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Vocal plasticity is presumed to be a key element underlying the evolution of human speech and language, but the mechanisms and neuroanatomical basis for this plasticity remain largely unknown. The Mexican free-tailed bat, Tadarida brasiliensis, presents a unique opportunity to advance our understanding of the evolution and neurobiology of mammalian vocal communication because this animal displays elements of vocal complexity and plasticity that are more sophisticated than any mammal other than humans, including non-human primates. Current models of vocal control in mammals do not account for the vocal complexity of free-tailed bats. The purpose of this dissertation is to fill that gap in knowledge by identifying a possible neuronal basis for vocal complexity in free-tailed bats. This will be achieved by 1) providing a detailed analysis of the free-tailed bat’s vocal behaviors, 2) mapping the distribution of neurotransmitter receptor types suspected of involvement in vocal control, 3) identifying brain regions that exhibit increased neuronal activity during vocalizing, and 4) pharmacologically manipulating putative vocal control regions to confirm and characterize their function in vocalizing. Analysis of Tadarida’s vocal behavior indicated that they have a vast vocal repertoire, including many different call types, context-dependent sensory-feedback driven vocal plasticity, and syntactically-organized stereotyped songs. Their vocal behavior changed seasonally, so I mapped the distribution of melatonin binding sites in the brain, finding high densities in the striatum, similar to dopamine receptor distribution. I then used immunohistochemical labeling of the immediate early gene cfos to map neuronal activation in brains of highly vocal bats to find ROIs activated by vocal production. This technique not only identified all previously known regions of the mammalian vocal motor pathway but also revealed activity in novel brain regions that could potentially account for vocal plasticity, including a localized region of the basal ganglia, the dorsolateral caudate nucleus, and the anterior cingulate region of the frontal cortex. Pharmacological excitation of these regions evoked complex vocal sequences similar to the songs recorded in the field and lab. These results support the hypothesis that the mammalian basal ganglia may play a crucial role in the plasticity and complexity of mammalian vocal behaviors.

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 3 uppsatser.

During development, intrinsic genetic programs give rise to distinct cellular lineages through the establishment of cell type specific chromatin states. These distinct chromatin states instruct gene expression primarily through the genome-wide demarcation of enhancers. In addition to maintaining cellular identity, the chromatin state of a cell provides a platform for transcriptional responses to environmental signals. However, relatively little is known about the influence of extracellular stimuli on chromatin state at enhancers, and it is not clear which enhancers among the tens of thousands that have been recently identified function to drive stimulus-responsive transcription. In the nervous system, the chromatin state of terminally differentiated neurons not only maintains neuronal identity but also provides a platform for sensory experience-dependent gene expression, which plays a critical role in the development and refinement of neural circuits and in long-lasting changes in neuronal function that underlie learning, memory, and behavior. Using chromatin-immunoprecipitation followed by high through put sequencing (ChIP-Seq), we determined the effects of neuronal stimuli on the active chromatin landscape of mouse cortical neurons. We discover that stimulation with neuronal activity and brain derived neurotrophic factor (BDNF) cause rapid, widespread, and distinct changes in the acetylation of histone H3 lysine 27 (H3K27Ac) at thousands of enhancers throughout the neuronal genome. We find that functional stimulus-responsive enhancers can be identified by stimulus- inducible H3K27Ac, and we use this dynamic chromatin signature to discover neuronal enhancers that respond to neuronal activity, BDNF, or both stimuli. Finally, we investigate the transcriptional mechanisms underlying the function of stimulus responsive enhancers. We show that a subset of stimulus-responsive enhancers in the nervous system require the coordinated action of the stimulus-general transcription factor activator protein 1 (AP1) with additional stimulus-specific factors. Our studies reveal the genome-wide basis for transcriptional specificity in response to distinct neuronal stimuli. Furthermore, the comprehensive identification of neuronal activity and BDNF-dependent enhancers in cortical neurons provides a critical resource for elucidating the role of stimulus-responsive transcription in synaptic plasticity, learning and memory, behavior, and disease. Finally, the epigenetic signature of stimulus-inducible H3K27Ac may aid in the identification and study of stimulus- regulated enhancers in other tissues.

