Indiana University-Purdue University Indianapolis (IUPUI) / Sensitization to the locomotor stimulant effects of alcohol (ethanol) is thought to be a heritable risk factor for the development of alcoholism that reflects progressive increases in the positive motivational effects of this substance. However, very little is known about the genetic influences involved in this phenomenon or the extent to which ethanol’s positive motivational effects are altered in parallel to its development. The first goal of this work was to determine the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection. Genetically heterogeneous C57BL/6J (B6) x DBA/2J (D2) F2 mice were generated from B6D2F1 progenitors, phenotyped for the expression of locomotor sensitization, and bred for high (HLS) and low (LLS) expression of this behavior. A secondary goal was to characterize possible line differences in ethanol’s positive motivational effects using a conditioned place preference assay. There were large and significant differences in locomotor sensitization between HLS and LLS lines by the fourth generation. Twenty-two percent of the observed line difference(s) were attributable to genes (h2=.22). However, there were no significant differences in conditioned place preference between lines despite significant line differences in ethanol-stimulated locomotion following repeated exposures. The results of this work have several implications. First, that changes in ethanol sensitivity following repeated exposures are in part genetically regulated highlights the relevance of studies aimed at determining how genes regulate susceptibility to ethanol-induced behavioral and neural adaptations. Additionally, the lack of line differences in ethanol-induced CPP, and the observation that CPP and ethanol sensitization are dissociable, suggests that 1) different genes regulate these two behaviors and 2) the utility of locomotor sensitization as a model of alterations in ethanol’s positive motivational effects is, at best, still unclear. Together these studies provide evidence that genes are capable of regulating alterations in ethanol-induced locomotor behavior but provide little support for ethanol-induced locomotor sensitization as a model for increases in ethanol’s positive subjective effects in mice.

Students with Attention-Deficit/Hyperactivity Disorder (ADHD) are usually inattentive and disruptive in class, are at high risk for chronic academic achievement difficulties, and may develop problems in relationships with peers, parents, and teachers (DuPaul, Stoner, 2003). One of the primary goals of behavioural treatment for ADHD is to enable a student to develop adequate levels of self-control (Barkley, 1990; DuPaul & Stoner, 1994). Methods are needed in the classroom, which give the child or adolescent with ADHD, control over his or her condition and thus increased independence, more experiences with success, and increased resiliency. Listening to music has many therapeutic applications, including the development of cognitive skills such as attention and memory (Canadian Association for Music Therapy, 2006). Music is accessible to all teachers and students, and is an easy strategy to implement in classrooms. Yet, despite the knowledge that adolescents are active users of music media (North, Hargreaves, & ONeill, 2000), little research on music and ADHD participants has been completed. Through the use of a single subject case study, the purpose of this research was: look at the academic experience that an adolescent male diagnosed with ADHD faced in his life at school; and to gain a better understanding of how music could potentially affect his ability to self-regulate and cope with the detrimental effects of ADHD during in-class seat work and homework. Multiple interviews with one boy, his parents, and teachers across a 14-week period of time provided a primary source of data. Results indicated that the adolescents experiences with listening to music during school and homework increased the time that he was able to attend and concentrate. Unexpected gains included an increase in his ability to recall information during exams, and an increase in motivation, positive attitude, and mood towards school work as a result of enjoying listening to his favourite music. However, the study also involved the unexpected and disheartening discovery of clashing and competing voices that perhaps ultimately rendered the boys positive experiences with music insignificant, given the louder rule-and-order school culture. The pragmatic realities of working within a school context will need to be considered and strategically addressed if students are to benefit from practices that help even though they may be unconventional and not fully understood.

Students with Attention-Deficit/Hyperactivity Disorder (ADHD) are usually inattentive and disruptive in class, are at high risk for chronic academic achievement difficulties, and may develop problems in relationships with peers, parents, and teachers (DuPaul, Stoner, 2003). One of the primary goals of behavioural treatment for ADHD is to enable a student to develop adequate levels of self-control (Barkley, 1990; DuPaul & Stoner, 1994). Methods are needed in the classroom, which give the child or adolescent with ADHD, control over his or her condition and thus increased independence, more experiences with success, and increased resiliency. Listening to music has many therapeutic applications, including the development of cognitive skills such as attention and memory (Canadian Association for Music Therapy, 2006). Music is accessible to all teachers and students, and is an easy strategy to implement in classrooms. Yet, despite the knowledge that adolescents are active users of music media (North, Hargreaves, & ONeill, 2000), little research on music and ADHD participants has been completed. Through the use of a single subject case study, the purpose of this research was: look at the academic experience that an adolescent male diagnosed with ADHD faced in his life at school; and to gain a better understanding of how music could potentially affect his ability to self-regulate and cope with the detrimental effects of ADHD during in-class seat work and homework. Multiple interviews with one boy, his parents, and teachers across a 14-week period of time provided a primary source of data. Results indicated that the adolescents experiences with listening to music during school and homework increased the time that he was able to attend and concentrate. Unexpected gains included an increase in his ability to recall information during exams, and an increase in motivation, positive attitude, and mood towards school work as a result of enjoying listening to his favourite music. However, the study also involved the unexpected and disheartening discovery of clashing and competing voices that perhaps ultimately rendered the boys positive experiences with music insignificant, given the louder rule-and-order school culture. The pragmatic realities of working within a school context will need to be considered and strategically addressed if students are to benefit from practices that help even though they may be unconventional and not fully understood.

