of brain visualization. We mean primarily the functional magnetic resonance tomography, though at present it is mainly used for clinical purposes. As for positron emission tomography, it is used in basic studies by Svyatoslav Medvedev*, Corresponding Member of the Russian Academy of Sciences, and his colleagues at N. Bekhtereva Institute of Human Brain (St. Petersburg).

It has been shown using these methods that memory is not diffusely distributed in the brain (as was assumed previously), but is localized in its certain compartments. This is a principally important conclusion for physiology (neuro- and psychophysiology) and medicine (neurology, neurosurgery, psychiatry).

And now about consciousness. It is a problem at the interface of at least three sciences: physiology, psychology, and philosophy. What is the main thing here? Understanding of the most important condition, according to which CONSCIOUSNESS is a process, action, but not just a passive "something" lying in the brain. At present nobody can clearly define what consciousness is. Quite a number of hypotheses about its mechanisms have been put forward. One of them was suggested in the 1980s-1990s by Alexei Ivanitsky**, Corresponding Member of the Russian Academy of Sciences (RAS Institute of Higher Nervous Activity and Neurophysiology). The gist of the matter is as follows: the most important element of consciousness (subjective image of the external world) emerges in the projection cerebral cortex as a result of synthesis of sensory information, getting from without, and the information stored in memory. The comparison of the flow of new information with the stored information is a key moment in the "flow of consciousness". The synthesis is a result of annular movement of nerve impulses. Similar ideas were

* See: S. Medvedev, "'Universe' of the Brain", Science in Russia, No. 3, 2003.-Ed.

** See: A. Ivanitsky, "Physiological Basis of Consciousness", Science in Russia, No. 3, 2007.-Ed.

later developed by other scientists, including Gerald Edel-man (USA), Nobel Prizewinner (1972).

Concluding this section, we should like to emphasize that the problem of "consciousness and the brain" can be solved by joint efforts of natural and humanitarian scientists.

NEUROINFORMATICS

It now becomes obvious that the scientific strategy of countries with developed economy in the first half of the 21st century will be oriented to studies of the brain and its higher functions. Neuroinformatics plays an important role in the solution of these problems. Mathematics and calculations in neuroinformatics are impossible without neurobiology.

Electric nerve pulses in the synapses—from neuron to neuron—serve as a material substratum for information transmission, processing, and analysis in the brain. Hence, when we speak about information processing in "nerve networks", we mean the understanding of the codes of information-carrying impulses and the structure of these "networks" (systems of connections between the neurons). In addition, it is essential to understand the "molecular machinery" of separate neurons. It is important as many physicochemical processes in the cell not only provide its viability, but, most likely, at the same time as calculation operators.

Despite an enormous scope of studies in neuroinformatics, we have to admit that no satisfactory mathematical language for description of nonformalized living systems (living cell or "nerve networks") has been created up to the present time. It is one of the "hot points" of modern science of the brain. Computation neurostudies are in progress all over the world. In Russia the problem is studied (with good results) by groups and laboratories in Moscow, Rostov-on-Don, St. Petersburg, Nizhni Novgorod. But, in contradistinction to the USA and many countries of Europe and Asia, such groups and laboratories are rather few.

As for practical applications, specifically, in medicine, they are rather impressive. One of them is a technology of direct conjugation of the brain with an external technological device. Systems capable of information transmission in one direction—from brain to computer—are available today. For example, by recording stimulated potentials of certain compartments of the brain cortex and transmitting them to an external device, the patient (unable to speak and move) can send important information to medical workers. Very soon implantation of an electron system into the brain will enable to control a carriage for invalids, a hand or foot prosthesis.

In all these cases we mean registration and transmission of reliably detectable electrical signals (potentials), generated by certain compartments of the brain. Works in this sphere are carried out by several groups of scientists. For example, the laboratory headed by Alexander Frolov, Dr. Sc. (Biol.), at the Institute of Higher Nervous Activity and Neurophysiology suggested original methods for early diagnostics of motor diseases.

One more medical application is making a neuropros-thetic appliance. Millions of patients have already received acoustic chips, perceiving the sound and transmitting information directly to the neurons of respective cerebral centers. Thus, deaf people hear and understand speech. In future, it will be possible to create visual and olfactory electron prostheses. Attempts are made to transmit information from without directly to the brain (apart from organs of senses).

Another rapidly developing trend of applied neuroinformatics is a robot technology. Pioneer studies within the framework of the national lunar program were carried out in this sphere in the 1970s-1990s. We mean creation of a robot moving in broken terrain. At first the problem seemed to be almost impossible to solve. The comprehension of the mechanisms of animal motor activity organization helped to solve it. The group of physiologists headed by Academician Viktor Gurfinkel (Institute of Information Transmission Problems, the USSR Academy of Sciences) and the mechanics headed by Academician Dmitry Okhotsimsky and Yevgeny Devyanin, Dr. Sc. (Phys. & Math.), from the Institute of Applied Mathematics of the USSR Academy of Sciences and the Institute of Mechanics, Lomonosov Moscow State University, worked at the problem. The efforts resulted in creation of the famous "hexapod"—a mechanical "insect". It became a prototype of numerous sophisticated anthropomorphic robots which can, for example, play table tennis (Japan). Works in this direction (control of movements) are in progress at the laboratory headed by Yuri Levik, Dr. Sc. (Biol.), at A. Kharkevich Institute of Information Transmission, RAS.

As for creation of artificial intellect and new generation computers, specialists of different profiles are engaged in this rapidly developing sphere. Of course, modern supercomputers in many respects are superior to the potentialities of human brain. But in contradistinction to Homo sapiens, even the most sophisticated of them have no intellect. However, some specialists in the field of informatics think that this problem is purely technical, and will be solved in the near future.

What is in store for the mankind? Is it bright or awful? The headlong progress in neurosciences leads us to this key ethical problem. Surprising potentialities, opening up for the development of human personality and social life of the society, prospects of creating anthropomorphic "cognitive computers" and many other things inevitably pose this "damned" question. The answer, as it was the case not once in history, depends not only and not so much on scientists, but on the society itself.