Heparin-binding growth-associated molecule (HB-GAM) in activity-dependent neuronal plasticity in hippocampus

Cell adhesion and extracellular matrix (ECM) molecules play a significant role in neuronal plasticity both during development and in the adult. Plastic changes in which ECM components are implicated may underlie important nervous system functions, such as memory formation and learning. Heparin-binding growthassociated molecule (HB-GAM, also known as pleiotrophin), is an ECM protein involved in neurite outgrowth, axonal guidance and synaptogenesis during perinatal period. In the adult brain HB-GAM expression is restricted to the regions which display pronounced synaptic plasticity (e.g., hippocampal CA3-CA1 areas, cerebral cortex laminae II-IV, olfactory bulb). Expression of HB-GAM is regulated in an activity-dependent manner and is also induced in response to neuronal injury. In this work mutant mice were used to study the in vivo function of HB-GAM and its receptor syndecan-3 in hippocampal synaptic plasticity and in hippocampus-dependent behavioral tasks. Phenotypic analysis of HBGAM null mutants and mice overexpressing HB-GAM revealed that opposite genetic manipulations result in reverse changes in synaptic plasticity as well as behavior in the mutants. Electrophysiological recordings showed that mice lacking HB-GAM have an increased level of long-term potentiation (LTP) in the area CA1 of hippocampus and impaired spatial learning, whereas animals with enhanced level of HB-GAM expression have attenuated LTP, but outperformed their wild-type controls in spatial learning. It was also found that GABA(A) receptor-mediated synaptic transmission is altered in the transgenic mice overexpressing HB-GAM. The results suggest that these animals have accentuated hippocampal GABAergic inhibition, which may contribute to the altered glutamatergic synaptic plasticity. Structural studies of HB-GAM demonstrated that this protein belongs to the thrombospondin type I repeat (TSR) superfamily and contains two β-sheet domains connected by a flexible linker. It was found that didomain structure is necessary for biological activity of HB-GAM and electrophysiological phenotype displayed by the HB-GAM mutants. The individual domains displayed weaker binding to heparan sulfate and failed to promote neurite outgrowth as well as affect hippocampal LTP. Effects of HB-GAM on hippocampal synaptic plasticity are believed to be mediated by one of its (co-)receptor molecules, namely syndecan-3. In support of that, HB-GAM did not attenuate LTP in mice deficient in syndecan-3 as it did in wild-type controls. In addition, syndecan-3 knockout mice displayed electrophysiological and behavioral phenotype similar to that of HB-GAM knockouts (i.e. enhanced LTP and impaired learning in Morris water-maze). Thus HB-GAM and syndecan-3 are important modulators of synaptic plasticity in hippocampus and play a role in regulation of learning-related behavior.

Neurotrophins and neuronal plasticity in the action of antidepressants and morphine

Neuronal plasticity is a well characterized phenomenon in the developing and adult brain. It refers to capasity of a single neuron to modify morphology, synaptic connections and activity. Neuronal connections and capacity for plastic events are compromised in several pathological disorders, such as major depression. In addition, neuronal atrophy has been reported in depressive patients. Neurotrophins are a group of secretory proteins functionally classified as neuronal survival factors. Neurotrophins, especially brain derived neurotrophic factor (BDNF), have also been associated with promoting neuronal plasticity in dysfunctional neuronal networks. Chronic antidepressant treatment increases plastic events including neurogenesis and arborization and branching of neurites in distinct brain areas, such as the hippocampus. One suggested mode of action is where the antidepressants elevate the synaptic levels of BDNF thus further activating several signaling cascades via trkB-receptor. In our studies we have tried to clarify the mechanisms of action for antidepressants and to resolve the role of BDNF in this process. We found that chronic antidepressant treatment increases amount of markers of neuronal plasticity in both hippocampus and in the medial prefrontal cortex, both of which are closely linked to the etiology of major depression. Secondary actions of antidepressants include rapid activation of the trkB receptor followed by a phosphorylation of transcription factor CREB. In addition, activation of CREB by phosphorylation appears responsible for the regulation of the expression of the BDNF gene. Using transgenic mice we found that BDNF-induced trkB-mediated signaling proved crucial for the behavioral effects of antidepressants in the forced swimming test and for the survival of newly-born neurons in the adult hippocampus. Antidepressants not only increased neurogenesis in the adult hippocampus but also elevated the turnover of hippocampal neurons. During these studies we also discovered that another trkB ligand, NT-4, is involved in morphine-mediated anti-nociception and tolerance. These results present a novel role for trkB-mediated signaling in plastic events present in the opioid system. This thesis evaluates neuronal plasticity and trkB as a target for future antidepressant treatments.

