Developmental Disruption of Erbb4 in Pet1+ Neurons Impairs Serotonergic Sub-System Connectivity and Memory Formation

The serotonergic system of mammals innervates virtually all the central nervous system and regulates a broad spectrum of behavioral and physiological functions. In mammals, serotonergic neurons located in the rostral raphe nuclei encompass diverse sub-systems characterized by specific circuitry and functional features. Substantial evidence suggest that functional diversity of serotonergic circuits has a molecular and connectivity basis. However, the landscape of intrinsic developmental mechanisms guiding the formation of serotonergic sub-systems is unclear. Here, we employed developmental disruption of gene expression specific to serotonergic subsets to probe the contribution of the tyrosine kinase receptor ErbB4 to serotonergic circuit formation and function. Through an in vivo loss-of-function approach, we found that ErbB4 expression occurring in a subset of serotonergic neurons, is necessary for axonal arborization of defined long-range projections to the forebrain but is dispensable for the innervation of other targets of the serotonergic system. We also found that Erbb4-deletion does not change the global excitability or the number of neurons with serotonin content in the dorsal raphe nuclei. In addition, ErbB4-deficiency in serotonergic neurons leads to specific behavioral deficits in memory processing that involve aversive or social components. Altogether, our work unveils a developmental mechanism intrinsically acting through ErbB4 in subsets of serotonergic neurons to orchestrate a precise long-range circuit and ultimately involved in the formation of emotional and social memories.

Simultaneous administration of coffee and rasagiline/l-dopa protects against paraquat-induced neurochemical and motor behavior impairments in vivo

Background Caffeine is a natural alkaloid present in a variety of highly consumed popular drinks such as coffee, tea and soft drinks as well as chocolate. Its consumption elicits beneficiary psychostimulant that has been linked to a reduced risk of developing Parkinson’s disease (PD). The aim of the present study is to investigate the possible synergistic neuroprotective effects of co-administration of caffeine (CAF) or coffee (COF) with rasagiline (R) or l-dopa against paraquat (PQ)-induced neurochemical and motor behavior impairments in mice. Results In behavioral tests, R + COF increased the locomotor activity in rotarod test compared to l-dopa + COF. l-Dopa combinations decreased the immobility time in FST compared to rasagiline combinations; l-dopa + CAF provided a similar increase in locomotor activity compared to R + CAF. Combination of CAF or COF with l-dopa or rasagiline resulted in a substantial improvement in brain neurotransmitter and antioxidant levels as they significantly increased dopamine and super oxide dismutase but significantly decreased nitric oxide levels as compared to l-dopa or rasagiline, respectively. Furthermore, they also exerted a protective effect against the neurodegenerative histopathological changes induced by PQ. Conclusions Our findings demonstrated co-administration of COF or CAF, adenosine 2A receptor antagonists, along with l-dopa or rasagiline possesses a new therapeutic strategy for the management of PD neurochemical disturbances and motor behavior impairments through preservation of the brain dopamine and serotonin content, antioxidants level and histological features.

Maternal Serotonin: Shaping Developmental Patterns and Behavioral Strategy on Progeny in Molluscs

Serotonin is a well-known neurotransmitter and neurohormone regulating mood, sleep, feeding, and learning in high organisms. Serotonin also affects the embryonic events related to neurogenesis and maturation of hormonal systems, the underlying organism adaptation to a changing environment. Such serotonin-based mother-to-embryo signaling is realized via direct interactions in case of internal fertilization and embryonic development inside the mother body. However, the possibility of such signaling is less obvious in organisms with the ancestral type of embryogenesis and embryo development within the egg, outside the mother body. Our data, based on the investigation of freshwater gastropod molluscs (Lymnaea and Helisoma), demonstrated a correlation between seasonal variations of serotonin content within the female reproductive system, and developmental patterns and the behavioral characteristics of progeny. The direct action of serotonin via posttranslational protein modification—serotonylation—during early development, as well as classical receptor-mediated effects, underlies such serotonin-modulated developmental changes. In the present paper, I will shortly overview our results on freshwater molluscs and parallel the experimental data with the living strategy of these species occupying almost all Holarctic regions.

