Effect of M2 Macrophage-Derived Soluble Factors on Behavioral Patterns and Cytokine Production in Various Brain Structures in Depression-Like Mice.

We studied the effect of soluble factors derived from human macrophages polarized to M2 phenotype under conditions of serum deprivation (M2-SF) on behavioral pattern and cytokine production in various brain structures in mice with modeled stress-induced depression. Intranasal administration of M2-SF for 7 days led to stimulation of locomotor and exploratory activities and a decrease in emotional reactivity in the open-field test as well as reduction in depression-like behavior in Porsolt forced swimming test and a decrease in anxiety and anhedonia. Correction of depression-like behavior was accompanied by down-regulation of proinflammatory cytokines (IL-1ß, IL-6, TNFα, and IFNγ) in pathogenetically important brain structures (striatum, hippocampus, and frontal cortex). These data indicate that the antidepressant potential of M2 type macrophages can be mediated by the anti-inflammatory effects of M2-SF.

Alterations in the social-conditioned place preference and density of dopaminergic neurons in the ventral tegmental area in Clsnt2-KO mice.

The incidence of autistic spectrum disorders (ASD) constantly increases in the world. Studying the mechanisms underlying ASD as well as searching for new therapeutic targets are crucial tasks. Many researchers agree that autism is a neurodevelopmental disorder. Clstn2-KO mouse strain with a knockout of calsyntenin 2 gene (Clstn2) is model for investigating ASD. This study aims to evaluate the social-conditioned place preference as well as density of dopaminergic (DA) neurons in the ventral tegmental area (VTA), which belongs to the brain reward system, in the males of the Clstn2-KO strain using wild type C57BL/6J males as controls. Social-conditioned place preference test evaluates a reward-dependent component of social behavior. The results of this test revealed differences between the Clstn2-KO and the control males, as the former did not value socializing with the familiar partner, spending equal time in the isolation- and socializing-associated compartments. The Clstn2-KO group entered both compartments more frequently, but spent less time in the socializing-associated compartment compared to the controls. By contrast, the control males of the C57BL/6J strain spent more time in socializing-associated compartment and less time in the compartment that was associated with loneness. At the same time, an increased number of DA and possibly GABA neurons labeled with antibodies against the type 2 dopamine receptor as well as against tyrosine hydroxylase were detected in the VTA of the Clstn2-KO mice. Thus, a change in social-conditioned place preference in Clstn2-KO mice as well as a higher number of neurons expressing type 2 dopamine receptors and tyrosine hydroxylase in the VTA, the key structure of the mesolimbic dopaminergic pathway, were observed.

Neuronal density in the brain cortex and hippocampus in Clsnt2-KO mouse strain modeling autistic spectrum disorder.

Autistic spectrum disorders (ASD) represent conditions starting in childhood, which are characterized by diff iculties with social interaction and communication, as well as non-typical and stereotyping models of behavior. The mechanisms and the origin of these disorders are not yet understood and thus far there is a lack of prophylactic measures for these disorders. The current study aims to estimate neuronal density in the prefrontal cortex and four hippocampal subf ields, i. e. СA1, СA2, СA3, and DG in Clstn2-KO mice as a genetic model of ASD. In addition, the level of neurogenesis was measured in the DG area of the hippocampus. This mouse strain was obtained by a knockout of the calsinthenin-2 gene (Clsnt2) in C57BL/6J mice; the latter (wild type) was used as controls. To estimate neuronal density, serial sections were prepared on a cryotome for the above-mentioned brain structures with the subsequent immunohistochemical labeling and confocal microscopy; the neuronal marker (anti-NeuN) was used as the primary antibody. In addition, neurogenesis was estimated in the DG region of the hippocampus; for this purpose, a primary antibody against doublecortin (anti-DCX) was used. In all cases Goat anti-rabbit IgG was used as the secondary antibody. The density of neurons in the CA1 region of the hippocampus was lower in Clstn2-KO mice of both sexes as compared with controls. Moreover, in males of both strains, neuronal density in this region was lower as compared to females. Besides, the differences between males and females were revealed in two other hippocampal regions. In the CA2 region, a lower density of neurons was observed in males of both strains, and in the CA3 region, a lower density of neurons was also observed in males as compared to females but only in C57BL/6J mice. No difference between the studied groups was revealed in neurogenesis, nor was it in neuronal density in the prefrontal cortex or DG hippocampal region. Our new f indings indicate that calsyntenin-2 regulates neuronal hippocampal density in subf ield-specif ic manner, suggesting that the CA1 neuronal subpopulation may represent a cellular target for early-life preventive therapy of ASD.