Origins of the sex differences in handedness and mental rotation ability : genetic, environmental and hormonal effects

In humans, well-replicated and robust sex differences in cognitive functions exist for handedness and mental rotation ability. A common characteristic in human cognitive functions is the lateralization of language functions. Handedness is a common measure of laterality and is related to language lateralization. The prevalence of left-handedness is higher in males than in females, the male to female ratio being about 1.2. Among cognitive abilities, the largest sex difference is evident in the Vandenberg and Kuse Mental Rotation Test (MRT), which requires the ability to rotate objects in mental space. On average, males achieve scores one standard deviation higher than females in the MRT. The present thesis investigated the origins of the sex differences in laterality and spatial ability as represented by handedness and mental rotation ability, respectively. Two population-based Finnish twin cohorts were utilized in this study. Handedness was studied in 25 810 twins and 4068 singletons born before 1958 from the Older Finnish Twin Cohort, and in 4736 twins born in 1983-87 from the FinnTwin12. MRT was studied in a sub-sample of 804 young adult participants from the FinnTwin12 sample. The main findings of this study were: 1) the prevalence of left-handedness was higher among males than among females in both singletons and in twins; 2) males had significantly higher scores than females in MRT; 3) about one quarter of the variance in handedness and about half of the variance in MRT was explained by genetic effects, whereas the remainder of the variance in these traits was explained by environmental effects unique to each individual. The magnitude of the genetic effects was similar in both sexes; 4) left-handedness was significantly less common in female co-twins of a male than in female co-twins of a female, and female co-twins of a male scored significantly higher than did female co-twins of a female in the Mental Rotation Test. This dissertation discusses whether these differences between females from opposite- and same-sex twin pairs are due to the prenatal transfer of testosterone from the male fetus in females with male co-twins or whether they arise from postnatal socialization effects.

Intraspecific variation in brain size and architecture : population divergence and phenotypic plasticity

Brain size and architecture exhibit great evolutionary and ontogenetic variation. Yet, studies on population variation (within a single species) in brain size and architecture, or in brain plasticity induced by ecologically relevant biotic factors have been largely overlooked. Here, I address the following questions: (i) do locally adapted populations differ in brain size and architecture, (ii) can the biotic environment induce brain plasticity, and (iii) do locally adapted populations differ in levels of brain plasticity? In the first two chapters I report large variation in both absolute and relative brain size, as well as in the relative sizes of brain parts, among divergent nine-spined stickleback (Pungitius pungitius) populations. Some traits show habitat-dependent divergence, implying natural selection being responsible for the observed patterns. Namely, marine sticklebacks have relatively larger bulbi olfactorii (chemosensory centre) and telencephala (involved in learning) than pond sticklebacks. Further, I demonstrate the importance of common garden studies in drawing firm evolutionary conclusions. In the following three chapters I show how the social environment and perceived predation risk shapes brain development. In common frog (Rana temporaria) tadpoles, I demonstrate that under the highest per capita predation risk, tadpoles develop smaller brains than in less risky situations, while high tadpole density results in enlarged tectum opticum (visual brain centre). Visual contact with conspecifics induces enlarged tecta optica in nine-spined sticklebacks, whereas when only olfactory cues from conspecifics are available, bulbus olfactorius become enlarged.Perceived predation risk results in smaller hypothalami (complex function) in sticklebacks. Further, group-living has a negative effect on relative brain size in the competition-adapted pond sticklebacks, but not in the predation-adapted marine sticklebacks. Perceived predation risk induces enlargement of bulbus olfactorius in pond sticklebacks, but not in marine sticklebacks who have larger bulbi olfactorii than pond fish regardless of predation. In sum, my studies demonstrate how applying a microevolutionary approach can help us to understand the enormous variation observed in the brains of wild animals a point-of-view which I high-light in the closing review chapter of my thesis.

