Recent studies have significantly expanded our understanding of the functions of GABAergic interneurons in cortical neural networks. Interneurons of specific classes are involved in generating interictal activity in the cortex not only in certain types of pathology, but also in conditions in which inhibition is mediated mainly via GABAB receptors. Interictal activity consists of high-amplitude spikes, where a short excitatory phase is followed by a long inhibitory phase occurring almost simultaneously in different parts of the cortex. Highamplitude spikes reflect the synchronous action of excitatory neurons in a local area, while synchronous activity in remote areas is determined by feedback between pyramidal cells and interneurons, when the activity of a large mass of neurons occurs simultaneously within a narrow time interval. Synchronization of interictal spikes involves Martinotti cells, as well as parvalbumin, neurogliaform, and vasoactive intestinal peptide-expressing interneurons, which, as experimental data show, also inhibit via GABAB receptors. Several mechanisms are now known which synchronize neuron activity in cortical neural networks: via electrical connections, volume conduction, and synaptic feedback – both between pyramidal neurons and interneurons and between interneurons. We propose that the mechanism of synchronization of interictal spikes in cortical neural networks operates as follows. This mechanism appears to operate in the same way both in local neural networks and over distances. When excitation occurs, it is followed by inhibition mediated by feedback; this limits the excitation period and thus creates a time window for integration, and this also occurs in neighboring cortical neural networks. At the initial stage, the amplitudes of interictal spikes are small and nonsimultaneous in different parts of the cortex. As time progresses, ever more pyramidal neurons become active during the time window, thus increasing the amplitude of the interictal spike, in turn increasing inhibition. Increased inhibition due to feedback ultimately begins to affect neighboring neural networks, with the result that interictal spikes appear almost simultaneously in different parts of the cortex. This produces a significant lengthening of postspike inhibition, as inhibition within a neural network is supplemented by inhibition from neighbors via inhibitory feedback.

Treatment of bladder cancer remains a critical unmet need and requires advanced approaches, particularly the development of local drug delivery systems. The physiology of the urinary bladder causes the main difficulties in the local treatment of bladder cancer: regular voiding prevents the maintenance of optimal concentration of the instilled drugs, while poor permeability of the urothelium limits the penetration of the drugs into the bladder wall. Therefore, great research efforts have been spent to overcome these hurdles, thereby improving the efficacy of available therapies. The explosive development of nanotechnology, polymer science, and related fields has contributed to the emergence of a number of nanostructured vehicles (nano- and micro-scale) applicable for intravesical drug delivery. Moreover, the engineering approach has facilitated the design of several macro-sized depot systems (centimeter scale) capable of remaining in the bladder for weeks and months. In this article, the main rationales and strategies for improved intravesical delivery are reviewed. Here, we focused on analysis of colloidal nano- and micro-sized drug carriers and indwelling macro-scale devices, which were evaluated for applicability in local therapy for bladder cancer in vivo.

Current experimental evidence shows that interictal discharges consist of a short spike and a slow wave, which is regarded as long-lasting hyperpolarization. Feedback inhibitory connections were studied by modeling the synchronization of interictal discharges. Studies in rats in a state of light narcotic sleep with application of GABAA receptor blockers to the cortex showed that interictal discharges arose in neighboring areas of the cortex, first independently of each other and then synchronized. The durations of slow waves (inhibitory phase) were identical in experiments in which interictal discharges arose simultaneously. Recording in these and other experiments showed increases in the time delay between the moments at which interictal discharges were generated. The durations of the slow waves (inhibitory phase) of interictal discharges increased in conditions of increased synchronization. Interictal discharges occurring initially had longer durations of inhibition than those at a neighboring point, as inhibition from neighboring networks via feedback inhibitory connections is added to the intrinsic inhibition in the neural network. When excitation occurred, it was followed by onset of feedback inhibition, which restricted the duration of excitation, thus creating a time window for integration; this also occurred in neighboring neural networks in the cortex.