Activity of the positive and negative reinforcement motivation systems and baseline arterial blood pressure in humans.

The aim of the present work was to identify possible associations between individual balances in the activity of the positive and negative reinforcement motivation systems using a method based on emotional modulation of the startle reaction (EMSR) by motivationally significant emotionally positive and negative contextual visual stimuli and measures of cardiovascular system activity. Studies were performed using healthy males (mean age 30.29 +/- 9.8 years) with normal and first-episode excessive increases in arterial blood pressure (systolic blood pressure to greater than 140 mmHg, diastolic to greater than 90 mmHg). Cluster analysis of EMSR data identified groups of individuals with different activity profiles for the positive and negative reinforcement systems. Groups of subjects with changes in the balance of activity towards a lower level of positive reinforcement system activity (smaller startle reflexes to positive contextual stimuli) or a higher level of negative reinforcement system activity (larger startle reactions to threatening contextual stimuli) showed significantly greater baseline SBP and DBP. The possible mechanisms of the modulatory influences of the balance of system activities on autonomic vascular regulatory processes are discussed.

Effects of administration of sodium glutamate during the neonatal period on behavior and blood corticosterone levels in male mice.

Treatment of male DBA/2 mice with sodium glutamate (4 mg/g) on postnatal days 1, 3, 5, 7, and 9 induced reductions in the numbers of square crossings, vertical rearings, excursions to the center, and the time spent in the center in adulthood, as compared with a group of males given physiological saline at the same times. These measures showed no change as compared with intact animals. In the light-dark test, the time spent by mice in the light sector was greater after administration of sodium glutamate than after administration of physiological saline but did not differ from that in intact animals. In the acoustic startle reflex test, sodium glutamate decreased startle amplitude but had no effect on the magnitude of prestimulus inhibition. Sexual motivation in males decreased after sodium glutamate, physiological saline producing a tendency to decreased sexual motivation. Neonatal administration of sodium glutamate increased basal blood corticosterone in adult males by a factor of 4, while physiological saline had no effect on this measure. These results lead to the conclusion that neonatal administration of sodium glutamate decreases motor and investigative activity, anxiety, and sexual motivation in adult male mice and increases basal corticosterone. Physiological saline increased all these parameters apart from sexual motivation, though this was not associated with changes in basal corticosterone.

Features of emotional and social behavioral phenotypes of calsyntenin2 knockout mice.

Calsyntenin-2 (Clstn2) is the synaptic protein that belongs to the super family of cadherins, playing an important role in learning and memory. We recently reported that Clstn2 knockout mice (Clstn2-KO) have a deficit of GABAergic interneurons coupled with hyperactivity and deficient spatial memory. Given, that impaired functioning of GABA receptors is linked to several psychopathologies, including anxiety and autism, we sought to further characterize Clstn2-KO mice with respect to emotional and social behavior. Clstn2-KO males and females were tested in the elevated plus-maze (EPM), open field (OF), forced swim test, social affiliation and recognition test, social transmission of food preference (STFP), dyadic social interactions and marble burying test. Clstn2-KO mice demonstrated high exploration and hyperactivity in the dimly lit EPM that affect anxiety parameters. In contrast, in a more adverse situation in the OF have increased emotionality in Clstn2-KO males, not females. Assessment of hyperactivity for prolong period in the OF showed that Clstn2-KO animals were able to decline their hyperactivity, but their ambulation still remained higher than in WT littermates. Additionally, Clstn2-KO mice expressed stereotyped behavior. Strikingly, analysis of social behavior identified deficient social motivation and social recognition only in Clstn2-KO males, but not in females. Further analysis of social communication in the STFP and direct observation of agonistic interactions confirmed the reduced social behavior in Clstn2-KO males. Altogether, current results showed Clstn2 gene and sex interactions on socio-emotional performance in mice, suggesting a possible role of calsyntenin2 in psychopathological mechanisms of autism.

[Lipid profile and psychometric traits in patients with psychosomatic disorders and chronic cerebral ischemia]. / Lipidnyi spektr krovi i psikhometricheskie pokazateli u patsientov s psikhosomaticheskoi patologiei i khronicheskoi ishemiei golovnogo mozga.