Kirurgisen operaation teatteri : Teatterillinen kuva ja ihmismuodon esitettävyys avantgardistisen väkivallan näkökulmasta

Dissertation considers the birth of modernist and avant-gardist authorship as a reaction against mass society and massculture. Radical avant-gardism is studied as figurative violence done against the human form. The main argument claims avant-gardist authorship to be an act of masculine autogenesis. This act demands human form to be worked to an elementary state of disarticulateness, then to be reformed to the model of the artist's own psychophysical and idiosyncratic vision and experience. This work is connected to concrete mass, mass of pigment, charcoal, film, or flesh. This mass of the figure is worked to create a likeness in the nervous system of the spectator. The act of violence against the human figure is intended to shock the spectator. This shock is also a state of emotional and perceptional massification. I use theatrical image as heuristic tool and performance analysis, connecting figure and spectator into a larger image, which is constituted by relationships of mimesis, where figure presents the likeness of the spectator and spectator the likeness of the figure. Likeness is considered as both gestural - social mimetic - and sensuous - kinesthetically mimetic. Through this kind of construction one can describe and contextualize the process of violent autogenesis using particular images as case studies. Avant-gardist author is the author of theatrical image, not particular figure, and through act of massification the nervous system of the spectator is also part of this image. This is the most radical form and ideology of avant-gardist and modernist authorship or imagerial will to power. I construct a model of gestural-mimic performer to explicate the nature of violence done for human form in specific works, in Mann's novella Death in Venice, in Schiele's and Artaud's selfportaits, in Francis Bacon's paintings, in Beckett's shortplat NOT I, in Orlan's chirurgical performance Operation Omnipresense, in Cindy Sherman's Film/Stills, in Diamanda Galás's recording Vena Cava and in Hitchcock's Psycho. Masspsychology constructed a phobic picture of human form's plasticity and capability to be constituted by influencies coming both inside and outside - childhood, atavistic organic memories, urban field of nervous impulses, unconsciousness, capitalist (image)market and democratic masspolitics. Violence is then antimimetic and antitheatrical, a paradoxical situation, considering that massmedias and massaudiences created an enormous fascination about possibilities of theatrical and hypnotic influence in artistic elites. The problem was how to use theatrical image without coming as author under influence. In this work one possible answer is provided: by destructing the gestural-mimetic performer, by eliminating representations of mimic body techniques from the performer of human (a painted figure, a photographed figure, a filmed figure or an acted figure, audiovisual or vocal) figure. This work I call the chirurgical operation, which also indicates co-option with medical portraitures or medico-cultural diagnoses of human form. Destruction of the autonomy of the performer was a parallel process to constructing the new mass media audience as passive, plastic, feminine. The process created an image of a new kind of autotelic masculine author-hero, freed from human form in its bourgeois, aristocratic, classical and popular versions.