A fundamental question in the neurobiological study of drug addiction concerns the mechanisms mediating the motivational effects of chronic drug withdrawal. According to one theory, drugs of abuse activate opposing motivational processes after both acute and chronic drug use. The negative experience of withdrawal is the opponent process of chronic drug use that drives relapse to drug-seeking and -taking, making the identification of the neurobiological substrates mediating withdrawal an issue of central importance in addiction research. In this thesis, I identify the involvement of the neurotransmitters dopamine (DA) and corticotropin-releasing factor (CRF) in the opponent motivational a- and b-processes occurring after acute and chronic nicotine administration. I report that acute nicotine stimulates an initial aversive a-process followed by a rewarding opponent b-process, and chronic nicotine stimulates a rewarding a-process followed by an aversive opponent b-process (withdrawal). These responses can be modeled using a place conditioning paradigm. I demonstrate that the acute nicotine a-process is mediated by phasic dopaminergic activity and the DA receptor subtype-1 (D1R) but not by tonic dopaminergic activity and the DA receptor subtype-2 (D2R) or CRF activity, and the opponent b-process is neither DA- nor CRF-mediated. I also demonstrate that the chronic nicotine a-process is DA- but not CRF-mediated, and that withdrawal from chronic nicotine (the b-process) decreases tonic but not phasic DA activity in the ventral tegmental area (VTA), an effect that is D2R- but not D1R-mediated. I show that a specific pattern of signaling at D1Rs and D2Rs mediates the motivational responses to acute nicotine and chronic nicotine withdrawal, respectively, by demonstrating that both increasing or decreasing signaling at these receptors prevents the expression of the conditioned motivational response. Furthermore, I report that the induction of nicotine dependence increases CRF mRNA in VTA DA neurons, and that blocking either the upregulation of CRF mRNA or the activation of VTA CRF receptors prevents the anxiogenic and aversive motivational responses to withdrawal from chronic nicotine. The results described in this thesis provide novel evidence of a VTA DA/CRF system, and demonstrate that both CRF and a specific pattern of tonic DA activity in the VTA are necessary for the aversive motivational experience of nicotine withdrawal.

A fundamental question in the neurobiological study of drug addiction concerns the mechanisms mediating the motivational effects of chronic drug withdrawal. According to one theory, drugs of abuse activate opposing motivational processes after both acute and chronic drug use. The negative experience of withdrawal is the opponent process of chronic drug use that drives relapse to drug-seeking and -taking, making the identification of the neurobiological substrates mediating withdrawal an issue of central importance in addiction research. In this thesis, I identify the involvement of the neurotransmitters dopamine (DA) and corticotropin-releasing factor (CRF) in the opponent motivational a- and b-processes occurring after acute and chronic nicotine administration. I report that acute nicotine stimulates an initial aversive a-process followed by a rewarding opponent b-process, and chronic nicotine stimulates a rewarding a-process followed by an aversive opponent b-process (withdrawal). These responses can be modeled using a place conditioning paradigm. I demonstrate that the acute nicotine a-process is mediated by phasic dopaminergic activity and the DA receptor subtype-1 (D1R) but not by tonic dopaminergic activity and the DA receptor subtype-2 (D2R) or CRF activity, and the opponent b-process is neither DA- nor CRF-mediated. I also demonstrate that the chronic nicotine a-process is DA- but not CRF-mediated, and that withdrawal from chronic nicotine (the b-process) decreases tonic but not phasic DA activity in the ventral tegmental area (VTA), an effect that is D2R- but not D1R-mediated. I show that a specific pattern of signaling at D1Rs and D2Rs mediates the motivational responses to acute nicotine and chronic nicotine withdrawal, respectively, by demonstrating that both increasing or decreasing signaling at these receptors prevents the expression of the conditioned motivational response. Furthermore, I report that the induction of nicotine dependence increases CRF mRNA in VTA DA neurons, and that blocking either the upregulation of CRF mRNA or the activation of VTA CRF receptors prevents the anxiogenic and aversive motivational responses to withdrawal from chronic nicotine. The results described in this thesis provide novel evidence of a VTA DA/CRF system, and demonstrate that both CRF and a specific pattern of tonic DA activity in the VTA are necessary for the aversive motivational experience of nicotine withdrawal.