Immunohistochemical Inflammation in Histologically Normal Appendices in Patients with Right Iliac Fossa Pain

Background Histologically normal appendices resected for right iliac fossa pain in children demonstrate immunohistochemical markers of inflammation. We aimed to establish if subclinical inflammation was present in histologically normal appendices resected from adults with right iliac fossa pain. Methods Immunohistochemistry was performed on formalin-fixed paraffin-embedded appendices for tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-2R and serotonin in four groups: Group I (n = 120): uncomplicated appendicitis, Group II (n = 118): complicated appendicitis (perforation or gangrene), Group III (n = 104): histologically normal appendices resected for right iliac fossa pain and Group IV (n = 106) appendices resected at elective colectomy. Expression was quantified using the H-scoring system. Results Median, interquartile range expression of TNF-α was increased in Groups I (5.9, 3.1–9.8), II (6.8, 3.6–12.1) and III (9.8, 6.2–15.2) when compared with Group IV (3.0, 1.4–4.7, p < 0.01). Epithelial expression of IL-6 in Groups II (44.0, 8.0–97.0) and III (71.0, 18.5–130.0) was increased when compared with Group IV (9.5, 1.0–60.2, p < 0.01). Expression of mucosal IL-2R in Groups I (47.4, 34.8–69.0), II (37.8, 25.4–60.4) and III (18.4, 10.1–34.7) was increased when compared with Group IV (2.8, 1.2–5.7, p < 0.01). Serotonin content in Groups I (3.0, 0–30.0) and II (0, 0–8.5) was decreased when compared with Groups III (49.7, 16.7–107.5) and IV (43.5, 9.5–115.8, p < 0.01). Conclusion Histologically normal appendices resected from symptomatic patients exhibited increased proinflammatory cytokine expression on immunohistochemistry suggesting the presence of an inflammatory process not detected on conventional microscopy.

Serotonin and cyclic sleep organization in healthy full-term newborns

Relevance: The growth of neuropsychiatric diseases caused by perinatal pathology indicates the need to study the biochemical markers of brain damage in the newborn for the timely prevention of adverse consequences. Serotonin in early ontogenesis provides intensive development of neuronal structures and cortical networks involved in the mechanisms of formation of cyclic sleep organization a fine criterion of morphofunctional development of the brain. aim: The aim of the work is to study the content of serotonin in healthy full-term newborns in comparison with the quantitative and qualitative characteristics of the electropoligraphic sleep pattern. Material and methods: 84 healthy newborns were examined, which, depending on the gestational age, were divided into 3 groups: I 37 weeks (20 people), II 38 weeks (24 people), III 39-40 weeks (40 people). The content of serotonin in platelet-rich plasma of blood from the umbilical cord vein and in platelet suspension prepared from venous blood taken from mothers and children on the first day of life and again on day 5 was determined by high-performance liquid chromatography with electrochemical detection. A quantitative and qualitative analysis of the sleep electropoligram was performed 7-12 hours after birth. Results: The content of serotonin in platelet-rich plasma in umbilical cord blood in children does not depend on the method of birth, is 2 times lower than in the venous blood of mothers (0.379 0.116 microns/l, versus 0.756 0.200 microns/l, but there is a high correlation between the indicators (r = 0.8, p 0.05). At the gestational age of 39-40 weeks, the level of serotonin in platelet-rich plasma and in venous blood platelets is significantly higher than in those born at 37 weeks. In the latter, the increase in the content of serotonin in platelets continues after birth (at day 1, 0.539 0.149 nM/109 Tr, and on day 5 0.846 0.094 nM/109 Tr; p 0.05), whereas the indicators for those born at 39-40 weeks of pregnancy. They do not change (0.797 0.190 nM/109 Tr and 0.749 0.142 nM/109 Tr, respectively). A significant increase in the content of serotonin in the platelet-rich plasma and in the platelets of the child in the period from 37 to 39 weeks, both during intrauterine development and in the first days of life, correlates with an increase in the representation of the orthodox phase in the sleep cycle. Conclusion: The general pattern of changes in serotonin content and cyclic sleep organization in the early neonatal period in healthy newborns, depending on gestational age, indicates the possibility of using the obtained standard values of serotonin as a biochemical marker of functional brain development.

