<p>Vocal learning is the ability modify vocal output based on auditory input and is the basis of human speech acquisition. It is shared by few distantly related bird and mammal orders, and is thus very likely to be an example of convergent evolution, having evolved independently in multiple lineages. This complex behavior is presumed to require networks of regulated genes to develop the necessary neural circuits for learning and maintaining vocalizations. Deciphering these networks has been limited by the lack of high throughput genomic tools in vocal learning avian species and the lack of a solid computational framework to understand the relationship between gene expression and behavior. This dissertation provides new insights into the evolution and mechanisms of vocal learning by taking a top-down, systems biology approach to understanding gene expression regulation across avian and mammalian species. First, I worked with colleagues to develop a zebra finch Agilent oligonucleotide microarray, including developing programs for more accurate annotation of oligonucleotides and genes. I then used these arrays and tools in multiple collaborative, but related projects, to measure transcriptome expression data in vocal learning and non-learning avian species, under a number of behavioral paradigms, with a focus on song production. To make sense of the avian microarray data, I compiled microarray data from other sources, including expression analyses across over 900 human brain regions generated by Allen Brain Institute. To compare these data sets, I developed and performed a variety of computational analyses including clustering, linear models, gene set enrichment analysis, motif discovery, and phylogenetic inference, providing a novel framework to study the gene regulatory networks associated with a complex behavior. Using the developed framework, we are able to better understand vocal learning at different levels: how the brain regions for vocal learning evolved and how those brain regions function during the production of learned vocalizations. At the evolutionary level, we identified genes with unique expression patterns in the brains of vocal learning birds and humans. Interesting candidates include genes related to formation of neural connections, in particular the SLIT/ROBO axon guidance pathway. This algorithm also allowed us to identify the analogous regions that are a part of vocal learning circuit across species, providing the first quantitative evidence relating the human vocal learning circuit to the avian vocal learning circuit. With the avian song system verified as a model for human speech at the molecular level, we conducted an experiment to better understand what is happening in those brain regions during singing by profiling gene expression in a time course as birds are producing song. Surprisingly, an overwhelming majority of the gene expression identified was strongly enriched in a particular region. We also found a tight coupling between the behavioral function of a particular region and the gene expression pattern. To gain insight into the mechanisms of this gene regulation, we conducted a genomic scan of transcription factor binding sites in zebra finch. Many transcription factor binding sites were enriched in the promoters of genes with a particular temporal patterns, several of which had already been hypothesized to play a role in the neural system. Using this data set of gene expression profiles and transcription factor binding sites along with separate experiments conducted in mouse, we were able uncover evidence that the transcription factor CARF plays a role in neuron homeostasis. These results have broadened our understanding of the molecular basis of vocal learning at multiple levels. Overall, this dissertation outlines a novel way of approaching the study of the relationship between genes and behavior.</p> / Dissertation

Choosing with whom to mate is one of the most important decisions a female makes in her lifetime and inter-individual variation of these preferences can have important evolutionary consequences. In order to get a complete understanding of why and how females choose a mate, we must identify factors that can contribute to variation of female mate choice. Many decades of research sought to understand ultimate mechanisms of female mate choice with proximate mechanisms receiving a lot more attention in recent years. For my thesis, I identify intrinsic and extrinsic factors that correlate with individual variation of female Xiphophorus nigrensis mate preference. I provide evidence that a female’s size (e.g. age and sexual experience) as well as male behavioral displays can predict female mate preference. Using genes associated with female mate preference (neuroserpin, neurologin-3), I identify four brain regions (Dl, Dm, HV, POA) that show significant differences in gene expression between females exhibiting high preference for males relative to females displaying little mate preference. Neuroserpin and neuroligin-3 gene expression within these brain regions are also positively correlated with female mate preference behavior. Two of these brain regions (Dm and Dl) integrate multisensory information and are found in the putative teleost mesolimbic reward circuitry; the other two regions (HV and POA) are involved in sexual behaviors. With the implication of the reward circuitry, I assess whether there are changes in dopamine synthesis (via tyrosine hydroxylase, TH) in dopaminergic brain regions associated with the degree of mate preference. I do not find evidence of rapid changes (within 30 minutes) of TH expression (i.e. dopamine synthesis) in dopaminergic brain regions related to variation in female mate preference. Collectively my results suggest that mate preference behavior in the brain may be coordinated not just through regions associated with sexual response but also through forebrain areas that may integrate primary sensory information, with no associated changes of a proxy for dopamine synthesis in dopaminergic brain regions. / text

No description available.

