Protein Metabolism Changes and Alterations in Behavior of Trace Amine-Associated Receptor 1 Knockout Mice Fed a High-Fructose Diet.

Trace amines and their receptors are a family of G protein-coupled receptors widely distributed in the central nervous system and periphery. The trace amine-associated receptor 1 (TAAR1) plays a significant role as a therapeutic target for schizophrenia, depression, diabetes, and obesity. In this study, TAAR1 knockout mice and WT groups were tested in conditions of a high-fructose diet. The consumption of a high-fructose diet may be due to the influence on the metabolism processes by dopamine in the brain, neuromotor function, and level of anxiety of TAAR1 knockout mice. During a comparative analysis of behavioral, biochemical, and morphological parameters, significant differences were found between liver and biochemical parameters, the regulation of protein metabolism (AST/ALT ratio, creatine kinase activity, urea), and alterations in behavior. An elevated plus maze analysis showed the influence of fructose and genetic factors on the level of anxiety. A new marker of the grooming microstructure (depression ratio) was tested, which showed high efficiency as a marker of depression-like behavioral changes and a possible association with dopamine-dependent regulation of protein metabolism. These results confirm a possible association of the TAAR1 gene knockout with an increase in catabolic reaction levels by AST/ALT-dependent and possible dopamine-mediated protein metabolism regulation and depression-like behavior.

Differential Influence of Amyloid-ß on the Kinetics of Dopamine Release in the Dorsal and Ventral Striatum of Rats.

Dopaminergic dysfunction is a part of Alzheimer's disease pathology. The brain accumulation of amyloid-ß of toxic form is a key link of the pathology, which, according to the literature, is also true for dopaminergic dysfunction. An increase in the amyloid-ß level in the brain changes the maximum of the evoked dopamine release in the dorsal and ventral parts of the striatum of the experimental animals. Theoretically, this may be due to the change in the intensity of dopamine release from the nerve terminals or its reuptake. However, it has not been studied. To fill this gap, we examined the amyloid-ß induced changes in the kinetics of the evoked dopamine release in the dorsal striatum and the nucleus accumbens core and shell. Amyloid-ß solution (fragments 25-35) was injected into the ventricular system of the anesthetized male Wistar rats. Before and after injection, electrically evoked dopamine kinetics was registered with fast-scan cyclic voltammetry. The results had shown that the amount of dopamine release decreases in the dorsal striatum and increases in the nucleus accumbens shell. No changes were found in the intensity of dopamine reuptake.

A common genetic variant rs2821557 in KCNA3 is linked to the severity of multiple sclerosis.

The rate of symptom accumulation distinguishes between slowly and rapidly progressing forms of multiple sclerosis (MS). Given that a patient's genetics can affect the rate of disease progression, identification of genetic variants associated with rapid disease progression should provide valuable information for timely prognosis and development of optimal treatment plans. We hypothesized that the polymorphism rs2821557 in the human KCNA3 gene encoding a voltage-gated potassium channel Kv1.3 might be one of these genetic variants, given the role of Kv1.3 in neuroinflammation, as well as the location and gain-of-function effect of this polymorphism. To test this hypothesis we performed an analytic study exploring the relationships between rs2821557 polymorphism and disease progression in a cohort of MS patients. The rs2821557 genotype and the rate of disease progression based on Multiple Sclerosis Severity Score (MSSS) were determined for 101 patients (68 females and 33 males). Peripheral blood CD4+ lymphocyte subpopulations (Tnaive , TCM , TEM ) and the expression of chemokine receptors (CXCR5, CXCR3, CCR6, CCR4) were estimated by flow cytometry. The comparisons between groups by genotype (TT, TC, CC) and allelic approach analysis (T vs. C) revealed a significantly higher incidence of the rapid disease course (MSSS ≥ 7.5) among minor C allele carriers (CC and TC) compared to patients with the TT genotype. Furthermore, C allele carriers had higher counts of CXCR3+ TEM cells than homozygous T allele carriers. In conclusion, accelerated MS progression in C allele carriers is likely linked to enhanced Kv1.3-mediated accumulation of pathogenic CXCR3+ TEM cells and exacerbated neuroinflammation.