Cortical processing of speech and non-speech sounds in adults and newborns

Comprehension of a complex acoustic signal - speech - is vital for human communication, with numerous brain processes required to convert the acoustics into an intelligible message. In four studies in the present thesis, cortical correlates for different stages of speech processing in a mature linguistic system of adults were investigated. In two further studies, developmental aspects of cortical specialisation and its plasticity in adults were examined. In the present studies, electroencephalographic (EEG) and magnetoencephalographic (MEG) recordings of the mismatch negativity (MMN) response elicited by changes in repetitive unattended auditory events and the phonological mismatch negativity (PMN) response elicited by unexpected speech sounds in attended speech inputs served as the main indicators of cortical processes. Changes in speech sounds elicited the MMNm, the magnetic equivalent of the electric MMN, that differed in generator loci and strength from those elicited by comparable changes in non-speech sounds, suggesting intra- and interhemispheric specialisation in the processing of speech and non-speech sounds at an early automatic processing level. This neuronal specialisation for the mother tongue was also reflected in the more efficient formation of stimulus representations in auditory sensory memory for typical native-language speech sounds compared with those formed for unfamiliar, non-prototype speech sounds and simple tones. Further, adding a speech or non-speech sound context to syllable changes was found to modulate the MMNm strength differently in the left and right hemispheres. Following the acoustic-phonetic processing of speech input, phonological effort related to the selection of possible lexical (word) candidates was linked with distinct left-hemisphere neuronal populations. In summary, the results suggest functional specialisation in the neuronal substrates underlying different levels of speech processing. Subsequently, plasticity of the brain's mature linguistic system was investigated in adults, in whom representations for an aurally-mediated communication system, Morse code, were found to develop within the same hemisphere where representations for the native-language speech sounds were already located. Finally, recording and localization of the MMNm response to changes in speech sounds was successfully accomplished in newborn infants, encouraging future MEG investigations on, for example, the state of neuronal specialisation at birth.

Cortical processing of musical pitch as reflected by behavioural and electrophysiological evidence

In a musical context, the pitch of sounds is encoded according to domain-general principles not confined to music or even to audition overall but common to other perceptual and cognitive processes (such as multiple pattern encoding and feature integration), and to domain-specific and culture-specific properties related to a particular musical system only (such as the pitch steps of the Western tonal system). The studies included in this thesis shed light on the processing stages during which pitch encoding occurs on the basis of both domain-general and music-specific properties, and elucidate the putative brain mechanisms underlying pitch-related music perception. Study I showed, in subjects without formal musical education, that the pitch and timbre of multiple sounds are integrated as unified object representations in sensory memory before attentional intervention. Similarly, multiple pattern pitches are simultaneously maintained in non-musicians' sensory memory (Study II). These findings demonstrate the degree of sophistication of pitch processing at the sensory memory stage, requiring neither attention nor any special expertise of the subjects. Furthermore, music- and culture-specific properties, such as the pitch steps of the equal-tempered musical scale, are automatically discriminated in sensory memory even by subjects without formal musical education (Studies III and IV). The cognitive processing of pitch according to culture-specific musical-scale schemata hence occurs as early as at the sensory-memory stage of pitch analysis. Exposure and cortical plasticity seem to be involved in musical pitch encoding. For instance, after only one hour of laboratory training, the neural representations of pitch in the auditory cortex are altered (Study V). However, faulty brain mechanisms for attentive processing of fine-grained pitch steps lead to inborn deficits in music perception and recognition such as those encountered in congenital amusia (Study VI). These findings suggest that predispositions for exact pitch-step discrimination together with long-term exposure to music govern the acquisition of the automatized schematic knowledge of the music of a particular culture that even non-musicians possess.

Developmental origins of psychological vulnerability factors for mental disorders