<p>Estradiol modulates the use of spatial navigation strategies in female rats. The presence of circulating estradiol enhances learning on tasks that require the use of a hippocampus-dependent place strategy and impairs learning on tasks that require the use of a dorsal striatum-dependent response strategy. When either strategy may be used successfully, estradiol biases females to use a place strategy. While this behavioral effect has been well-described in the young adult female rat, little is known about the mechanisms in the brain that underlie it or how it changes across age. The experiments in this dissertation examined how age, previous experience, and hormonal condition affect the ability of estradiol to modulate learning during explicit training of place and response tasks, as well as navigation strategy use during ambiguous navigation tasks. Age highly influenced the ability of estradiol to influence strategy use. While female rats could use place and response strategies to navigate by postnatal day (PD) 21, estradiol did not bias them to use a response strategy until PD26, just before puberty. In adulthood, previous navigation experience and estradiol interacted to influence navigation strategy use on a series of experiences to an ambiguous navigation task. And, estradiol impaired learning during explicit response training but did not affect place learning. In middle age, estradiol further impaired response learning but still did not affect place learning. Long-term hormone deprivation, however, was detrimental to acquisition of a place task but did not affect response learning. These experiments also examined the effects of estradiol on activity, plasticity, and reliability of neuronal ensembles in several subregions of the hippocampus and striatum during spatial navigation using cellular and molecular techniques that take advantage of the kinetics of the immediate-early genes c-fos and Arc. Increased activation and plasticity during active exploration across several subregions of the hippocampus and striatum reflected similar inputs to these neural systems and similar effects of exploration. However, estradiol modulated the plasticity and reliability of neuronal ensembles in the hippocampus and striatum specifically during goal-directed spatial navigation. Estradiol increased plasticity in CA1 of all behaviorally-trained rats, but only place strategy users displayed high reliability in this plasticity across training and probe trials on a navigation task. Estradiol prevented increase in plasticity and reliability in the dorsolateral striatum displayed by low estradiol response strategy users. These experiments reveal how several factors, including age, influence estradiol's modulation of spatial navigation strategy use and suggest functional mechanisms by which this modulation occurs.</p> / Dissertation

Thesis (Ph. D.)--University of South Florida, 2004. / Includes vita. Includes bibliographical references.

abstract: The capability of cocaine-associated stimuli in eliciting craving in human addicts, even after extended periods of abstinence, is modeled in animals using cue reinstatement of extinguished cocaine-seeking behavior. This study aimed to examine brain activation in response to cocaine cues in this model apart from activation produced by test novelty using a novel cue control. Rats trained to self-administer cocaine paired with either an oscillating light or tone cue underwent daily extinction training and were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either their assigned cocaine-paired cue or the alternate, novel cue. Additional controls received saline infusions and cue presentations yoked to a cocaine-trained rat. Brains were harvested for Fos immunohistochemistry immediately after the 90-min reinstatement test. Surprisingly, conditioned and novel cues both reinstated responding to a similar degree; however magnitude of reinstatement did vary by cue modality with the greatest reinstatement to the light cues. In most brain regions, Fos expression was enhanced in rats with a history of cocaine training regardless of cue type with the exception of the Cg1 region of the anterior cingulate cortex, which was sensitive to test cue modality. Also Fos expression within the dorsomedial caudate-putamen was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel light and tone, but not a familiar cue. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a history of operant-delivered drug or a natural reinforcer. Furthermore, similar brain circuits as those involved in cocaine-seeking behavior are activated by novel cues, suggesting converging processes exist to drive conditioned and novel reinforcement seeking. / Dissertation/Thesis / M.A. Psychology 2012

