The disinhibitory influence of the activating system when artificially excited from different points in the brain]

EEG activation can be produced by electrical stimulation of some cortical points with the same threshold current strength as by the midbrain RF and thalamic CM stimulation. Near-threshold stimulation of all these points acting simultaneously with inhibitory conditioned signals does not disturb the effector inhibition but displays an EEG difference between negative signals: the fine differentiation sound evokes considerable EEG desynchronization, while the rough one does not change the background rhythms. The same stimulation combined with a positive signal which has been made ineffective by successive inhibition or extinction, reestablishes the intensive EEG activation in response to this signal and the effector conditioned reflex. Therefore a mode-rate additional stimulation of the activating points in the cortex, RF and CM has a disinhibitory influence. When initiated in the cortex this influence may be transmitted from the cortical point to other parts of the brain along transcortical and corticofugal connections.     

Experimental neuroses in dogs caused by an increase in the intensity of (light) stimuli conditions

The influence of enhanced intensity of general illumination on conditioned reactions of a different degree of complexity was studied on dogs by the classical method of secretory conditioned reflexes. In most of the dogs, increase of general illumination from 30 to 300 luxes leads to more intensive secretory conditioned and unconditioned reactions, a smaller number of errors in differentiation, and stabilization of parameters of conditioned activity, which testifies to the improved general functional state of the brain. In two animals in the same conditions of the experiment, an experimental neurosis set it, not connected with the complexity of the elaborated activity. It is assumed that the neurotizing agent was the superfluous situational (photic) stimulation which presented excessive requirements to the mechanisms regulating the general functional state of the brain.     

Regulation of the total functional state of the brain in dogs in the presence of the 1st and repeated increases in total illumination

The influence of the first and repeated increases of total illumination of the experimental chamber on conditioned activity was studied in chronic experiments on six dogs by the secretory alimentary conditioned reflex method. It was found that such repeated functional loads exert a training effect on the mechanism regulating the general functional state of the brain. In preliminarily trained animals different components of the conditioned reflex are rapidly and synchronously reorganized. In non-trained animals the reorganization of the brain general functional state was prolonged and accompanied by development of a pronounced emotional stress. It has been assumed that training of the functions controlling the general functional state of the brain is based on conditioned mechanisms. An important part is played by the mechanism of conditioned inhibition, which prevents a prolonged retention and reproduction of an excessively intensive level of emotional stress.     

Effect of the microiontophoretic application of acetylcholine on the formation of conditioned reactions in motor cortex neurons

In alert rabbits the activity of the motor cortex neurones was recorded with simultaneous application of acetylcholine to them in the process of defensive conditioning. Conditioned reorganization, mainly of activation type, were found in 60% of neurones. In most cases conditionally reacting cells were sensitive to acetylcholine. Ionophoretic application of the transmitter promoted the formation of conditioned neuronal responses and increased them in comparison with conditioned reactions evoked in absence of acetylcholine. It is supposed that the influence of acetylcholine on conditioned cellular process is realized due to its action on the state of excitability of the cortical neurones.     

Effect of the inhibitory neurotransmitter glycine on slow destructive processes in brain cortex slices under anoxic conditions

Slow destructive processes in brain cortex were studied under deep hypoxia (anoxia). Study of the character and dynamics of DNA destruction showed that apoptosis and necrosis run in parallel under the experimental conditions. These processes typically develop in tens of hours. A similar conclusion was reached from electron microscopic study of the tissue ultrastructure. More detailed study revealed that a relatively rare type of apoptosis not involving cytochrome c release from the intermembrane space of mitochondria and not associated with opening of the mitochondrial nonspecific pore occurs under the experimental conditions. As this is occurring, the process can be slowed by high concentrations of glycine, an inhibitory neurotransmitter. The study of DNA destruction demonstrated that high concentrations of glycine selectively slow apoptosis but have almost no effect on necrosis. Glycine also drastically decreases changes in the tissue ultrastructure, particularly of mitochondria, arising under anoxia. Glycine does not notably influence the mitochondrial oxidative phosphorylation system. Study of impairment of mitochondrial function demonstrated that the oxidative phosphorylation system is not disturbed for 1 h, which is several times longer than the inhibition time of brain function under deep hypoxia. The mitochondrial respiratory system is preserved for a relatively long time (24 h). Malate oxidase activity is deactivated after 48 h. The succinate oxidase fragment of the mitochondrial respiratory chain proved especially resistant; it retains activity under anoxia for more than 72 h. A possible mechanism of the effect of high glycine concentrations is discussed.     