Premature birth and associated small body size are known to affect health over the life course. Moreover, compelling evidence suggests that birth size throughout its whole range of variation is inversely associated with risk for cardiovascular disease and type 2 diabetes in subsequent life. To explain these findings, the Developmental Origins of Health and Disease (DOHaD) model has been introduced. Within this framework, restricted physical growth is, to a large extent, considered either a product of harmful environmental influences, such as suboptimal nutrition and alterations in the foetal hormonal milieu, or an adaptive reaction to the environment. Whether inverse associations exist between body size at birth and psychological vulnerability factors for mental disorders is poorly known. Thus, the aim of this thesis was to study in three large prospective cohorts whether prenatal and postnatal physical growth, across the whole range of variation, is associated with subsequent temperament/personality traits and psychological symptoms that are considered vulnerability factors for mental disorders. Weight and length at birth in full term infants showed quadratic associations with the temperamental trait of harm avoidance (Study I). The highest scores were characteristic of the smallest individuals, followed by the heaviest/longest. Linear associations between birth size and psychological outcomes were found such that lower weight and thinness at birth predicted more pronounced trait anxiety in late adulthood (Study II); lower birth weight, placental size, and head circumference at 12 months predicted a more pronounced positive schitzotypal trait in women (Study III); and thinness and smaller head circumference at birth associated with symptoms of attention-deficit hyperactivity disorder (ADHD) in children who were born at term (Study IV). These associations occured across the whole variation in birth size and after adjusting for several confounders. With respect to growth after birth, individuals with high trait anxiety scores in late adulthood were lighter in weight and thinner in infancy, and gained weight more rapidly between 7 and 11 years of age, but weighed less and were shorter in late adulthood in relation to weight and height measured at 11 years of age (Study II). These results suggest that a suboptimal prenatal environment reflected in smaller birth size may affect a variety of psychological vulnerability factors for mental disorders, such as the temperamental trait of harm avoidance, trait anxiety, schizotypal traits, and symptoms of ADHD. The smaller the birth size across the whole range of variation, the more pronounced were these psychological vulnerability factors. Moreover, some of these outcomes, such as trait anxiety, were also predicted by patterns of growth after birth. The findings are concordant with the DOHaD model, and emphasise the importance of prenatal factors in the aetiology of not only mental disorders but also their psychological vulnerability factors.

Viisi vuotta tiedonrakentamista yhteisö- ja teknologiaelementtien muovautumisen näkökulmasta

The object of this study was to examine the phenomena of a long-term Knowledge Building process. The subject was OECD/ENSI/FI-project's Knowledge Building in Knowledge Forum®3.4 environment from 8.9.2000 to 8.9.2005. Research was based on socio-cognitive and socio-cultural learning approaches and the theoretical background consisted of models of collaborative learning and knowledge processing. These theoretical applications were first structured using metaphors of language and then assembled into five main theoretical motifs. The main motifs were 1) context, 2) inter-subjective, shared area, 3) community's practices and participation, 4) developing expertise and 5) the sequential construction of processes. These themes were assembled in interpreting the results using the Mutual Shaping of Technological and Social Elements by Boczkowski (1999) as a conceptual tool. The social elements of the mutual shaping process were defined as 1) community structure, 2) discourse and 3) the meanings of activity. The technological elements were defined as 1) shared artefacts, 2) features of technology-use and 3) other technological conventions perceived in activity. The five main theoretical motifs were used as the basis for creating the research problems, which were divided into three themes: 1) shared artefacts, themes of Knowledge Building and participant formation, 2) patterns of participation and interaction and 3) the meanings of activity. As methods I used content analysis of the messages, the quantitative profiling of changes in the database, social network analysis, discourse analysis of selected message threads and theme interviews of eleven participants. Based on my study it's possible to say, that a long-term setting of this kind provides a different perspective on Knowledge Building from most of the previous research. The most valuable conclusions from the data are: 1) The centralisation of interaction in this type of setting is a feature that supports the improvement in the quality of action. 2) The participation in a long-term Knowledge Building process seems to support the concious effort on professional development and the expert-identity. 3) The quality of plasticity of the technology-in-use has implication for how the communal features of activity will develop. The agency is seen to initiate processes that in turn open up new possibilities for the quality of action on both the communal and individual levels.