AIM: To explore the correlation of serum cholesterol and triglycerides with psychometric traits in patients with psychosomatic disorders and chronic cerebral ischemia (CCI). MATERIAL AND METHODS: One hundred and ten patients with CCI, aged from 46 to 76 years, were examined. Total cholesterol and triglycerides were measured in the blood. A battery of tests for assessment of cognitive functions and neurotic traits was used. RESULTS: The level of cholesterol was higher in patients with post-infarction cardiosclerosis (PICS) compared to patients with CCI without psychosomatic disorders but did not differ from that in patients with gastric ulcer (GU). The level of triglycerides was higher in both groups with psychosomatic disorders, patients with PICS had higher levels compared to patients with GU. No differences between total cholesterol and triglycerides and assessment of cognitive functions in patients of different age were observed. CONCLUSION: Patients with psychosomatic disorders had lower cognitive function and higher level of neuroticism. Results of regression analysis indicate that blood contents of cholesterol and triglycerides can be considered as a prognostic factor for cognitive decline.

Hypothalamic monoamines in cold stress on the background of changes in the activity of the nitric oxide system.

The effects of the NO donor sodium nitroprusside and the NO synthase blocker L-omega-N-nitroarginine (LNA) on body temperature, hypothalamic monoamines, and plasma corticosterone in conditions of cooling were studied in Male Wistar rats. Reductions in body temperature on cooling, both after administration of sodium nitroprusside and LNA, were no different from those seen without treatment. The basal corticosterone level after treatment with sodium nitroprusside increased from 5.3 +/- 2.2 to 29.1 +/- 1.8 microg%. Cooling led to a multiple increase in corticosterone levels in all animals, both in control conditions and after treatment with sodium nitroprusside and LNA. Sodium nitroprusside significantly decreased the basal hypothalamic noradrenaline level, by 37%. Cooling of the animals in these conditions led to an additional drop in the noradrenaline level. Noradrenaline levels 48 h after cold stress applied to animals cooled after treatment with LNA or sodium nitroprusside were significantly higher than in those cooled without treatment. No changes in serotonin and 5-hydroxyindoleacetic acid levels were seen in these experiments. The basal dihydroxyphenylacetic acid and dopamine levels increased after treatment with sodium nitroprusside, by 379% and 239% respectively. No dopamine response to cold was observed, though the dihydroxyphenylacetic acid level in the control group and animals treated with LNA increased. Thus, cold stress did not reveal differently directed directions for the actions of the NO donor and the NO synthase blocker, as seen with other types of stress.

[The lipid profile and psychometric assessments in patients with psychosomatic illnesses and chronic cerebral ischemia]. / Lipidnyi spektr krovi i psikhometricheskie pokazateli u patsientov s psikhosomaticheskoi patologiei i khronicheskoi ishemiei golovnogo mozga.

OBJECTIVE: To explore the correlations between plasma cholesterol and triglyceride levels and psychometric assessments in patients with psychosomatic illnesses and chronic cerebral ischemia (CCI). MATERIAL AND METHODS: One hundred and ten patients (51% women, 49% men), aged from 46 to 76 years (mean 65.1 years) with CCI were examined. The study included cholesterol and triglyceride tests and a battery of tests for assessment of cognitive functions and neurotization level. RESULTS: Cholesterol levels were higher in patients with post-infarct cardiosclerosis (PICS) compared to the comparison group but did not differ from those of patients with peptic ulcer disease (PUD). Triglyceride levels were high in both psychosomatic groups, with higher levels in the patients with PICS compared to the patients with PUD. Plasma cholesterol and triglyceride levels were not correlated with assessments of cognitive functions in patients of different age. CONCLUSION: Cognitive impairment and higher level of neurotization were characteristic of patients with psychosomatic illnesses. Regression analysis has demonstrated that plasma cholesterol and triglyceride levels may be a prognostic factor for cognitive impairment.

Effect of repeated experience of victory and defeat in daily agonistic confrontations on brain tryptophan hydroxylase activity.

The rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase (TPH), was studied in brain areas of male mice with repeated experience of victory (winners) or defeat (losers) gained in 10 daily agonistic confrontations. A reduction of TPH activity in the midbrain and an increase in the hypothalamus was demonstrated for winners compared with controls. In contrast, repeated defeat in social confrontations was associated with higher TPH activity in the striatum and hypothalamus in losers compared with controls. Agonistic interactions did not affect TPH activity in the amygdala, nucleus accumbens or hippocampus in either winners or losers. The sensory contact technique used in this work for generating winners and losers may be productive in the analysis of TPH gene regulation.

Involvement of the 5-HT(1A) and 5-HT(1B) serotonergic receptor subtypes in sexual arousal in male mice.

