The role of the glycoprotein gp130 in serotonin mediator system in mouse brain

Glycoprotein gp130 is involved in signaling out of significant cytokine receptors as interleukin-6 (IL-6), leukemia inhibitory factor and ciliary neurotrophic factor, which play critical role in immunity, inflammation and neurogenesis. IL-6 and brain neurotransmitter serotonin are involved in the mechanism of depression. The aim of this work was to investigat the role of protein gp130 in the regulation of expression of genes, coding the key enzyme of serotonin synthesis--tryptophan hydroxylase 2 (TPH2), 5-HT-transporter, 5-HT(1A)- and 5-HT(2A)-receptors of serotonin. The study was carried out on adult mouse males of AKR and congenic AKR.CBA-D13Mit76 strains, created by transfer of the fragment of chromosome 13 containing the gene coding gp130 protein from CBA/Lac strain to the genome of AKR/J strain. Decreased expression of 5-HT(1A) - 5-HT(2A)-receptor genes in hippocampus midbrain and TPH2 gene in midbrain in AKR.CBA-D13Mit76 mice compared with AKR mice were shown. Activation of nonspecific immunity by bacterial endotoxin lipopolysaccharide (LPS) administration did not affect the genes expression in AKR mice, but increased 5-HT(2A)-receptor expression in midbrain and decreased 5-HT(1A)-receptor expression in cortex in AKR.CBA-D13Mit76 mice. The results indicate: 1) the participation of gp130 in the regulation of TPH2, 5-HT(1A)- and 5-HT(2A)-receptor genes and 2) association of this protein in the genetically determined sensitivity to LPS.     

The role of the glycoprotein gp130 in the serotonin mediator system in the mouse brain

Glycoprotein gp130 is involved in signal transduction from the receptors of such important cytokines as interleukin-6 (IL-6), leukemia inhibitory factor, and ciliary neurotrophic factor, which play a critical role in immunity, inflammation, and neurogenesis. Both IL-6 and the brain neurotransmitter serotonin are involved in the mechanism of depression. The aim of this work was to investigate the role of gp130 in regulating the gene expression of the tryptophan hydroxylase 2 (TPH2), the key enzyme of the serotonin synthesis, as well as of the 5-HT transporter and the 5-HT_1A and 5-HT_2A receptors. The study was carried out on adult male mice of the congenic strains AKR and AKR.CBA-D13Mit76; the latter was created by transferring a gp130-containing fragment of chromosome 13 from the CBA/Lac strain into the AKR/J genome. The expression of 5-HT_1A and 5-HT_2A receptor genes in the hippocampus and midbrain and of the TPH2 gene in the midbrain was decreased in AKR.CBA-D13Mit76 mice in comparison to AKR mice. Activation of nonspecific immunity by administration of a bacterial endotoxin lipopolysaccharide did not affect the gene expression in AKR mice but increased the 5-HT_2A receptor expression in the midbrain and decreased the 5-HT_1A receptor expression in the cortex in AKR.CBA-D13Mit76 mice. These results suggest that gp130 is involved in the regulation of TPH2, 5-HT_1A and 5-HT_2A receptor genes and is associated with the genetically determined sensitivity to lipopolysaccharides.     

Discrimination: from behaviour to brain

Discrimination is a skill needed by many organisms for survival: decisions about food, shelter, and mate selection all require the ability to distinguish among stimuli. This article reviews the how and why of discrimination and how researchers may exploit this natural skill in the laboratory to learn more about what features of stimuli animals use to discriminate. The paper then discusses the possible neurophysiological basis of discrimination and proposes a model, based on one of stimulus-association put forth by Beninger and Gerdjikov (2004) [Beninger, R.J., Gerdjikov, T.V., 2004. The role of signaling molecules in reward-related incentive learning. Neurotox. Res., 6, 91-104], to account for the role of dopamine in how an animal learns to discriminate rewarded from non-rewarded stimuli.     

Genes regulating the serotonin metabolic pathway in the brain stem and their role in the etiopathogenesis of the sudden infant death syndrome

