Institute of Normal Physiology named after P.K. Anokhin

Natural learning involves multiple sensory modalities receiving complex stimuli. Elemental learning theories suggest separate encoding and association of each component in a compound signal. Configural theories predict the formation of a representation of the entire complex signal, which is associated with the second event. We developed a mouse model of fear conditioning to a compound tone-light cue or its separate components to test these alternative theories. First, we investigated the memory dynamics of compound cues and their individual components and discovered that they mature at varying times following conditioning. We demonstrated that the memory of the components matures at different intervals after training: memory of the auditory stimulus and the auditory component of CCS is demonstrated behaviorally right after training, whereas memory of the light stimulus and the light component of CCS matures within three days. The memory of CCS, its components, and discrete conditioned stimuli persists for an extended period, up to one month. A similar dissociation was observed in extinction experiments, revealing that the extinction of memory for one CCS component did not affect the memory of the other component when the extinction procedure began a day after training. In addition, when the extinction procedure began seven days after training, while the memory was fully mature, the extinction of one component of contextual conditional stimuli led to the extinction of the other component. Next, c-Fos imaging was conducted to examine cellular activity across multiple brain regions, including the frontal, prelimbic, cingulate, retrosplenial, parietal, primary and secondary visual, primary and secondary auditory cortices, as well as the hippocampus and amygdala. This examination was performed following conditioning using either the entire compound cue or its individual components. We discovered different cortical activation patterns between compound-cue and single-cue conditioning. Conditioning to the compound cue activated prelimbic and frontal associative cortices, whereas single cues did not. Third, we demonstrated that retrieval of memory only through the entire compound cue, and not through single cues, activated the parietal cortex, primary visual cortex, mediolateral secondary visual cortices, and hippocampal CA1. Fourth, through in vivo two-photon imaging, we examined retrieval-induced c-Fos expression in the parietal cortex of fos-EGFP transgenic mice and identified at least three distinct neuronal populations with differential response specificity to the compound signal and its components. Taken together, our data suggest that intricate signals have the potential to establish both integral and elemental neuronal representations. These representations can be used separately in behavior and have different long-term memory dynamics.

Musculoskeletal pain (MSP) is common and accounts for about a third of all acute and chronic pain syndromes. MSP is a collective term for various diseases. It is a significant burden for patients, society and healthcare. Patients with MSP need for a multimodal therapeutic approach, and correct assessment of clinical status from the perspective of psychophysiological model will be important for determining and influencing the pathogenetic mechanisms of disease. The review is devoted to non-drug treatment of MSP. The authors analyze neuroimaging correlates of analgesia process involving gray matter near cerebral aqueduct and ventral medial prefrontal cortex in patients with MSP. Various pain syndromes and types of nonpharmacological (hardware and psychophysiological) management are considered (therapy with biofeedback based on EMG or cerebral alpha-rhythm, neuromodulation using transcranial magnetic stimulation or transcranial direct current stimulation, virtual and additional reality technologies, stable platforms with biofeedback).

Lactoferrin (Lf) is a multifunctional protein from the transferrin family. Of particular interest is the ability of Lf to affect a wide range of neuronal processes by modulating the expression of genes involved in long-term neuroplasticity. The expression of the immediate early gene c-fos that is rapidly activated in response to external influences, and its product, transcription factor c-Fos, is widely used as a marker of long-term neuronal plasticity. The present study aims to examine the effect of human Lf on the induction of transcription factor c-Fos in the primary mouse neuronal cultures after stimulation and to determine the cellular localization of human Lf and its colocalization with induced c-Fos protein. Primary dissociated cultures of hippocampal cells were obtained from the brains of newborn C57BL/6 mice (P0-P1). On day 7 of culturing, human Lf was added to the medium. After 24 h (day 8 in culture), c-Fos protein was induced in cells by triple application of 50 mM KCl. c-Fos content was analyzed using the immunofluorescent method 2 h after stimulation. Stimulation promoted exogenous Lf translocation into the nuclei of cultured neuronal cells, which correlated with increased induction of transcription factor c-Fos and was accompanied by nuclear colocalization of these proteins. These results attest to the potential of Lf as a modulator of neuronal processes and open up new prospects in studying the mechanisms of the regulatory effects of lactoferrin on cell function.

The participation of DNA methylation and histone acetylation in the mechanisms of anterograde amnesia and memory recovery was studied on grape snails trained in conditioned food aversion. Anterograde amnesia developed 10 days after memory reconsolidation impairment with an NMDA glutamate receptor antagonist and was characterized by long-term memory formation impairment upon repeated training. DNA methyltransferase inhibitor injections to snails 1 h before repeated training, as well as 15 min or 4 h after repeated training, caused rapid formation of memory that persisted for at least 10 days. Injections of histone deacetylase inhibitor before repeated training also induced the formation of a stable long-term memory. However, administration of histone deacetylase inhibitor 15 min after repeated training initiated a temporary memory recovery. Injections of the inhibitor 4 h after repeated training were ineffective. These results indicate that histone-dependent chromatin remodeling and DNA methylation are selectively involved in the mechanisms of anterograde amnesia and memory recovery.