The presence of a sexually receptive female behind a partition that prevents physical contact, but not seeing or smelling, increases blood testosterone level and induces the specific behavior in CBA male mice so that they more frequently approach the partition and spend more time near it in an attempt to make their way to the female. Treatment with the selective 5-HT(1A) serotonin receptor agonist 8-OH-DPAT (0.1, 0.25, 0.5 and 2.0 mg/kg) induced a dose-dependent decrease in the amount of time spent by the males near the partition, or "partition time", which is considered the main pattern of sexual motivation. The activating effect of female exposure on the male's pituitary-testicular system was totally blocked, as no increase in plasma testosterone level was observed. The 5-HT(1A) antagonist p-MPPI (0.1, 0.2 and 0.4 mg/kg) itself did not affect behavior or alter plasma testosterone, but attenuated the inhibiting effect of 8-OH-DPAT on behavior and totally antagonised the effect of the 5-HT(1A) agonist on testosterone response. The 5-HT(1B) agonist CGS-12066A (1.0 and 2.0 mg/kg) has no influence on the plasma testosterone increase exhibited by the male in response to female exposure. At the same time, either dose of CGS-12066A significantly reduced the partition time. The conclusion was made that the 5-HT(1A) subtype is involved in controlling both behavioral and hormonal indices of sexual arousal in male mice, while the 5-HT(1B) receptors antagonise sexual motivation, but do not modify the hypothalamic-pituitary-testicular response.

Methoxychlor given in the periimplantation period blocks sexual arousal in male mice.

To determine whether pesticide methoxychlor (MXC) alters sexual arousal in male offspring, pregnant ICR mice remained untreated or received daily subcutaneous injections (s.c.) of olive oil, 33.0 mg/kg bw purified (95%) MXC, or 0.33 mg/kg bw estradiol-173 in vehicle on Days 5 to 7 of pregnancy. Live births were recorded in all groups except the estradiol group. At 4 months, untreated or olive oil-treated male offspring exhibited normal sexual arousal. When placed near a plastic partition with an estrus female behind it, these males spent significantly more time near the partition than near a vacant half of the cage and exhibited a sharp increase in plasma testosterone. MXC-exposed males showed no sexual arousal, spent much less time near the partition with an estrus female, and exhibited significantly lower plasma testosterone levels. Exposure to purified MXC close to implantation alters the function of the hypothalamic-pituitary-testicular axis and compromises male sexual behavior in offspring.

The roles of different types of serotonin receptors in activation of the hypophyseal-testicular complex induced in mice by the presence of a female.

Placing of receptive females in the sector of a cage separated by a partition preventing physical contact but allowing sight and olfaction induced increases in blood testosterone levels in male mice. The selective agonist of 5-HT1A receptors 8-OH-DPAT (0.1 mg/kg) and the mixed 5-HT1A/1B receptor agonist eltoprazine (3.0 and 10.0 mg/kg) blocked the activatory effect of presentation of females on the hypothalamohypophyseal-testicular complex (HHTC) in males, while the 5-HT1A receptor antagonist p-MPPI (0.2 mg/kg) prevented the inhibitory effects of 8-OH-DPAT and eltoprazine. The 5-HT1B receptor agonist CGS-12066A (1.0 and 2.0 mg/kg) had no effect, while the mixed 5-HT1B/2C agonist TFMPP (5.0 mg/kg) blocked the increase in blood testosterone in males in response to presentation of females. The 5-HT2A receptor antagonist ketanserin (1.0 and 2.0 mg/kg) prevented the increase in testosterone induced by the presence of females. The 5-HT3 receptor antagonist ondansetron (0.05 and 0.1 mg/kg) increased the initial plasma testosterone level but blocked activation of the HHTC induced by the presence of receptive females. These results led to the conclusion that 5-HT receptors are involved in controlling the sexual activation of males. Different types and even subtypes of the same type of 5-HT receptor had different effects, both inhibitory and activatory, on activation of the HHTC by receptive females. Blockade of HHTC activation induced by the presence of females appears to involve 5-HT1A and 5-HT2C receptors, while activation involves 5-HT2A and 5-HT3 receptors.

Involvement of the catecholamine mechanisms in the activation of mouse hypophyseotesticular complex induced by the female presence effect.

We have studied the role of the adrenergic and dopaminergic mechanisms in the activation of the endocrine testicular function of CBA/Lac and A/He male mice induced by the presence of a female in estrus without any tactile contact with a male. The alpha-adrenoreceptor blocker phentolamine inhibited an increase in the peripheral blood plasma testosterone level caused by the receptive female challenge. Propranolol blockade of beta-adrenoreceptors abruptly increased the stimulating effect of the receptive female presence on the blood testosterone level. The expression of the adrenoblocker action on the blood male sex hormone level depended on a male genotype. The dopamine receptor blocker pimozide produced a moderate effect on the blood testosterone but an attempt to separate its influence into the male sex hormone tonic secretion and the blood testosterone level against a background of sexual activation failed. It was concluded that the adrenergic mechanisms were involved in the activation of the hypothalamo-hypophyseotesticular complex induced by the presence of the receptive female.