Genotypes and allelic frequencies of TPH2, 5-HTTLPR, the 5-HTT (SLC6A4) intron 2 variable-number tandem repeat (VNTR) region, and the MAOA VNTR region were determined in brain-stem samples of 20 "genuine" SIDS cases and compared with results obtained from 150 healthy controls. The SNP G1463A responsible for 80% functionality loss of TPH2 (tryptophan hydroxylase 2) was not detected, neither in SIDS infants nor in the controls. In contrast, a strict relation was found between the 5-HTTLPR genotype and its allelic frequencies with SIDS cases. The L/L genotype and the long allele (L) of the promoter region of the serotonin transporter were significantly associated (likelihood ratio (LR) test, p<0.001) with the syndrome (L/L, 60% SIDS vs 14% controls; L, 80% SIDS vs 42.6% controls). Polymorphisms of the intron 2 VNTR of the same gene showed a trend for significant differences between genotypes 10/10 and 12/12 (LR test, p=0.068), with the L-12 haplotype being almost twofold in SIDS (44.5%) with respect to controls (23.4%). Differences were even higher considering the genotype combination L/L-12/12 (20% SIDS vs 2.6%), and variations among categories were statistically highly significant (p<0.001). Although additional differences were observed in the frequency of the MAOA (monoamine oxidase A) VNTR genotype 3R/3R between SIDS and controls (respectively 15% vs 26%), the results were not supported by statistical significance. Molecular polymorphisms are discussed considering their functional role in regulating serotonin synthesis (TPH2), neuronal reuptake (5-HTTLPR and 5-HTT intron 2), and catabolism (MAOA) in the nervous system of Italian SIDS infants. Comparisons are made with previous data obtained in different ethnic groups.     

On the role of gene of SER-4 serotonin receptor in thermotolerance of Caenorhabditis elegans behavior

Serotonin reduces the behavior tolerance of Caenorhabditis elegans of the N2 wild-type strain (swimming induced by the mechanical stimulus) to a temperature of 36°C. The sensitivity to the serotonin influence on the behavior thermotolerance remains intact in strains with null mutations of mod-1(ok103) and ser-1(ok345) serotonin receptor genes, and is almost completely lost in the ser-4(ok512) strain with null mutation in the gene of the SER-4 serotonin receptor, which is a homologue of 5-HT₁ mammalian serotonin receptor. In addition, nematodes of the ser-4(ok512) strain have high behavior thermotolerance in the absence of the exogenous serotonin compared to the N2 strain. These data indicate the involvement of the ser-4 gene in the serotonin regulation of the tolerance of C. elegance nervous system functions to hyperthermia.     

Potassium signalling in the brain: its role in behaviour

This paper examines evidence that glial cells respond to changes in extracellular potassium ([K+]e) in ways that contribute to modulation of neuronal activity and thereby behaviour. Glial cells spatially (and probably directionally) redistribute potassium from regions of increasing concentration to those with a lesser concentration. This redistribution is largely responsible for slow potential shifts associated with behavioural responses of animals. These slow shifts are related in amplitude to the level of 'arousal' of an animal, and its motivational state. In addition, glia, especially astrocytes, respond to changes in [K+]e, the presence of transmitters like nor-adrenaline and glutamate and at least some hormones with changes in their metabolism and/or the morphological characteristics of the cell. The ionic, metabolic and morphological responses of glia to changes in extracellular potassium after neuronal activity have been associated with at least some forms of learning, including habituation, one trial passive avoidance learning and changes associated with enriched environments. The implication of these effects of potassium signalling in the brain is that there is considerable involvement of glia in a number of processes crucial to neuronal activity. Glia may also form another route for information distribution in the brain that is at least bi-directional, though less specific than its neuronal counterparts. It is evident that the Neuroscience of the future will have to incorporate much more study of neuron-glial interactions than hitherto.     

Host behaviour alteration by its parasite: from brain gene expression to functional test

Many parasites with complex life cycles modify their intermediate hosts'' behaviour, presumably to increase transmission to their final host. The threespine stickleback (Gasterosteus aculeatus) is an intermediate host in the cestode Schistocephalus solidus life cycle, which ends in an avian host, and shows increased risky behaviours when infected. We studied brain gene expression profiles of sticklebacks infected with S. solidus to determine the proximal causes of these behavioural alterations. We show that infected fish have altered expression levels in genes involved in the inositol pathway. We thus tested the functional implication of this pathway and successfully rescued normal behaviours in infected sticklebacks using lithium exposure. We also show that exposed but uninfected fish have a distinct gene expression profile from both infected fish and control individuals, allowing us to separate gene activity related to parasite exposure from consequences of a successful infection. Finally, we find that selective serotonin reuptake inhibitor-treated sticklebacks and infected fish do not have similarly altered gene expression, despite their comparable behaviours, suggesting that the serotonin pathway is probably not the main driver of phenotypic changes in infected sticklebacks. Taken together, our results allow us to predict that if S. solidus directly manipulates its host, it could target the inositol pathway.     