The effect of galanin gene polymorphism rs948854 on the severity of multiple sclerosis: A significant association with the age of onset.

BACKGROUND: Data on genetic markers that determine the prognosis of multiple sclerosis (MS) is still limited. The association between galanin gene polymorphism rs948854 and prognosis of MS had been demonstrated earlier. OBJECTIVES: To confirm earlier findings in a distinct from the previously studied cohort of patients, and to further characterized the rs948854 polymorphism as one of the candidates for the risk stratification in patients with MS. METHODS: To assess the rate of disease progression, the MS severity score (MSSS) and Age Related Multiple Sclerosis Severity (ARMSS) score were used, along with the Progression Index (PI). RESULTS: The significant association of a minor allele of rs948854 polymorphism with the severity of the course of multiple sclerosis was revealed, confirming earlier findings. An increase in the proportion of patients with a MSSS > 5 (high rate of progression) was observed among the minor G allele carriers (genotypes AG and GG) compared to patients with AA genotype. Furthermore, the age at onset correlated with the MSSS value only in the group of minor allele carriers and the effect of a minor allele appeared only in patients with the late age at onset (>30 years). CONCLUSION: Collectively, our data support the contribution of galanin gene polymorphism rs948854 to the mechanisms of adverse course of the disease in the late onset MS.

Prefrontal mRNA expression of long and short isoforms of D2 dopamine receptor: Possible role in delayed learning deficit caused by early life interleukin-1ß treatment.

Long (D2L) and short (D2S) isoform of the D2 dopamine receptor are believed to play different roles in behavioral regulation. However, little is known about differential regulation of these isoforms mRNA expression during the process of learning in physiological and pathological states. In this study, we have investigated the combined effect of training in active avoidance (AA) paradigm and chronic early life treatment with pro-inflammatory cytokine interleukin (IL)-1ß (1µg/kg i.p., P15-21) on D2S and D2L dopamine receptor mRNA expression in the medial prefrontal cortex (mPFC) of adult rats. We have shown differential regulation of D2 short and long mRNA isoform expression in the mPFC. There was no effect of AA-training on D2S mRNA expression, while D2L mRNA was downregulated in AA-trained control (intact and saline-treated) animals, and this effect was not observed in rats treated with IL-1ß. D2S mRNA expression level negatively correlated with learning ability within control (saline-treated and intact) groups but not in IL-1ß-treated animals. Thus, prefrontal expression of distinct D2 dopamine receptor splice variants is supposed to be implicated in cognitive decline caused by early life immune challenge.

Postnatal LPS Challenge Impacts Escape Learning and Expression of Plasticity Factors Mmp9 and Timp1 in Rats: Effects of Repeated Training.

Bacterial intoxication associated with inflammatory conditions during development can impair brain functions, in particular evolutionarily novel forms of memory, such as explicit learning. Little is known about the dangers of early-life inflammation on more basic forms of learning, for example, the acquisition of motor escape abilities, which are generally better preserved under pathological conditions. To address this limitation in knowledge, an inflammatory response was elicited in Wistar pups by lipopolysaccharide (LPS) injections (25 µg/kg) on postnatal days P15, P18 and P21. The acquisition of escape behaviour was tested from P77 by active avoidance footshock model and water maze. Open-field behaviour and blood corticosterone levels were also measured. Rat brain tissue was collected from pups 2 h post-injection and from adult rats which either underwent escape training on P77-P81 or remained untrained. mRNA levels of developmental brain plasticity factors MMP-9 and TIMP-1 were investigated in the medial prefrontal cortex and ventral/dorsal hippocampus. LPS-challenged rats displayed moderately deficient escape responses in both memory tests, increased freezing behaviour and, surprisingly, reduced blood cortisol levels. Mmp9 and Timp1, and their ratio to one another, were differentially altered in pups versus adult untrained rats but remained unchanged overall in rats trained in either learning task. Together, our data indicate that systemic pro-inflammatory response during early postnatal development has long-lasting effects, including on the acquisition of motor escape abilities and plasticity factor expression, into adulthood. Our data suggest that altered stress response could possibly mediate these deviations and repeated training might generate positive effects on plasticity under the employed conditions.