Effect of mexidol on status of conditioned reflex activity after traumatic brain damage

Even partial hippocampal lesions in rats resulted in a disturbance of time interval determination over the course of several months (1200-1500 presentations) other complex conditioned reactions being preserved. As distinct from the control animals, the long period of failure of time interval counting was absent in rats receiving Mexidol. Continuous time conditioning took place in these animals. Due to substantial improvement of autonomic processes and emotional reactions, it was possible to present a higher number of conditioned stimuli in experiments. Mexidol seems to improve the compensatory and recovery processes after brain injuries: the impaired functions recover faster, the rate of the retrograde degeneration in the lesioned brain structures decreases, phenomena like Monakov's diaschis are not observed etc.     

The effect of single maximal physical loading on the emotional behavior of rats

In experiments on 250 Wistar female rats the influence was studied of a single maximum and submaximum physical loads on the emotional behaviour and the state of conditioned activity. It has been established, that as a result of maximum possible run of the animals depression takes place of orienting investigatory activity in conditions of the "open field" and disturbance of elaboration and reproduction of the conditioned reflex of two-way avoidance. Normalization of these parameters took place in 48 hours after the maximum load action. Analogous effect was observed in the period of aftereffect of the submaximum physical load, characterized by lowering of the level of behavioural activity in the "open field", disturbance of the elaboration of two-way avoidance as a result of presumable increase of functional tonus of the brain inhibitory systems.     

Acquisition of enhanced natural killer cell activity under anesthesia

An increase in natural killer (NK) cell activity can be conditioned with a one trial learning paradigm to demonstrate the interaction between the central nervous system (CNS) and the immune system. In order to demonstrate learning possibilities during ‘non-conscious’ state, mice were anesthetized with a ketamin/rompun mixture and underwent one trial learning with odor cue as the conditioned stimulus (CS) preceding the unconditioned stimulus (US). The results indicated that mice that were exposed to camphor odor cue under the influence of anesthesia can associate the signal with the poly I:C unconditioned stimulus and were able to recall the conditioned response upon reexposure to the CS. Secondly, the conditioned association made in a conscious state can be recalled by exposure to the same olfactory odor cue in a ‘non-conscious’ state. The increase in the conditioned change in NK cell activity of both situations was significantly higher than the control group. The results demonstrate that learning can take place and the learned response can be recalled under the reduced awareness caused by anesthesia. The findings we report are unusual and novel in that they demonstrate that the CNS can learn new associations under conditions where the host is apparently unaware of the signals being linked. Anesthesia combined with the long interstimulus interval indicates that certain neuronal pathways in the CNS are receptive to second signals (elicited by the US) even when the second signal is separated by one day. This means the conditioned learning of a physiological response can take place unconsciously at a separate level and under situations where the host is totally unaware of the events which the brain is processing and linking as incoming information.     

Distinct neural signatures for safety and danger in the amygdala and striatum of the mouse

The ability to identify, develop, and exploit conditions of safety and security is central to survival and mental health, but little is known of the neurobiology of these processes or associated positive modulations of affective state. We studied electrophysiological and affective correlates of learned safety by negatively correlating an auditory conditioned stimulus (CS) with aversive events (US). This CS came to signify a period of protection, reducing fear responses to predictors of the US and increasing adventurous exploration of a novel environment. In nonaversive conditions, mice turn on the CS when given the opportunity. Thus, conditioned safety involves a reduction of learned and instinctive fear, as well as positive affective responses. Concurrent electrophysiological measurements identified a safety learning-induced long-lasting depression of CS-evoked activity in the lateral nucleus of the amygdala, consistent with fear reduction, and an increase of CS-evoked activity in a region of the striatum involved in positive affect, euphoric responses, and reward.     

Brain microenvironment promotes the final functional maturation of tumor-specific effector CD8+ T cells