Trafficking and ethanol-induced inhibition of AMPA receptors

AMPA receptors are an important class of ionotropic glutamate receptors which participate in fast excitatory synaptic transmission in most brain areas. They have a pivotal role in adjustment of cell membrane excitability as their cell membrane expression levels is altered in brain physiology such as in learning and memory formation. AMPA receptor function and trafficking is regulated by several proteins, such as transmembrane AMPA receptor regulatory proteins (TARPs). NMDA-type glutamate receptors are important target molecules of ethanol. The role of AMPA receptors in the actions of ethanol has not been clarified as thoroughly. Furthermore, the regulation of AMPA receptor synthesis and their possible adaptation in neurons with altered inhibitory mechanisms are poorly understood. In this thesis work AMPA receptor pharmacology, trafficking and synaptic localization was studied using patch-clamp electrophysiology. Both native and recombinant AMPA receptors were studied. Hippocampal slices from transgenic Thy1alfa6 mice with altered inhibition were used to study adaptation of AMPA receptors. Ethanol was found to inhibit AMPA receptor function by increasing desensitization of the receptor, as the steady-state current was inhibited more than the peak current. Ethanol inhibition was reduced when cyclothiazide was used to block desensitization and when non-desensitizing mutant receptors were studied. Ethanol also increased the rate of desensitization, which was increased further by the coexpression of TARP-proteins. We found that the agonist binding capability is important for trafficking AMPA receptors from endoplasmic reticulum to the cell membrane. TARP rescues the surface expression of non-binding AMPA receptor mutants in HEK293 cells, but not in native neurons. Studies with Thy1alfa6 mice revealed that decreased inhibition decrease AMPA receptor mediated excitation keeping the neurotransmission in balance. Thy1alfa6 mice also had lower sensitivity to electroshock convulsions, presumably due to the decreased AMPA receptor function. The results suggest that during alcohol intoxication ethanol may inhibit AMPA receptors by increasing the rate and the extent of desensitization. TARPs appear to enhance ethanol inhibition. TARPs also participate in trafficking of AMPA receptors upon their synthesis in the cell. AMPA receptors mediate also long-term adaptation to altered neuronal excitability, which adds to their well-known role in synaptic plasticity.

The Functions and Regulation of Ornithine Decarboxylase

Ornithine decarboxylase (ODC) regulates the synthesis of polyamines which are involved in many cellular functions e.g. proliferation and differentiation. Due to its critical role, ODC is a tightly regulated enzyme by antizymes and antizyme inhibitors. If the regulation fails, the activity of ODC increases and may lead to malignant transformation of a cell. Increased ODC activity is found in many common cancers, including colon, prostate, and breast cancer. In a transformed cell, dynamics of the actin cytoskeleton is disturbed. A small G-protein, RhoA regulates organization of the cytoskeleton, and its overactivity increases malignant potential of the cell. The present results indicate that covalent attachment of polyamines by transglutaminase is a physiological means of regulating the activity of RhoA. The translocation of RhoA to the plasma membrane, where it exerts its activity is dependent on the presence of catalytically active ODC. As the overactivity of ODC and RhoA are implicated in cell transformation, the results provide a mechanistic explanation of the interrelationship between the polyamine metabolism and the reorganization of the actin cytoskeleton occurring in cancer cells. ODC and polyamines have also an important role in the function of central nervous system. They participate in the regulation of brain morphogenesis in embryos. In adult nervous tissue, polyamines regulate K+ and glutamate channels. K+ inward rectifying channels control membrane potentials and NMDA-type glutamate receptors (NMDAR) regulate synaptic plasticity. High ODC activity and polyamine levels are considered important in the development of ischemic brain damage and they are implicated in the pathogenesis of Alzheimer s disease (AD). A homolog of ODC was cloned from a human brain cDNA library, and several alternatively spliced variants were detected in human brain and testis. The novel protein was nevertheless devoid of ODC catalytic activity. It was subsequently found to be a novel inductor of ODC activity and polyamine synthesis, called antizyme inhibitor 2 (AZIN2). The accumulation of AZIN2 in vesicle-like formations along the axons and beneath the plasma membrane of neurons as well as in steroid hormone producing Leydig cells and luteal cells of the gonads implies that AZIN2 plays a role in secretion and vesicle trafficking. An accumulation of AZIN2 was detected also in specimens of AD brains. This increased expression of AZIN2 was specific for AD and was not found in brains with other neurodegenerative diseases including CADASIL or dementia with Lewy bodies.