On the evolution of brain size in relation to migratory behaviour in birds

Migratory birds appear to have relatively smaller brain size compared to sedentary species. It has been hypothesized that initial differences in brain size underlying behavioural flexibility drove the evolution of migratory behaviour; birds with relatively large brains evolved sedentary habits and those with relatively small brains evolved migratory behaviour (migratory precursor hypothesis). Alternative hypotheses suggest that changes in brain size might follow different behavioural strategies and that sedentary species might have evolved larger brains because of differences in selection pressures on brain size in migratory and nonmigratory species. Here we present the first evidence arguing against the migratory precursor hypothesis. We compared relative brain volume of three subspecies of the white-crowned sparrow: sedentary Zonotrichia leucophrys nuttalli and migratory Z. l. gambelii and Z. l. oriantha. Within the five subspecies of the white-crowned sparrow, only Z. l. nuttalli is strictly sedentary. The sedentary behaviour of Z. l. nuttalli is probably a derived trait, because Z. l. nuttalli appears to be the most recent subspecies and because all species ancestral to Zonotrichia as well as all older subspecies of Z. leucophrys are migratory. Compared to migratory Z. l. gambelii and Z. l. oriantha, we found that sedentary Z. l. nuttalli had a significantly larger relative brain volume, suggesting that the larger brain of Z. l. nuttalli evolved after a switch to sedentary behaviour. Thus, in this group, brain size does not appear to be a precursor to the evolution of migratory or sedentary behaviour but rather an evolutionary consequence of a change in migratory strategy.     

Acoustic communication in crocodilians: from behaviour to brain

Crocodilians and birds are the modern representatives of Phylum Archosauria. Although there have been recent advances in our understanding of the phylogeny and ecology of ancient archosaurs like dinosaurs, it still remains a challenge to obtain reliable information about their behaviour. The comparative study of birds and crocodiles represents one approach to this interesting problem. One of their shared behavioural features is the use of acoustic communication, especially in the context of parental care. Although considerable data are available for birds, information concerning crocodilians is limited. The aim of this review is to summarize current knowledge about acoustic communication in crocodilians, from sound production to hearing processes, and to stimulate research in this field. Juvenile crocodilians utter a variety of communication sounds that can be classified into various functional categories: (1) “hatching calls”, solicit the parents at hatching and fine‐tune hatching synchrony among siblings; (2) “contact calls”, thought to maintain cohesion among juveniles; (3) “distress calls”, induce parental protection; and (4) “threat and disturbance calls”, which perhaps function in defence. Adult calls can likewise be classified as follows: (1) “bellows”, emitted by both sexes and believed to function during courtship and territorial defence; (2) “maternal growls”, might maintain cohesion among offspring; and (3) “hisses”, may function in defence. However, further experiments are needed to identify the role of each call more accurately as well as systematic studies concerning the acoustic structure of vocalizations. The mechanism of sound production and its control are also poorly understood. No specialized vocal apparatus has been described in detail and the motor neural circuitry remains to be elucidated. The hearing capabilities of crocodilians appear to be adapted to sound detection in both air and water. The ear functional anatomy and the auditory sensitivity of these reptiles are similar in many respects to those of birds. The crocodilian nervous system likewise shares many features with that of birds, especially regarding the neuroanatomy of the auditory pathways. However, the functional anatomy of the telencephalic auditory areas is less well understood in crocodilians compared to birds.     

The role of brain serotonin in the expression of genetically determined defensive behavior

The review summarizes the results of long-term studies on the role of the brain mediator serotonin and genetic predisposition to various types of defensive behavior. The involvement of the serotonergic brain system in the mechanisms of genetic control of both active and passive defensive responses has been established using silver foxes, Norway rats of S40 selection for low and high aggressiveness to humans, aggressive mice with genetic knockout of monoaminoxidase A, and S40 rats selected for predisposition to passive defensive response of freezing (catalepsy). The changes in the serotonergic 5-HT1A-brain receptors of rats genetically predisposed to different strategies of defensive behavior were similar. However, the activity of the key enzyme of serotonin biosynthesis and the brain structures, in which serotonin metabolism was altered, significantly differed with regard to the preferred strategy. The conclusion was drawn that the 5-HT1A-receptors and enzymes of serotonin metabolism in the brain are involved in implementing genetic control of defensive behavior. Expression of the 5-HT1A-brain receptors was suggested to determine the levels of fear and anxiety and, consequently, the predisposition to defensive behavior, whereas the preferred strategy of defensive response (active or passive defensive) depends on genetically determined features of serotonin metabolism in the brain structures.     