Brain serotonin metabolism during water deprivation and hydration in rats.

The effects of two-day water deprivation and hyperhydration (provision of 4% sucrose solution for 48 h) on levels of serotonin and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the midbrain and hypothalamus were studied in Wistar rats. The rates of diuresis (0.05 +/- 0.01 and 0.84 +/- 0.12 ml/h/100 g in water deprivation and hyperhydration respectively) and urine osmolality (1896 +/- 182 and 50 +/- 13 mOsm/kg) reflected increases and decreases in blood vasopressin levels. Water deprivation was associated with a significant increase in 5-HIAA levels in the midbrain and hypothalamus, along with a decrease in serotonin levels and a three-fold increase in serotonin catabolism (the 5-HIAA:serotonin concentration ratio). Hyperhydration induced moderate increases in serotonin and 5-HIAA levels in the hypothalamus with no changes in the midbrain. The blood corticosterone level doubled in water deprivation and decreased in hyperhydration. It is suggested that activation of the serotoninergic system induces a complex adaptive reaction in water deprivation. including mechanisms specific for the regulation of water-electrolyte homeostasis and non-specific stress mechanisms (vasopressin and corticoliberin secretion).

Behavioral characteristics of mice with genetic knockout of monoamine oxidase type A.

Transgenic mice of line Tg8 were used to study the effects of deletion of the monoamine oxidase type A gene and the absence of the corresponding enzyme on behavior. These experiments showed that Tg8 mice with genetic knockout of monoamine oxidase type A differed from mice of the parental line C3H/HeJ by lower levels of the startle reflex in response to an acoustic signal, while there was no difference in the prestimulus inhibition of the startle response. Tg8 mice showed decreased investigative activity and decreases in the number of sector crossings in the light-dark anxiety test. There were significant increases in aggression as a motivation in male Tg8 mice, which was manifest as an increase in the number of mice demonstrating aggression and a decrease in the latent period of attack. The intensity of aggression changed to a lesser extent - the number of fights even decreased, though longer periods of keeping mice together resulted in increased numbers of deaths among intruder mice. At the same time, there were no significant differences between mice with genetic knockout of monoamine oxidase type A and control mice in terms of the expression of sexual activation: the behavioral responses of Tg8 males to presentation of females was marked and was no different from that of male C3H/HeJ mice. Knockout of the gene had no effect on movement activity on behavior in an elevated cross-shaped maze or in the test for predisposition to catalepsy.

Chronic administration of imipramine normalizes decreased sexual motivation and increased predisposition to catalepsy induced by propylthiouracil in rats.

Thyroxine synthesis inhibitors increase the predisposition to catalepsy and decrease sexual motivation and the amplitude of the acoustic startle reflex in rats. The sensitivity of these behavioral changes to antidepressants remains uncertain. Chronic administration of the classical tricyclic antidepressant imipramine (15 mg/kg, 21 days) prevented the appearance of high sensitivity to catalepsy and the decrease in sexual motivation in Wistar rats given propylthiouracil (50 mg/liter, 28 days), without altering the amplitude of the startle reflex. Normalization of behavior in response to imipramine was not associated with changes in movement activity in the open field test or the animals' body weight. There was also no change in the expression of the 5-HT2A serotonin receptor gene in the frontal cortex. The model of propylthiouracilinduced catalepsy with reduced sexual motivation in rats has potential for studying the role of thyroid abnormalities in the development of depression and the mechanisms of action of antidepressants.

Hypothermic effect of 5-HT1A receptor agonist: comparison of intranasal, intraperitoneal, and subcutaneous routes of administration.

The hypothermic effects of 5-HT1A serotonin receptor agonist 8-OH-DPAT after intranasal, intraperitoneal, and subcutaneous administration were compared. In a dose of 1 mg/kg 8-OH-DPAT induced similar thermal reactions after administration by all three routes. In a dose of 0.5 mg/kg 8-OH-DPAT caused no appreciable changes in body temperature after intraperitoneal injection and decreased it after subcutaneous and intranasal administration. No genotypic differences in the effects of 5-HT1A receptor agonist administered by different routes were detected in four inbred mouse strains.