John s. Sarkissian

Head of Laboratory, D.Sc., professor

E-mail: johnsarkissyan@gmail.com
Tel: (37491) 51-9247

Achievements of the laboratory on the subject: "plasticity of morphofunctional organization and reorganization of the CNS under conditions of protective impact of biomodulators in cases of acute and chronic nuerodegeneration of specific and nonspecific origin".

The main trend in the activities of the laboratory`s team in the past consisted in the continuation of the long-term research launched by the head of the laboratory and was dedicated to the investigation of the reserve possibilities of the CNS - a "sprouting" phenomenon (collateral and terminal axon growth) as modeled on local strokes in the links of the central organization of movement under formation of new ways and functional synapses (plastic synaptogenesis) based on differences in the characteristics of synaptic processes of various types (axo-somatic and axo-dendritic ones) which create a possibility of the identification of new synapses emerging as a result of reorganization of the retained linkages; this amended the main postulates of the founders of this school of the contemporary neurophysiology - Japanese scientists, - and was conducive to its further successful development. The study of this interesting phenomenon by the method of intracellular lead, which discloses the unique reserve possibilities of the brain across its different sections, was somewhat restricted due to the recognition by the renowned Japanese school of investigators (the first and unique in neurophysiology that described the said phenomenon at the level of the red nucleus) of the reference model that involved the obligatory succinct spatial differentiation of the destroyed and reorganized synaptic inputs on the somadendritic membrane of neurons predominantly with the immature animals. The laboratory study conducted by the electrophysiological and morphological methods was aimed at the development of new test models and methodological approaches towards revealing the above phenomenon of collateral and terminal sprouting under formation of new synapses at the level of both universal subcortical (red nucleus, thalamus nuclei) and highly specialized cortical structures, identification of direct mono- and polysynaptic remote manifestations of the reorganization of projections (while replacing the contralateral with noncontralateral), inclusive of feedbacks ensuring and controlling the reliability of the newly formed ones with the mature animals as modeled by the stereotyped (without spatial demarcation on the somadendritic membrane of neurons) distribution of the destroyed and reorganized contacts.

The main scientific results related to the study of mechanisms of synaptic reorganization across the ways of the conduct of somatosensory information of the central and peripheral (specific, diffusive) origin in the sensomotor cortex (including interthalamic and transcallosive) projections mediated by the specific and nonspecific nuclei of the thalamus and the corpus callosum during the respective one-sided disconnections (at the cortical and subcortical levels). The results of the investigation enabled to reveal the specificities of the functional organization of the reverberating reciprocal system «thalamus - cerebral cortex (on the ipsy and contralateral side) which represent a target for the marked central and peripheral inputs in the norm and the plastic synaptic reorganization during the formation of an efferent flow under conditions of partial interhemispheric cortical and cerebellar diafferentation, inclusive of the formation of new noncontralateral direct and reverse cerebellar-thalamic-cortical connections after the destruction of the contralateral ones.

On the whole, based on the new test models and methodical approaches, while investigating the peculiarities of the formation of new ways and connections in the important links of the central organization of movement at the level of both subcortical and cortical structures (under conditions of subcortical and cortical destructions), techniques of intracellular lead, the following amendments have been made:

1. Revealed is the marked neuronal re-organization across the wide span with mature animals in contrast with the statement by the authors according to which the reorganization was possible only with immature animals and within a small number of target-neurons which virtually took away from the practical significance of the phenomenon;
2. The Japanese researchers accept as a universal model the one with mandatory spatial demarcation of the destroyed and reorganized synaptic inputs on the SD-membrane, which allows for the re-dislocation of the contacts in the dendro-somatic direction as a result of the discharge of a vacancy on the somatic level, which inevitably leads to the loss of the evolutional purchase as the thin modulation is replaced with the launch. On the similar cortical level, along with the confirmation of the indicated data, identified is the re-dislocation of the contacts in the reverse direction which does not envisage the availability of a vacancy at all. Moreover, on the new model without a spatial demarcation of the synaptic inputs on the more specialized cortical structures confirmed is the re-dislocation which does not require the availability of a vacancy;
3. For the first time, under the application of the technique of the intracellular lead (including a more improved technique of a simultaneous intracellular lead from two monosynaptically linked cortical and subcortical neurons), given the compensatory substitution of the contralateral ways with noncontralateral ones is in place, demonstrated is the formation of the reverse connections which ensure and control the reliability of the newly formed direct ones by the like pattern, which are detected practically in all the links of the motor system of the brain;
4. For the first time it is detected the formation of the "remote" polysynaptic sprouting as opposed to the statement by the Japanese scientists saying that at the CNS level this was possible only in a monosynaptic projection;
5. Revealed is a comparatively lesser degree of the expression of the collateral sprouting inside the hierarchically higher and specialized structures;
6. It is proven the necessity of a systemic approach to provide for the assessment of the phenomenon of the collateral sprouting on the intact hemisphere with due regard to the temporal ratio of the incoming information in the adjacent projections to the possibility of a reorganization inside them, unlike the more restricted approach of the mentioned Japanese researchers who take account of the changes only in the section symmetrical to the damaged one;
7. Demonstrated is the unusual sustainability and irreversibility of the compensatory shifts over prolonged endurance in the wake of the post-operational period (up to 2-3 years).