The conflicting role of brain cholesterol in Alzheimer's disease: lessons from the brain plasminogen system

Retrospective clinical studies indicate that individuals chronically treated with cholesterol synthesis inhibitors, statins, are at lower risk of developing AD (Alzheimer's disease). Moreover, treatment of guinea pigs with high doses of simvastatin or drastic reduction of cholesterol in cultured cells decrease Abeta (beta-amyloid peptide) production. These data sustain the concept that high brain cholesterol is responsible for Abeta accumulation in AD, providing the scientific support for the proposed use of statins to prevent this disease. However, a number of unresolved issues raise doubts that high brain cholesterol is to blame. First, it has not been shown that higher neuronal cholesterol increases Abeta production. Secondly, it has not been demonstrated that neurons in AD have more cholesterol than control neurons. On the contrary, the brains of AD patients show a specific down-regulation of seladin-1, a protein involved in cholesterol synthesis, and low membrane cholesterol was observed in hippocampal membranes of ApoE4 (apolipoprotein E4) AD cases. This effect was also evidenced by altered cholesterol-rich membrane domains (rafts) and raft-mediated functions, such as diminished generation of the Abeta-degrading enzyme plasmin. Thirdly, numerous genetic defects that cause neurodegeneration are due to defective cholesterol metabolism. Fourthly, in female mice, the most brain-permeant statin induces neurodegeneration and high amyloid production. Altogether, this evidence makes it difficult to accept that statins are beneficial through acting as brain cholesterol-synthesis inhibitors. It appears more likely that their advantageous role arises from improved brain oxygenation.     

Descending interneurones from the brain and suboesophageal ganglia and their role in the control of locust behaviour

Lesion and stimulation experiments suggest that the suboesophageal ganglion (SOG) plays a special role in the control of insect behaviour: in bilateral coordination and by maintaining ongoing motor activity. Anatomical observations indicate that there are descending interneurones (DINs) originating in the SOG in addition to those from the brain. An SOG preparation for sampling both types of DIN intracellularly in walking locusts is described. Forty-three units showing activity changes during leg movements and walking were recorded. Using dye injection six were shown to be through-running axons; one was an SOG ascending interneurone; and eight were SOG DINs, 7 contralateral, one ipsilateral. All fired before or during movements and received various sensory inputs. Many gave complex responses to different modalities, several showing directional preferences. Some SOG neurones showed spontaneous changes in activity; activity outlasting movements; or responses to passive as well as active movements. These preliminary results suggest neuronal substrates for the special functions of the SOG in behaviour. They also indicate that DINs, rather than being simple relays, are part of a dynamic network which includes the motor centres. Regulation of complex and subtle aspects of behaviour may be achieved by dynamic and sequential patterns of activity in groups of DINs, some of which may be multifunctional.     

Immunohistochemical analysis of the serotonin system in the brain of lizard Ophisaurus apodus

The distribution of serotoninergic neurons (localization of somata, principal fiber tracts and projection zones) was investigated in the brain of the lizard Ophisaurus apodus using a specific antibody directed against serotonin (5-HT). A comparison of the results with those of the literature revealed that in spite of minor variations in the distribution of 5-HT in the different reptiles examined there exist common features which correspond to a general organizational pattern.     

Distribution of serotonin and FMRF-amide in the brain of Lymnaea stagnalis with respect to the visual system

Despite serotonin’s and FMRF-amide’s wide distribution in the nervous system of invertebrates and their importance as neurotransmitters,the exact roles they play in neuronal networks leaves many questions.We mapped the presence of serotonin and FMRF-amide-immunoreactivity in the central nervous system and eyes of the pond snail Lymnaea stagnalis and interpreted the results in connection with our earlier findings on the central projections of different peripheral nerves.Since the chemical nature of the intercellular connections in the retina of L.stagnalis is still largely unknown,we paid special attention to clarifying the role of serotonin and FMRF-amide in the visual system of this snail and compared our findings with those reported from other species.At least one serotonin-and one FMRF-amidergic fibre were labeled in each optic nerve,and since no cell bodies in the eye showed immunoreactivity to these neurotransmitters,we believe that efferent fibres with somata located in the central ganglia branch at the base of the eye and probably release 5HT and FMRF-amide as neuro-hormones.Double labelling revealed retrograde transport of neurobiotin through the optic nerve,allowing us to conclude that the central pathways and serotonin-and FMRF-amideimmunoreactive cells and fibres have different locations in the CNS in L.stagnalis.The chemical nature of the fibres,which connect the two eyes in L.stagnalis,is neither serotoninergic nor FMRF-amidergic.     

On the possible role of serotonin in the regulation of regeneration of cilia

A study was made of the interrelationship of serotonin, cAMP, and calcium ions in the regulation of regeneration of cilia by Tetrahymena pyriformis. All these compounds stimulated the regeneration, whereas a blocker of serotonin synthesis, p-chlorophenylalanine, and a calcium chelator, EGTA, inhibited the process. This inhibition could be overcome by the addition of any of the stimulatory compounds. cAMP was also found to be inhibitory at high concentrations. The intracellular concentration of this nucleotide was found to increase during the regeneration, and this increase occurred precociously in the presence of serotonin. It was concluded that serotonin may regulate ciliary regeneration by a mechanism involving cAMP And calcium ions, but that the causal relationships among these compounds still need to be established.