Brain neurons as quantum computers: {\it in vivo} support of background physics

The question: whether quantum coherent states can sustain decoherence, heating and dissipation over time scales comparable to the dynamical timescales of the brain neurons, is actively discussed in the last years. Positive answer on this question is crucial, in particular, for consideration of brain neurons as quantum computers. This discussion was mainly based on theoretical arguments. In present paper nonlinear statistical properties of the Ventral Tegmental Area (VTA) of genetically depressive limbic brain are studied {\it in vivo} on the Flinders Sensitive Line of rats (FSL). VTA plays a key role in generation of pleasure and in development of psychological drug addiction. We found that the FSL VTA (dopaminergic) neuron signals exhibit multifractal properties for interspike frequencies on the scales where healthy VTA dopaminergic neurons exhibit bursting activity. For high moments the observed multifractal (generalized dimensions) spectrum coincides with the generalized dimensions spectrum calculated for a spectral measure of a {\it quantum} system (so-called kicked Harper model, actively used as a model of quantum chaos). This observation can be considered as a first experimental ({\it in vivo}) indication in the favour of the quantum (at least partially) nature of the brain neurons activity

Magnetic resonance spectroscopy of hippocampal and striatal neurometabolites in experimental PTSD rat modeling

The spectrum of the metabolites in the dorsal region of the hippocampus and striatum was studied using the method of 1H magnetic resonance spectroscopy at experimental modeling of the posttraumatic stress disorder syndrome (PTSD) in rats. PTSD was reproduced by exposure of the cat cue to rats daily along 10 day by 10 minutes at once. The anxiety level of animals was estimated 12 days later after the end of the experimental series of stress. Based on the anxiety index, the rats were divided into 3 phenotypes. The animals with an anxiety index > 0.8 (group 1) had lower plasma corticosterone compared with rats form the control group. In animals with an anxiety index in the range 0.7–0.8 (group 2), an elevated corticosterone level was noted. The rats with an anxiety index < 0.7 (group 3) had a lower plasma corticosterone level compared with animals from the control group. Rats of group 2 were characterized by an increased level of GABA in the hippocampus compared with controls. In the remaining groups, the percentages of GABA in the hippocampus and striatum did not differ significantly from the control. The distribution of NAA differed form that of GABA. The highest level of NAA was found in the striatum for rats from group 1, whereas NAA in animals form groups 1 or 3 did not differ from the control. The NAA level in the hippocampus was similar between all groups, including the control. The results obtained indicate that multiple exposures to psychological stress associated with the sense of proximity of a natural enemy in some animals cause an anxiolytic reaction. These animals are characterized by a stable corticosterone level and a stable level of neurometabolites in the studied structures of the brain. For rats with the highest level of anxiety, a lowered level of corticosterone with a constant level of neurometabolites in the hippocampus and striatum is characteristic. And only in rats with an intermediate level of anxiety, synchronization was observed between the increase in plasma corticosterone and the increase in hippocampal GABA content. The results obtained are in good agreement with the ideas of the protective action of glucocorticoids under PTSD manifested in  restraining violations of the psycho-physiological status. The mate rials allow the neurobiological mechanisms of the protective action of glucocorticoids to be detailed

Combined in Silico, Ex Vivo, and in Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro-and Cardioprotective and Antidepressant Effects

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepres-sants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobro-mide (L-17), a recently designed thiadiazine derivative with putative neuro-and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A receptors, respectively. L-17 robustly increased c-Fos immunoreac-tivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro-and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Funding: The work of the authors of this study was supported by the Slovak Research and Development Agency (contract APVV-19-0435), Scientific Grant Agency of the Ministry of Education of the Slovak Republic, the Slovak Academy of Sciences (grant VEGA 2/0046/18), and a Government Contract of the Russian Federation with the Institute of Immunology and Physiology (AAAA-A18-118020690020-1)

Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder - Possible Role for Methoxyindole Pathway

10.1371/journal.pone.0068283PLoS ONE87-POLN

Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression

Brain serotonergic signaling is coupled to arachidonic acid (AA)-releasing calcium-dependent phospholipase A2. Increased brain serotonin concentrations and disturbed serotonergic neurotransmission have been reported in the Flinders Sensitive Line (FSL) rat model of depression, suggesting that brain AA metabolism may be elevated. To test this hypothesis, (14)C-AA was intravenously infused to steady-state levels into control and FSL rats derived from the same Sprague-Dawley background strain, and labeled and unlabeled brain phospholipid and plasma fatty acid concentrations were measured to determine the rate of brain AA incorporation and turnover. Brain AA incorporation and turnover did not differ significantly between controls and FSL rats. Compared to controls, plasma unesterified docosahexaenoic acid was increased, and brain phosphatidylinositol AA and total lipid linoleic acid and n-3 and n-6 docosapentaenoic acid were significantly decreased in FSL rats. Several plasma esterified fatty acids differed significantly from controls. In summary, brain AA metabolism did not change in FSL rats despite reported increased levels of serotonin concentrations, suggesting possible post-synaptic dampening of serotonergic neurotransmission involving AA