Made available in DSpace on 2014-12-17T15:16:09Z (GMT). No. of bitstreams: 1 AdrianaJOB_DISSERT.pdf: 1566198 bytes, checksum: 766db20794ef85bc19aa4a81b03784d3 (MD5) Previous issue date: 2010-08-30 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / To the vertebrates, maintain body balance against the gravitational field and be able to orient themselves in the environment are fundamental aspects for survival, in which the participation of vestibular system is essential. As part of this system, the vestibular nuclear complex is the first central station that, by integrating many information (visual, proprioceptive), and the vestibular, assumes the lead role in maintaining balance. In this study, the vestibular nuclear complex was evaluated in relation to its cytoarchitecture and neurochemical content of cells and axon terminals, through the techniques of Nissl staining and immunohistochemistry for neuronal specific nuclear protein (NeuN), glutamate (Glu), substance P (SP), choline acetyltransferase (ChAT) (enzyme that synthesizes acetylcholine-Ach) and glutamic acid decarboxylase (GAD) (enzyme that synthesizes gamma-amino butyric acid-GABA). The common marmoset (Callithrix jacchus) was used as experimental animal, which is a small primate native from the Atlantic Forest in the Brazilian Northeast. As results, the Nissl technique, complemented by immunohistochemistry for NeuN allowed to delineate the vestibular nucleus superior, lateral, medial and inferior (or descending) in the brain of the common marmoset. Neurons and terminals immunoreactive to Glu and ChAT and only immunoreactive terminals to SP and GAD were seen in all nuclei, although in varying density. This study confirms the presence in the vestibular nuclei of the common marmoset, of Glu and SP in terminals, probably from the first order neurons of vestibular ganglion, and of GABA in terminals, presumably from Purkinge cells of the cerebellum. Second-order neurons of the vestibular nuclei seem to use Glu and Ach as neurotransmitters, judging by their expressive presence in the cell bodies of these nuclei in common marmosets, as reported in other species / Para os vertebrados, manter o equil?brio corporal contra o campo gravitacional e ser capaz de orientar-se no ambiente s?o aspectos fundamentais para a sobreviv?ncia, nos quais ? essencial a participa??o do sistema vestibular. Como parte deste sistema, o complexo nuclear vestibular ? a primeira esta??o central que, ao integrar v?rias informa??es (visual, proprioceptiva), al?m da vestibular, assume o papel principal na manuten??o do equil?brio. Neste estudo, o complexo nuclear vestibular do sagui foi avaliado com rela??o a sua citoarquitetura e conte?do neuroqu?mico de c?lulas e terminais ax?nicos, atrav?s das t?cnicas de colora??o de Nissl e imuno-histoqu?mica para prote?na neuronal nuclear espec?fica (NeuN), glutamato (Glu), subst?ncia P (SP), colina acetiltransferase (ChAT) (enzima de s?ntese da acetilcolina-Ach), e descarboxilase do ?cido glut?mico (GAD) (enzima de s?ntese do ?cido gama-amino-but?rico-GABA). Foi utilizado como animal experimental o sagui (Callithrix jacchus), um pequeno primata nativo da Mata Atl?ntica do Nordeste Brasileiro. Como resultados, a t?cnica de Nissl, complementada pela imuno-histoqu?mica para NeuN, permitiu delinear os n?cleos vestibulares superior, lateral, medial e inferior (ou descendente) no enc?falo do sagui. Neur?nios e terminais imunorreativos a Glu e ChAT e apenas terminais imunorreativos a SP e GAD foram vistos em todos os n?cleos, embora em densidade vari?vel. Este trabalho confirma a presen?a nos n?cleos vestibulares do sagui, de Glu e SP em terminais, provavelmente provenientes dos neur?nios de primeira ordem do g?nglio vestibular, e de GABA em terminais, supostamente provenientes das c?lulas de Purkinge do cerebelo. Neur?nios de segunda ordem dos n?cleos vestibulares parecem usar Glu e Ach como neurotransmissores, a julgar pela sua expressiva presen?a em peric?rios destes n?cleos no sag?i, como relatado em outras esp?cies