Modern experimental data show that interictal discharges consist of a short spike and a slow wave, which is regarded as a prolonged hyperpolarization. On the model of interictal discharges synchronization, a study of reciprocal inhibitory connections was carried out. In rats in light narcotic sleep, after application of GABA A-receptor blockers to the cortex, interictal discharges occurred in neighboring cortical areas independently of each other, and then synchronization occurred. In the experiments in which the interictal discharges occurred simultaneously, the durations of the slow wave (inhibitory phase) were the same. During the registration in these and other experiments, there was an increase in the time delay between the moments of interictal discharges generation. Under conditions of increased synchronization, the duration of the slow wave (inhibitory phase) of interictal discharges increased. Interictal discharges, which occurred first, had a longer duration of inhibition compared to the duration in the neighboring point, because the inhibition from the neighboring networks via feedback inhibitory connections is added to its own inhibition in the neuronal network. When excitation occurred, it was followed by inhibition via feedback, which limited the period of excitation, and thus created a temporary integration window, and this also happened in the neighboring neural networks of the cortex.

The effects of weak electric fields with parameters close to those of the electrical activity of brain structures on neural networks in the brain have been studied for several decades. Interest in these studies has increased recently in connection with the fact that the treatment of a number of diseases uses transcranial stimulation methods. The present study used linear regression and correlation analysis to establish a relationship between the magnitude of the interictal spike potential and the magnitude of the potential at the cortical point located a few millimeters from the point at which the spike is generated. A link was also found between the occurrence of interictal spikes at one point of the cortex and the synchronous appearance of electric potentials in neighboring areas. Blockade of sodium channels at the recording points was followed by increases in the linear regression coefficient and the correlation coefficient. This indicated that the actions of electric field potentials were more significant. To identify whether this relationship was random, the time sequence of a single channel was shifted in relation to another using the random numbers principle. The magnitudes of the linear regression and correlation coefficients decreased by an order of magnitude. Our results showed that the electric potential of a small interictal spike arising at one point on the cortex propagates to other areas with a short time delay.

On the basis of the published data the scheme is proposed which explains the spread and synhronization of oscillatory activity in cortex. The main property of the neocortex is the existence of vertically oriented functional columns. Within and between the neuronal columns exist a feedforward and feedback morphological and functional connections. At the certain conditions inside the single module temporal windows are created using inhibitory process, and a synchronized activity can be generated of variable frequency (oscillations). The activity in the columns is enhanced by the synchronous involvement of great amount of neurons which is expressed in the form of local field potentials of high amplitude. Further the information about arisen in a single generator activity is transmitted through direct links to the nearby generator or to the group of such generators. In the nearby generator the activity increases and is transferred to the next generator. At the same time the signal is transmitted through feedback to the primary generator, and the activity is terminated until the next cycle will be initiated and so on along the cortex. The most important notion is that in the transfer of activity from one generator to another is involved a small number of elements. The major part of recorded oscillations of different frequency or epileptiform discharges, is not transmitted via the brain, but is generated in each module according to the characteristics transferred to it. The generation of epileptiform spikes occurs in cases when balance of inhibition determined by GABA A and GABA B receptors is disturbed.

Epileptiform potentials after the application of GABA A receptor antagonist first appeared in a local part of the cortex of anesthetized rats, and then with a small time lag appeared in other areas of the cortex. Externally, it looked like spreading. Potentials originally appeared at any point of recording, and then appeared (propagated) both in the rostral-caudal direction (forward) and reciprocally. The quantitative evaluation of this phenomenon showed that there are three periods of the epileptiform potential spreading. During the initial period, the epileptiform potentials appeared and spread relatively equally in rostrocaudal direction and backwards. In period 2 dominated potentials shift in rostrocaudal direction. After application of a sodium channel blocker epileptic activity significantly decreased. Frequency of initial appearance of potentials in the caudal areas increased. Propagation of the activity in one or another direction was observed. Obtained in this study quantitative characteristics of the initiation and spreading of epileptic activity suggest that in the cortex may exist independent generators, and distribution of the epileptiform potentials and the nature of this distribution implies that this process is based on direct and reciprocal functional connection of neurons.