Роль взаимодействий между нейромедиаторами головного мозга в патофизиологии и лечении аффективных расстройств

Дременков Элияху, PhD, Институт молекулярной физиологии и генетики, Словацкая академия наук; Институт экспериментальной эндокринологии, Центр биомедицинских исследований, Словацкая академия наук, Братислава, Словакия; Консалтинговая компания Neuroken Consulting, Гронинген, Нидерланды, [email protected]. E. Dremencov, [email protected] Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia; Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Science, Bratislava, Slovakia; Neuroken Consulting, Groningen, the NetherlandsAim of the review is to summarize the contemporary evidences on interactions between brain neurotransmitters and their role in pathophysiology and treatment of depression. Introduction. Brain neurotransmitters are biological molecules responsible for signal transduction between the neurons. Mammalian brain neurotransmitters belong to the different types of biological molecules, such as amino acids (glutamate and γ-aminobutyric acid, or GABA), monoamines (serotonin (5-HT), norepinephrine (NE), dopamine (DA), and histamine (HA)), neuropeptides (β-endorphin, neurokinin, vasopressin, and oxytocin), or nucleotides (adenosine). Materials and Methods. The author analyzes research papers dedicated to neurotransmitters and their functions in mood regulation and published between 1953 and 2014. The paper focuses on evaluation of data on mechanisms of interactions between different neurotransmitters and their role in development and treatment of certain mental disorders. Results. It has been reported that different neurotransmitters, often belonging to the different types of biological molecules, interact on behavioral, functional, system and molecular levels. These interactions play an important role in pathophysiology of brain diseases, particularly, depression and stress and anxiety-related disorders. Conclusion. Literally all existing antidepressant drugs act on monoamine systems of the brain (5-HT, NE, and DA). Although the last-generation antidepressants and mood stabilizers demonstrated higher safety and efficacy, their therapeutic potential remains limited. The brain adenosine neurotransmission is also a potential target for the future antidepressant, mood stabilizing and antipsychotic drugs. However, these drugs may have severe side effects, for example, on cardiac activity. It is necessary to perform further research and clinical trials to find a solution to the existing difficulties. Целью настоящей обзорной статьи является обобщение известных на текущий момент данных о взаимодействиях между нейромедиаторами головного мозга и их роли в патофизиологии и лечении депрессии. Введение. Нейромедиаторы головного мозга представляют собой биологические молекулы, ответственные за передачу сигнала между нейронами. Нейромедиаторы головного мозга у млекопитающих относятся к разным типам биологических молекул, включающим аминокислоты (глутамат и γ-аминомасляную кислоту, или ГАМК), моноамины (серотонин (5-HT), норадреналин (НА), допамин (Д), а также гистамин (Г)), нейропептиды (β-эндорфин, нейрокинин, вазопрессин и окситоцин) и нуклеотиды (аденозин). Материалы и методы. Автор анализирует научные работы, изданные в период с 1953 по 2014 г. и посвященные нейромедиаторам и их функциям в регуляции настроения. Статья посвящена в первую очередь оценке данных о механизмах взаимодействия различных нейромедиаторов и их роли в развитии и лечении отдельных психических расстройств. Результаты. Согласно литературным источникам, нейромедиаторы, нередко относящиеся к разным типам биологических молекул, взаимодействуют на поведенческом, функциональном, системном и молекулярном уровнях. Эти взаимодействия играют важную роль в патофизиологии заболеваний головного мозга, в частности, депрессии и стрессовых и тревожных расстройств. Заключение. Практически все существующие антидепрессанты воз- действуют на моноаминовые системы головного мозга (5-HT, НЭ и Д). Невзирая на то, что антидепрессанты и стабилизаторы настроения последнего поколения обладают высокой степенью надежности и эффективности, их терапевтический потенциал пока ограничен. Большой интерес представляет разработка антидепрессантов, стабилизаторов настроения и нейролептиков, воздействующих на нейропередачу с участием аденозина. Однако такие препараты могут иметь серьезные побочные эффекты, например, негативно влиять на сердечную деятельность. Для разрешения существующих трудностей необходимо проведение дальнейших научных и клинических исследований