L'objectif de cette thèse est d'étudier l'implication de deux structures de la formation hippocampique, le cortex entorhinal latéral (CEL) et l'hippocampe dorsal (DH), dans les processus sous-tendant la formation et la flexibilité d'associations entre deux stimuli de modalités sensorielles différentes : l'olfaction et le toucher. Pour cela, une tâche bimodale olfacto-tactile (OT) est développée chez le rat. Dans celle-ci, l'animal doit apprendre à identifier une combinaison "odeur-texture" spécifique parmi les trois proposées afin d'obtenir un renforcement (ex: O1T1+ O2T1 O1T2, + désignant la combinaison renforcée). Aucun indice spatial ou contextuel n'est pertinent pour résoudre cette tâche. Suite à l'acquisition de deux tâches différentes, les stimuli sont réassociés sous forme de combinaisons inédites dans une troisième tâche appelée « recombinaison ». La manipulation pharmacologique de l'activité du CEL a mis en évidence l'implication des systèmes glutamatergique NMDA et cholinergique de cette structure dans les processus sous-tendant ces deux types de tâche. En revanche, si le DH n'est pas indispensable pour l'acquisition, son système cholinergique est critique pour la recombinaison. En comparaison avec l'acquisition, l'étude électrophysiologique a montré que la recombinaison repose sur un découplage de la synchronisation entre les activités oscillatoires du CEL et celles du DH dans la bande thêta (5-12 Hz). De plus, cet apprentissage est associé à une augmentation de l'amplitude des oscillations bêta (15-45 Hz) dans le CEL. Ces travaux montrent que le CEL et le DH interviennent dans les processus sous-tendant la flexibilité des représentations bimodales / The goal of this thesis is to study the involvement of two structures of the hippocampal formation, the lateral entorhinal cortex (LEC) and the dorsal hippocampus (DH), in the processes underlying the formation and the flexibility of associations of stimuli between two different sensory modalities. To this aim, a new olfactory-tactile (OT) bimodal task has been developed in the rat. To solve the task, animals have to identity one “odor-texture” combination between three in order to obtain a reinforcement (ex: O1T1+ O2T1 O1T2, + for the baited cup). This procedure excludes the use of any spatial or contextual cues for solving the task. After the acquisition of two different tasks, the familiar stimuli used in acquisition were recombined in a third task (called “recombination”). The pharmacological manipulation of the LEC showed that the NMDA glutamatergic and cholinergic system in this structure are involved in the processes underlying the acquisition and the recombination. In contrast, the cholinergic system in the DH is selectively and critically involved in the recombination processes. Compared to acquisition, our electrophysiological data showed that the recombination is based on a desynchronization between the oscillatory activities of the LEC and of the DH in the theta band (5-12 Hz). Moreover, this task is associated with increased amplitude of beta oscillations (15-45 Hz) in the LEC. These data demonstrated that the LEC and the DH are critically involved in the processes underlying the flexibility of bimodal representations

Indiana University-Purdue University Indianapolis (IUPUI) / Methamphetamine (MA) is a widely abused psychostimulant that has been shown to evoke an array of neurobiological abnormalities and cognitive deficits in humans and in rodent models (Marshall & O'Dell, 2012). Alterations in cognitive function after repeated drug use may lead to impaired decision-making, a lack of behavioral control, and ultimately the inability to abstain from drug use. Human studies have shown that alterations in neurobiology resulting from prolonged MA use may lead to a number of cognitive deficits, including impairments in executive function, learning, memory, and impulsivity. These impairments, specifically those that engage the prefrontal cortex (PFC) or hippocampus (HC), may persist or recover based on the duration of abstinence. In rodents, repeated intermittent injections of MA yield protracted changes in neurobiology and behavior, which have been shown to effectively model a number of the biological and cognitive abnormalities observed in addiction. In order to assess the temporal evolution of impaired cognitive function throughout abstinence, sensitization was first induced in rats (7 x 5.0 mg/kg MA over 14 days). MA-treated rats initially exhibited a robust increase in locomotion that transitioned to stereotypy as the induction phase progressed. Then, the effects of MA sensitization on social interaction (SI), temporal order recognition (TOR) and novel object recognition (NOR) was assessed at one-day and 30-days post induction. No differences were observed in SI in either group or after a single injection of MA. However, an acute injection of 5.0 mg/kg of MA 30-minutes prior to testing dramatically reduced SI time. Impairments in TOR and NOR were observed in MA-treated rats after one day of abstinence, and impairments in TOR, but not NOR, were observed on day 30 of abstinence. No differences in TOR and NOR after a single injection of MA or saline were observed. These data establish that after 30 days of abstinence from a sensitizing regimen of MA, the ability to recall the temporal sequence that two stimuli were encountered was impaired and that was not attributable to impaired novelty detection. These data also suggest that at least some of the neurocognitive abnormalities caused by chronic MA administration may normalize after prolonged abstinence, since the ability to detect novelty recovered after 30 days of abstinence. These data provide compelling support that, since MA-sensitization caused temporal deficits in memory, PFC and HC function may be differentially impaired throughout the time course of abstinence.