The proposed model of a one-day spatial learning is of interest in research of how sleep influences the hippocamp-dependent memory consolidation. We have studied the influence of a one-day total sleep deprivation on spatial memory consolidation in hooded rats after a one-day learning in the Morris water maze according to Feldman et al. [2010] protocol. According to it rats had to find a submerged platform that was alternatively marked by a flag or completely invisible to an animal. In a previous study [Dorokhov et al., 2011] we have used another one-day learning protocol [Frick et al., 2000] and Wistar rats and have demonstrated a large interindividual variance in learning parameters and sleep deprivation effects on memory consolidation. In this study we confirm previously acquired results on negative impact of sleep deprivation on spatial memory consolidation. To demonstrate the effects of sleep deprivation on the results of one-day learning we are using for the first time an evaluation of the time spent by an animal in the area of the platform placement and corresponding areas in the other quadrants of the water maze.

На основании литературных данных предложена схема, объясняющая распространение (синхронизацию) осцилляторной активности в коре головного мозга. Основным свойством неокортекса является организация в функциональные вертикально ориентированные колонки. Между нейронами существуют прямые и обратные морфологические и функциональные связи как внутри колонки, так и между колонками. В определенных условиях внутри отдельного модуля с помощью торможения создаются временне окна и с участием прямых и обратных связей между нейронами (возбудительных и тормозных) может генерироваться синхронизированная активность различной частоты, регистрируемая как доминирующая осцилляция. Далее активность в колонке усиливается за счет вовлечения большого числа нейронов, что выражается в виде большой амплитуды локального полевого потенциала. Информация о возникшей в единичном генераторе активности по прямым связям передается на соседний генератор или группу таких же генераторов. В соседнем генераторе происходит усиление активности и передача следующему генератору. В то же самое время по обратным связям в первичный генератор передается сигнал и там прекращается активность до начала следующего цикла. И так далее по коре. Принципиальным положением является то, что в передаче активности от одного генератора к другому участвует небольшое число элементов. По существу, активность, будь то осцилляции любой частоты или эпилептические разряды, не передается, а генерируется на месте в каждом модуле по тем характеристикам, которые ему передаются от соседей. Генерация эпилептиформных спайков происходит, если нарушен баланс между торможением, определяемым ГАМК А и ГАМК Б рецепторами. е окна и с участием прямых и обратных связей между нейронами (возбудительных и тормозных) может генерироваться синхронизированная активность различной частоты, регистрируемая как доминирующая осцилляция. Далее активность в колонке усиливается за счет вовлечения большого числа нейронов, что выражается в виде большой амплитуды локального полевого потенциала. Информация о возникшей в единичном генераторе активности по прямым связям передается на соседний генератор или группу таких же генераторов. В соседнем генераторе происходит усиление активности и передача следующему генератору. В то же самое время по обратным связям в первичный генератор передается сигнал и там прекращается активность до начала следующего цикла. И так далее по коре. Принципиальным положением является то, что в передаче активности от одного генератора к другому участвует небольшое число элементов. По существу, активность, будь то осцилляции любой частоты или эпилептические разряды, не передается, а генерируется на месте в каждом модуле по тем характеристикам, которые ему передаются от соседей. Генерация эпилептиформных спайков происходит, если нарушен баланс между торможением, определяемым ГАМК А и ГАМК Б рецепторами.

We investigated parameters of excitation and inhibition in neurons of a visual cortex of a cat. On somatosensory cortex of rats temporary parameters ofepileptiform activity were investigated. The experimental results received have been used for construction of imitating model of a neural network by means of program of Neuroimitator for research of mechanisms of synchronization in a neural network. The neural network consisted from 30 neurons. The temporary parameters of excitation and inhibition were different. Two conditions of a neural network in the model were used. In the first case activity of every neuron was spontaneous, and in the second case the activity represented cycles of excitation--inhibition. Synchronization (simultaneous activity of the neurons) at the ordered time structure of excitation and inhibition cycles was considerably higher, than during the spontaneous activity. The results received show, that at strengthening the inhibition, the synchronization in local neural networks increases. The greater amplitude of field potential can be a direct reflection of synchronous activity of the elements of nervous system not connected with each other.