While the causes of myriad medical and infectious illnesses have been identified, the etiologies of neuropsychiatric illnesses remain elusive. This is due to two major obstacles. First, the risk for neuropsychiatric disorders, such as schizophrenia, is determined by both genetic and environmental factors. Second, numerous genes influence susceptibility for these illnesses. Genome-wide association studies have identified at least 108 genomic loci for schizophrenia, and more are expected to be published shortly. In addition, numerous biological processes contribute to the neuropathology underlying schizophrenia. These include immune dysfunction, synaptic and myelination deficits, vascular abnormalities, growth factor disruption, and N-methyl-D-aspartate receptor (NMDAR) hypofunction. However, the field of psychiatric genetics lacks a unifying model to explain how environment may interact with numerous genes to influence these various biological processes and cause schizophrenia. Here we describe a biological cascade of proteins that are activated in response to environmental stimuli such as stress, a schizophrenia risk factor. The central proteins in this pathway are critical mediators of memory formation and a particular form of hippocampal synaptic plasticity, long-term depression (LTD). Each of these proteins is also implicated in schizophrenia risk. In fact, the pathway includes four genes that map to the 108 loci associated with schizophrenia: GRIN2A, nuclear factor of activated T-cells (NFATc3), early growth response 1 (EGR1) and NGFI-A Binding Protein 2 (NAB2); each of which contains the "Index single nucleotide polymorphism (SNP)" (most SNP) at its respective locus. Environmental stimuli activate this biological pathway in neurons, resulting in induction of EGR immediate early genes: EGR1, EGR3 and NAB2. We hypothesize that dysfunction in any of the genes in this pathway disrupts the normal activation of Egrs in response to stress. This may result in insufficient electrophysiologic, immunologic, and neuroprotective, processes that these genes normally mediate. Continued adverse environmental experiences, over time, may thereby result in neuropathology that gives rise to the symptoms of schizophrenia. By combining multiple genes associated with schizophrenia susceptibility, in a functional cascade triggered by neuronal activity, the proposed biological pathway provides an explanation for both the polygenic and environmental influences that determine the complex etiology of this mental illness.

No description available.

Le lien d’appariement unissant un mâle et une femelle a été peu exploré chez les Oiseaux, alors que la plupart sont monogames. De plus, l’étude de la monogamie s’est souvent cantonnée à l’exploration des comportements liés à la reproduction et au choix du partenaire. L’objectif de cette thèse est d’identifier les comportements sociaux caractéristiques du lien d’appariement et leurs supports cérébraux chez un passereau social et monogame, le Diamant mandarin (Taeniopygia guttata). Grâce aux concepts de la théorie des réseaux appliqués à l’étude en laboratoire des interactions sociales, cette thèse s’intéresse à la valeur sociale du lien d’appariement. Elle montre qu’il représente un véritable partenariat social, suffisamment favorable pour que se forment des couples homosexuels en cas d’indisponibilité d’oiseaux du sexe opposé. Par l’étude en milieu naturel des communications acoustiques entre partenaires, ce lien est apparu comme le cadre d’échanges vocaux particuliers : de discrets duos de cris émis dans l’intimité du nid. En s’intéressant au rythme d’émission des vocalisations à l’échelle du groupe, cette thèse jette également un nouveau regard sur l’étude des communications acoustiques. La dynamique du réseau acoustique que représente le groupe est influencée par la proportion d’oiseaux appariés. Enfin, les causes proximales des liens sociaux sont abordées : l’activité du réseau cérébral impliqué dans l’expression des comportements sociaux, le « Social Behavior Network » (SBN), varie avec la possibilité de créer des liens chez les mâles. Cette thèse participe donc à définir le lien d’appariement comme un lien social complexe dont les avantages ne se limiteraient pas à la reproduction. Elle révèle ses conséquences tant sur le réseau social, que sur le réseau acoustique du groupe de diamants mandarins, et soulève l’implication potentielle du réseau cérébral SBN dans les mécanismes de sa formation et de son maintien / Although most birds are monogamous, the pair-bond between a male and a female remains relatively unexplored in these species. Moreover, the study of monogamy mainly focused on behaviours linked to reproduction and partner choice. The aim of this thesis is to identify the social behaviours and the neurophysiological mechanisms of pair-bonding in a social and monogamous passerine, the Zebra finch (Teaniopygia guttata). Using concepts of network theory to study social interactions in the laboratory, this thesis explores the social value of the pair-bond. We showed that the pair-bond is a genuine partnership, whose social value might explain why birds establish same-sex pair-bonds when partners of the opposite sex are scarce. The study of acoustic communication between mates in the field revealed that partners perform specific vocal displays : they use private duets of calls in the intimacy of their nest. By investigating the rhythm of emission of vocalizations at group scale, this thesis takes a fresh look at the study of acoustic communication. The proportion of paired birds in a group influences the dynamic of the acoustic network constituted by the social group. Finally, we tackled the proximal explanations of social bonding : in males, social relationships affect the activity of the brain network implicated in social behaviours, the Social Behavior Network (SBN). This thesis underlines the social complexity of the pair-bond that might bring benefits beyond reproduction. It reveals the consequences of pair-bonding on both social network and acoustic network, and points towards a role of the SBN in pair-bond establishment and maintenance

No description available.