During the priming phase of an antitumor immune response, CD8(+) T cells undergo a program of differentiation driven by professional APCs in secondary lymphoid organs. This leads to clonal expansion and acquisition both of effector functions and a specific adhesion molecule pattern. Whether this program can be reshaped during the effector phase to adapt to the effector site microenvironment is unknown. We investigated this in murine brain tumor models using adoptive transfer of tumor-specific CD8(+) T cells, and in spontaneous immune responses of patients with malignant glioma. Our data show proliferation of Ag-experienced tumor-specific T cells within the brain parenchyma. Moreover, CD8(+) T cells further differentiated in the brain, exhibiting enhanced IFN-gamma and granzyme B expression and induction of alpha(E)(CD103)beta(7) integrin. This unexpected integrin expression identified a subpopulation of CD8(+) T cells conditioned by the brain microenvironment and also had functional consequences: alpha(E)(CD103)beta(7)-expressing CD8(+) T cells had enhanced retention in the brain. These findings were further investigated for CD8(+) T cells infiltrating human malignant glioma; CD8(+) T cells expressed alpha(E)(CD103)beta(7) integrin and granzyme B as in the murine models. Overall, our data indicate that the effector site plays an active role in shaping the effector phase of tumor immunity. The potential for local expansion and functional reprogramming should be considered when optimizing future immunotherapies for regional tumor control.     

In vivo differentiated cytokine-producing CD4(+) T cells express functional CCR7

Chemokines and their receptors fulfill specialized roles in inflammation and under homeostatic conditions. CCR7 and its ligands, CCL19 and CCL21, are involved in lymphocyte recirculation through secondary lymphoid organs and additionally navigate lymphocytes into distinct tissue compartments. The role of CCR7 in the migration of polarized T effector/memory cell subsets in vivo is still poorly understood. We therefore analyzed murine and human CD4(+) cytokine-producing cells developed in vivo for their chemotactic reactivity to CCR7 ligands. The responses of cells producing cytokines, such as IFN-gamma, IL-4, and IL-10, as well as of subsets defined by memory or activation markers were comparable to that of naive CD4(+) cells, with slightly lower reactivity in cells expressing IL-10 or CD69. This indicates that CCR7 ligands are able to attract naive as well as the vast majority of activated and effector/memory T cell stages. Chemotactic reactivity of these cells toward CCL21 was absent in CCR7-deficient cells, proving that effector cells do not use alternative receptors for this chemokine. Th1 cells generated from CCR7(-/-) mice failed to enter lymph nodes and Peyer's patches, but did enter a site of inflammation. These findings indicate that CD4(+) cells producing effector cytokines upon stimulation retain the capacity to recirculate through lymphoid tissues via CCR7.     

Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and ¹⁸FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate''s attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2–5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate''s blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction.     

Effect of a change in the effectiveness of a benzodiazepine-GABA-ionophore complex blockade on the reproduction of an amnesic memory trace in mice after preliminary diazepam administration

The paper deals with the results of analysis of the influence of blocked of BD-GABA-ionophore complex and its separate components on recover of memory trace amnesia during BD-receptors activation in experiments on elaboration of CR of passive avoidance in mice. It is shown that at "neurochemical tuning" the improvement of conditioned reaction reproduction on the 2-nd and 21-st day after learning and amnestic action was observed only at GABAA receptor blockade by bicuculline, while the blockade of BD-receptor by flumazepil and of chlorine channel by picrotoxin was ineffective. Simultaneous blockade of all BD-GABA-ionophore complex components was not more effective in comparison with the blockade of its separate links in the recovery of conditioned reaction reproduction. The presented data allow to suppose that "psychogenic" amnesia development is determined by the functional state of neurotransmitter brain systems at learning and amnestic action which stipulates subsequent possibility of memory trace retrieval.     

Regulation of Succinate Dehyrogenase in Higher Plants: I. Some General Characteristics of the Membrane-bound Enzyme

The spectrophotometric phenazine methosulfate assay of succinate dehydrogenase was adapted to use with cauliflower (Brassica oleracea) and mung bean (Phaseolus aureus) mitochondria with suitable modifications to overcome the permeability barrier to the dye. Procedures in the literature for the isolation and sonic disruption of mitochondria from these sources were modified to assure maximal yield and stability of the enzyme. In tightly coupled mung bean mitochondria, as isolated, about half of the succinate dehydrogenase is in the deactivated state, and the enzyme is further extensively deactivated on sonication or freeze-thawing. In cauliflower mitochondria most of the enzyme is in the deactivated form, and little or no further deactivation occurs on sonication or freeze-thawing. Incubation of mitochondria from either source with succinate leads to full activation of the enzyme. The energy of activation for the conversion of the deactivated to the activated form in membranal preparations under the influence of substrate is about 30,000 cal/mole, essentially the same value as in animal tissues. Activation of the enzyme also occurs under the influence of a variety of other agents, among which the action of anions as activators is documented in the present paper. Activation is accompanied by the release of very tightly bound oxaloacetate. As in animal tissues, the enzyme appears to contain covalently bound flavin (histidyl 8α-FAD), and the turnover number is 19,400 moles of succinate oxidized/mole of histidyl flavin at pH 7.5, 38 C.     