THE ROLE OF THYROID HORMONES IN THE FORMATION OF SPATIAL MEMORY OF RATS IN EARLY ONTOGENESIS

Changes in behavioral and mnestic activity, as well as their neurochemical support in thyroid dysfunction were determined in juvenile Wistar rats. Behavioral activity was studied in an elevated cruciform labyrinth, the study of spatial memory was performed by the development of protective avoidance reaction in the Morris water labyrinth, and by the production of food reactions in the 8-beam labyrinth. The content of free amino acids of the neurotransmitter spectrum and serotonin was determined by thin layer chromatography followed by spectrophotometry. It was found that thyroid dysfunction in early ontogenesis was accompanied by significant impairments of emotional and cognitive activity depending on the thyroid status of rats; differences in the mechanisms of the formation of spatial memory with negative and positive reinforcement were also found. At the same time, the anxiolytic type of behavior and formation of spatial memory in juvenile animals with experimental hyperthyroidism are possibly provided by an increase in GABA content in the neocortex by 40% and a decrease in serotonin level in the hippocampus by 32%. Experimental hypothyroidism caused an anxiogenic effect and cognitive impairment, which were accompanied by an excessive increase by 51% in the neocortical serotonin content.

Effects of GABA/β-glucan supplements on melatonin and serotonin content extracted from natural resources

Objective This study aimed to monitor the secretion of serotonin and melatonin in the blood serum of rats in the presence of rice bran (RB), and Sarcodon aspratus (S) extracts for sleep promotion. Background Sleep is a natural physiological phenomenon, and sleep disorders may cause severe mental hazards leading to excessive daytime sleepiness (EDS). The γ-aminobutyric acid (GABA) and β-glucan are the essential active ingredients of RB and mushroom, respectively, exhibited stress-reduction and nerve stabilizing potential through regulation of melatonin and serotonin hormones. Methods Cytotoxicity of the extracts (RBS) was evaluated through WST-1 assay. The melatonin and serotonin concentrations in the blood serum were measured through ELISA kits. The Ig ELISA kit measured the immunoglobulin’s (IgG, IgM, and IgA) concentrations. Results Improved cell viability was observed in RBS treated groups than control, indicating their biocompatibility. The melatonin and serotonin levels were high in RBS (5:5 and 7:3) treated groups compared to the control. Enhanced expression of immunoglobulin (Ig) A and G level was observed in RBS treated rats. The serotonergic genes (5-HTT, 5-HT 1B, and MAO-A) expression levels were upregulated in RBS treated groups vis-à-vis the control. Conclusion Based on these results, we anticipated that RBS supplements could promote the sleep phenomenon by elevating the serotonin/melatonin level in the blood through the serotonergic system. Therefore, RBS supplements can be utilized as functional food material for sleep promotion.

Maternal adaptations of pancreatic islets and glucose metabolism after lactation

Pancreatic islets adapt to metabolic requirements and the hormonal milieu by modifying their size and hormone secretions. Maternal glucose demands and hormonal changes occur after weaning, to rapidly re-establish bone mineralization. Minimal information exists about glucose metabolism and pancreatic islets after lactation. This study investigated islet morphology and glucose homeostasis for 14 days after lactation in C57BL/6NHHsd mice. Compared to the day of weaning, rapid increases in the islets’ area and number of beta cells were found from the first day post-lactation, attaining maximum values on the third day post-weaning. These changes were accompanied by modifications in glucose-induced insulin secretion, glucose tolerance and insulin sensitivity. Islet-cell proliferation was already augmented before lactation ceased. Serum undercarboxylated osteocalcin concentrations increased significantly post-lactation; however, it is unlikely that this enhancement participates in earlier cell proliferation augmentation or in decreasing insulin sensitivity. Islet serotonin content was barely expressed, and serum calcium concentrations decreased. By the 14th day post-weaning, islets’ area and glucose homeostasis returned to age-matched virgin mice levels. These findings recognize for the first time that increases in islet area and insulin secretion occur during physiological post-weaning conditions. These results open up new opportunities to identify molecules and mechanisms participating in these processes, which will help in developing strategies to combat diabetes.