Single-nucleotide polymorphism rs948854 in human galanin gene and multiple sclerosis: a gender-specific risk factor.

We performed comparative analyses of the genotype distribution and allelic frequencies of the rs948854 polymorphism (G/A) in the galanin gene's promoter in patients with multiple sclerosis (MS) and in healthy matched controls. In total 111 patients and 115 control subjects were included. The analyses revealed that the presence of the minor allele (G) increased susceptibility to MS in men (OR = 2.49, P = 0.008) but not in women. The presence of the G allele in men was also significantly associated with the late onset of MS. Furthermore, rs948854 polymorphism affected the rate of MS progression depending on the sex of the patients. In woman (typically slowly progressing), the percentage of patients with the slow (<0.5 EDSS score per year) progression rate was significantly reduced (χ2 = 5.7, P = 0.017) in the minor allele carriers group (52.6%), in comparison with the wild-type carriers (83.9%). In men (typically quickly progressing), the number of patients with fast progression rate (≥0.75 EDSS score per year) tended to increase in the minor allele carriers group (50%) compared with number of patients with the wild-type carriers (31.3%). These data demonstrate for the first time an association between rs948854 polymorphism and multiple sclerosis and, further, that this association is sex specific. They also point to diagnostic and prognostic benefits of genetic screening of patients with multiple sclerosis. © 2016 Wiley Periodicals, Inc.

Understanding autism and other neurodevelopmental disorders through experimental translational neurobehavioral models.

Neurodevelopmental disorders (NDDs) are highly prevalent and severely debilitating brain illnesses caused by aberrant brain growth and development. Resulting in cognitive, social, motor, language and affective disabilities, common NDDs include autism spectrum disorder (ASD), intellectual disability, communication/speech disorders, motor/tic disorders and attention deficit hyperactivity disorder. Affecting neurogenesis, glia/neuronal proliferation and migration, synapse formation and myelination, aberrant neural development occurs over a substantial period of time. Genetic, epigenetic, and environmental factors play a key role in NDD pathogenesis. Animal models are an indispensable tool to study NDDs. Paralleling clinical findings, we comprehensively evaluate various preclinical tests and models which target key (social, cognitive, motor) neurobehavioral domains of ASD and other common NDDs. Covering both traditional (rodent) and alternative NDD models, we outline the emerging areas of research and emphasize how preclinical models play a key role in gaining translational and mechanistic insights into NDDs and their therapy.

The Pavlov Department of Physiology: a scientific history.

The scientific adventure of the Ivan Pavlov Department of Physiology is traced from Pavlov's and his students pioneer work on "psychic salivation" to the times of the Biological Station at Koltushi. The development of the Department after Pavlov's death is described and the research trends of the three present laboratories (Neurobiology of Integrative Brain Functions, Psychophysiology of Emotions, and Neurodynamic Correction of Psycho Neurological Pathology) are discussed.

Histologic verification of leukemia, myelodysplasia, and multiple myeloma diagnoses in patients in Ukraine, 1987-1998.

In preparation for a possible large epidemiological study of radiation-related leukemia in Chernobyl clean-up workers of Ukraine, histologic evaluation of 62 cases of leukemia and related disorders was conducted by a panel of expert hematologists and hematopathologists from the United States, France, and Ukraine. All cases were randomly selected from a surrogate population of men in the general population of 6 regions of Ukraine who were between the ages of 20 and 60 years in 1986 and were reported to have developed leukemia, myelodysplasia, or multiple myeloma between the years 1987 and 1998. The hematologists and hematopathologists on the panel were in agreement with one another and with the previously reported diagnoses and classifications of about 90% of the cases of acute and chronic leukemia in the study. These results suggest that strong reliance can be placed on the clinical diagnoses of acute and chronic forms of leukemia and multiple myeloma that have occurred in Ukrainian Chernobyl clean-up workers providing that the diagnoses are supported by records of the patients having had adequate histologic bone marrow studies. The number of cases in this study with the diagnosis of myelodysplasia, however, was too small to draw firm conclusions.