The personnel of the laboratory took an active part in the block program of the Academy of Sciences of the USSR titled "Cellular organization and its use toward the operation of the function of a cell and biotechnology» ("Signal") dedicated to the study of mechanisms of the neuronal and synaptic organization and plastic re-organization under conditions of mutual influence of afferent inputs on the neurons of the cerebella, brainstem , thalamus, and cortex which is evidenced by the materials from the reports on the above program during 1989-1992 in Moscow.

In the laboratory, along with explorations on the synaptic organization and plastic synaptic reorganization in the CNS in the norm and pathology (experimental strokes, spinal traumas, neurodegenerative diseases), conducted were also investigations in the following areas: 1. Formation of new ways and contacts in the important links of the cerebral motor system with the wakeful animals under conditions of the programmed development of the avoidance reflex (flexor reflex of the fore limb to the electrodermal irritation) when in norm and pathology (pyramidothomy) by the technique of stereotaxic registration of the single activity for the assessment of the systemic shifts in the CNS by means of determination of the functional state of the nervous system through the latency of the evoked responses to the sound and irritation, periods of the activity cycles over unconditioned movement and type of correlation between the cortex and cerebellum at different stages of the study; 2. Creation of the functional visual audio "adjusting/attuning" algorithms that apply the state-of- the-art technologies of noninvasive evocation of the hemispheric synchronization effect by means of "resonance" adjustment to the respective rhythms which possess definite functional possibilities (notably, conducive to the concentration of attention, improvement of perception, and speeding-up of the study process); 3. Neuromediatory aspects of the impact of acupuncture with the registration of the single activity of neurons in different segments of the cerebrum and spinal cord; detected is the multimediatory mechanism of their involvement through the activation of the «Skenar» device as opposed to the formally acknowledged opiate one.

It is apparent from the clinical picture that to rely only on the reserve capacity of the brain is not sufficient, and this quite often leads to disability if not death. It is contingent upon the degree and conditions of the lesion, age, sex, genetic and many other factors. On the other hand, the hitherto suggested therapeutic measures do not ensure a full curing of many neurodegenerative diseases which, alongside cardiovascular and oncologic nosologies, account for the most frequent and lethal ones. Therefore, since 1990 investigations have been carried on in the new directions basing on the models of nonspecific (spinal hemisection, neurotomy, intoxication, hypofunction of the endocrine glands – paratireoidectomy, adrenalectomy, ovariectomy) and specific (Altsheimer and Parkinson diseases, induced by the intracerebral nana-injector injection of toxic oligomers of beta-amyloid peptides, respectively) neurodegenartion; the initiation and acceleration of the processes of plastic rehabilitation within the framework of joint programs with a number of chairs at the ERGMU, State University, and the Institute of Biochemistry have also been within the compass of overall works. In the pipeline is the research on the protective effects of different biomodulators, different hormons (inclusive of parathyroid one), predominantly new hypothalamic neurohormons-immunomodulators from the family of prolinom-rich peptides discovered by Academician Galoyan (jointly with the Institute of Biochemistry), as well as hemo-and neuroleptic snake venoms, embryonal proteoglicans, melanin, and other substances to initiate and accelerate the processes of the plastic rehabilitation in the CNS (cortex, hippocampus, stryo-pallidar system, amigdala, Meinert nucleus, vestibular system, spinal cord, and others) and PNS ( flexor and extensor ramifications of the sciatic nerve) under conditions of the aforesaid neurodegenerative shifts. Also the research has been conducted which focused on the neoplastic neurodegeneration relating to the disruptions of hematosis and blood circulation as tested on the models of malignant anemia and protection with different biomodulators (as per МНТЦ program jointly with the Bunyatyan Institute of Biochemistry) as well as on the innervation of the bone marrow. In recent years the study has been conducted on the specific neurodegeneration (based on the rotenone model of the Parkinson disease and the amyloid Altsheimer disease) in combination with the hormonal deviations (parathyroidectomy, adrenalectomy, and ovariectomy- OVX) with the aim to near the natural state in advanced years where, actually, the said diseases do crop up, notably, with the post-menopausal women under OVX conditions, and with men who develop hypertrophy of adrenal glands, etc.

The abovementioned works are being carried out at a high interdisciplinary level with the use of the latest electrophysiological, behavioral, histochemical, immunohistohcemical, immunological and functional methods of exploration on the single neurons; the analysis is done on the level of the contemporary complicated mathematical programming with the perspective of further therapeutic usage of the animal venoms and different hormons under clinical practice both individually and in combination.

As a result expounded is the concept of strengthening the inhibitory synaptic processes conducive to the protection, in particular, relating to ГАМК. The indicated works, on the one hand, enlarge the fundamental conceptions on the potential possibilities of the brain, while on the other hand, enable to suggest new trends as to the curative measures (with the diagnostic and prognostic aim) during the rehabilitation of the affected brain structures under conditions of respective clinical pathology, particularly, accompanied by subtle motoric and mental disruptions.

Slated are explorations on the detection of neurogenesis (with the use of respective markers of vimentin, pectine, BRDU), in combination with immunohistochemical methods, in particular, during the impact of venoms on the restoration of the spinal cord under conditions of hemisection. The said investigations will be implemented in conjunction with Bunyatyan Institute of Biochemistry under the NAS of the RA. There have been and currently also are conducted intensive investigations with a number of theoretical chairs of YSMU after Heratsy. There will be assimilated the models of specific neurodegenerative diseases also provoked by the toxic peptides such as diseases of Hojkin, Creutzfeldt-Jacob, Schizophrenia, multiple sclerosis, epilepsia.