The status of conditioned reflex activity in cats after unilateral vestibular neurotomy]

In chronic experiments on 6 cats the influence was studied of unilateral vestibular neurotomy on conditioned, oculographic and electrocardiographic reactions. In operated animals appeared sharply expressed posetonic and oculomotor disturbances, lowered general functional brain state, what was manifested in an increase of specific weight of slow spindle-shaped rhythmics and lowering of the conditioned activity level. Against the background of the lowered functional brain state interhemispheric asymmetry developed with relative predominance of the contralateral hemisphere, what was reflected in electrocorticographic manifestations and disturbance of conditioned spatial differentiations. Significance is grounded of the appearing interhemispheric asymmetry in the development of disturbances of spatial analysis in operated animals.     

Neuronal correlates of the activation of the brain-reinforcing system in dogs

In analysis of neuronal activity of g. proreus of dogs brain in response to positive and differentiation conditioned cutaneous stimuli, in 44% of 78 studied neurons "late responses" appeared in the form of impulse activity intensification elicited by a positive conditioned stimulus after the end of eating and by a differentiation one--during conditioned signal action; it persisted in different neurones for 30--60 s. By means of various functional tests it has been shown that these reactions are a neurophysiological correlate of animals emotional state gradient.     

The differential sensitivity to a neurotigenic exposure of rat strains differing by the threshold of nervous system excitability]

The influence was studied of 15-days stressing on the appearance of stable neurosis-like state of rats lines, selected by the excitability of the nervous system. Unconditioned and conditioned components of behaviour were tested: pain sensitivity, behaviour in the open field, level of "anxiety", passive and active defensive avoidance. Differential reactivity was shown of the rats lines to prolonged stressing, depending on the genetically determined level of the nervous system functional state. Interlinear differences in dynamics of the development of neurosis-like state were established.     

Social odours, sexual arousal and pairbonding in primates

We describe the role of social odours in sexual arousal and maintaining pairbonds in biparental and cooperatively breeding primates. Social odours are complex chemical mixtures produced by an organism that can simultaneously provide information about species, kinship, sex, individuality and reproductive state. They are long lasting and have advantages over other modalities. Both sexes are sensitive to changes in odours over the reproductive cycle and experimental disruption of signals can lead to altered sexual behaviour within a pair. We demonstrate, using functional magnetic resonance imaging (fMRI), that social odours indicating reproductive state directly influence the brain areas responsible for sexual behaviour. Social odours also influence other brain areas typically involved in motivation, memory and decision making, suggesting that these signals have more complex functions in primates than mere sexual arousal. We demonstrate a rapid link between social odours and neuroendocrine responses that are modulated by a male's social status. Recent work on humans shows similar responses to social odours. We conclude with an integration of the importance of social odours on sexual arousal and maintaining pairbonds in socially biparental and cooperatively breeding species, suggesting new research directions to integrate social behaviour, neural activation and neuroendocrine responses.     

Conditioned reflex activity in the aging process in white rats

In Wistar rats, irrespectively of their age, conditioned reflexes to present stimuli are preserved and elaborated. Neither the mechanism of time intervals estimation is disturbed in aged and old rats (24-32 months). Long intervals between experiments (3-5 months) do not influence their state. Distinct changes are revealed of spatial-temporal differentiations in T-maze: significant worsening of their state is observed in 8-10 months age; in this age it is neither possible to elaborate them again. In simplified experimental conditions in the T-maze the old rats preserve the spatial orientation.     

Extinction learning in humans: role of the amygdala and vmPFC

Understanding how fears are acquired is an important step in translating basic research to the treatment of fear-related disorders. However, understanding how learned fears are diminished may be even more valuable. We explored the neural mechanisms of fear extinction in humans. Studies of extinction in nonhuman animals have focused on two interconnected brain regions: the amygdala and the ventral medial prefrontal cortex (vmPFC). Consistent with animal models suggesting that the amygdala is important for both the acquisition and extinction of conditioned fear, amygdala activation was correlated across subjects with the conditioned response in both acquisition and early extinction. Activation in the vmPFC (subgenual anterior cingulate) was primarily linked to the expression of fear learning during a delayed test of extinction, as might have been expected from studies demonstrating this region is critical for the retention of extinction. These results provide evidence that the mechanisms of extinction learning may be preserved across species.