INTRODUCTION. Chronic fatigue syndrome is a condition, characterized by a severe fatigue that lasts continuously for more than 6 months and has a significant negative impact on the psychophysiological functions. Cancer-related fatigue is identified as an important symptom associated with cancer, associated with autonomic dysfunction. AIM. To reveal objective autonomic and neurodynamic indicators of the severity of CRF in children suffered of neuro-oncological diseases. MATERIAL AND METHODS. Children (8-17 years old) who were under dynamic observation after neuro-oncological diseases for more than six months (n=67) performed maximal tapping tasks, auditory-motor synchronization, and filled out the questionnaire «The Turkish Scale for the Assessment of Fatigue in Pediatric Oncology Patients Aged 7-18». Physiological indices (heart rhythm, peripheral temperature, skin conductance, breathing amplitude and frequency) were recorded at rest and during sensorimotor task. RESULTS AND DISCUSSION. The subscale “Sleep-related fatigue” positively correlates with the average frequency of maximum tapping and with the degree of its slowdown towards the end, which also correlates with the total score of the questionnaire. Statistically significant correlations of scores on the subscale “Subjective feelings of fatigue” with LF/HF and pNN50 at rest were revealed. The amplitude of thoracic respiration positively correlates with the scores of “Fatigue associated with daily activities”, “Subjective feeling of fatigue”, and the total score. Comparison of groups with a low and high total score of the questionnaire does not reveal statistically significant differences in the background indicators of heart rate variability, however, in the process of maximum tapping, the RMSSD and pNN50 indicators are higher, and the indicator of nonlinear heart rate analysis SD2/SD1 is lower in the group with low scores on the questionnaire. CONCLUSION. Children with cancer-related fatigue had reduced heart rate variability, lower parasympathetic tone and greater exhaustion during the tapping test. The combination of objective and subjective indicators reflects the dynamics of cancer-related fatigue and the rehabilitation process more reliably

The role of cholinergic projection systems of the neocortex and hippocampus in memory consolidation in healthy and neuropathological conditions has been subject to intensive research. On the contrary, the significance of cholinergic cortical and hippocampal interneurons in learning has hardly been studied. We aimed to evaluate the role of both cholinergic projection neurons and interneurons of the neocortex and hippocampus at an early stage of spatial memory consolidation (2s1) in normal and chronic brain hypoperfusion conditions. Control rats and rats subjected to permanent two-vessel occlusion were trained with the Morris water maze, and the activity of membrane-bound and water-soluble choline acetyltransferase was evaluated in the sub-fractions of ‘light’ and ‘heavy’ synaptosomes of the neocortex and hippocampus, in which the presynapses of cholinergic projections and interneurons, respectively, are concentrated. Animals were ranked into quartiles according to their performance on stage 2s1. We found: (1) quartile-dependent cholinergic composition of 2s1 function and dynamics of cholinergic synaptic plasticity under cerebral hypoperfusion; (2) cholinergic hippocampal interneurons are necessary for successful 2s1 consolidation; (3) cholinergic neocortical interneurons and projections can be critical for 2s1 consolidation in less learning rats. We conclude that targeted modulation of cholinergic synaptic activity in the hippocampus and neocortex can be effective in reversing the cognitive disturbance of cerebral hypoperfusion. We discuss the possible ways to restore the impaired spatial memory 2s1 in the presence of cerebral hypoperfusion.

Comparison of brain samples representing different developmental stages often necessitates registering the samples to common coordinates. Although the available software tools are successful in registering 3D images of adult brains, registration of perinatal brains remains challenging due to rapid growth-dependent morphological changes and variations in developmental pace between animals. To address these challenges, we introduce CORGI (Customizable Object Registration for Groups of Images), an algorithm for the registration of perinatal brains. First, we optimized image preprocessing to increase the algorithm’s sensitivity to mismatches in registered images. Second, we developed an attention-gated simulated annealing procedure capable of focusing on the differences between perinatal brains. Third, we applied classical multidimensional scaling (CMDS) to align (“synchronize”) brain samples in time, accounting for individual development paces. We tested CORGI on 28 samples of whole-mounted perinatal mouse brains (P0–P9) and compared its accuracy with other registration algorithms. Our algorithm offers a runtime of several minutes per brain on a laptop and automates such brain registration tasks as mapping brain data to atlases, comparing experimental groups, and monitoring brain development dynamics.

A change of pain sensitivity in rats of different sex and age (21st day, suckling period; 30th day, infantile period; and 60th day, juvenile period) was studied after prenatal stress of forced swimming in cold water. The perceptual component of nociception in prenatally stressed animals was shown to decrease on the 60th day of life compared to that in 21-day-old specimens. Importantly, the intensity of pain perception in juvenile rats subjected to intrauterine stress was smaller than control specimens. After prenatal stress, the emotional component of nociception in juvenile males and females was lower than in younger specimens. Therefore, prenatal stress is accompanied by a decrease in the perceptual and emotional components of nociception during the juvenile period, but not at the earlier stages of postembryonic development. The observed fluctuations in the degree of perception of the pain stimulus in male animals are slightly greater than those in females.