Terrestrial salamanders of the genus Plethodon are among many vertebrates possessing both main olfactory and vomeronasal systems, which the Volatility Theory posits are for detection of volatile and soluble olfactory cues, respectively. Further recent work showing a high amount of convergence between the two olfactory subsystems at the level of the central nervous system suggests complementary or overlapping roles for them. This study examined the use of the olfactory subsystems in prey detection from the perspectives of behaviour and neurobiology. Red-backed salamanders, Plethodon cinereus, were observed in standardized behavioural assays with both volatile and soluble prey olfactory cues. Naïve salamanders showed an increase in nosetapping as well as a side preference in the presence of soluble and volatile prey cues when tested in a 22°C day/20°C night room. In a 15°C day /12°C night room, salamanders increased nosetapping in the presence of soluble prey cues. Salamanders showed a pattern of responses that differed based on their previous experience with the assay, as well as the temperature of the testing room. Attempts to study the neurobiology of olfactory function in Plethodon shermani were inconclusive up to this point, but future directions are discussed. This study shows the importance of olfaction in prey detection by salamanders and that prey searching behaviour is exhibited in the exclusive presence of olfactory cues.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Vita. Bibliography: 64-74.

Made available in DSpace on 2016-06-02T19:22:11Z (GMT). No. of bitstreams: 1 5903.pdf: 2922633 bytes, checksum: dfd272eca77563615a9e3fe15f5907c9 (MD5) Previous issue date: 2014-04-10 / Universidade Federal de Minas Gerais / The Locus coeruleus (LC) has been suggested as a CO2 chemoreceptor site in mammals. Most of the studies involving the role of LC in hypercapnic ventilatory response have been performed in males. Since, ovarian steroids modulate the activity of LC neurons and females have a different respiratory response to CO2 of males, we evaluated the activity of LC noradrenergic neurons during normocapnia and hypercapnia in diestrus, ovariectomized (OVX; 0,2 mL/rat of corn oil, s.c., for 3 days) and estradiol-treated ovariectomized (OVX+E2; 10 μg/0,2 mL/rat, s.c., for 3 days) female rats and in intact, orchidectomized (ORX; 0,2 mL/rat of corn oil, s.c., for 7 days), testosterone-treated orchidectomized (ORX+T; 0,25 mg/0,2 mL/rat, s.c., for 7 days) and estradiol-treated orchidectomized (ORX+E2; 10 μg/0,2 mL/rat, s.c., for 3 days) male rats by using double-label immunohistochemistry to c-Fos/TH. Additionally, we assessed the role of noradrenergic LC neurons in OVX and OVX+E2 females on respiratory response to hypercapnia by using 6-hydroxydopamine. Hypercapnia (7% CO2) increased the double-staining (c-Fos/TH-ir) in LC neurons in all groups when compared to air exposure. In the OVX+E2 group there was attenuation in the c-Fos expression in normocapnia and hypercapnia. Hypercapnia increased ventilation in OVX and OVX+E2 groups, which resulted from increases of respiratory frequency (fR) and tidal volume (VT) in sham and 6-OHDA-lesioned groups. The hypercapnic ventilatory response was significantly decreased in 6-OHDA-lesioned rats compared with sham group (29.4% in OVX group and 28.7% in OVX+E2 group) due to a reduced VT in OVX+E2 group and in OVX group due to a decrease in VT and fR. A reduction in TH+ neurons (~61% in OVX and OVX+E2 group) was observed seven days after the microinjections of 6-OHDA in the LC. LC chemical lesion and estradiol did not affect body temperature (Tb). However, hypercapnia caused reduction in Tb of sham (OVX 10 and OVX+E2) and lesioned groups. Thus, we can conclude that noradrenergic neurons in the LC of female and male rats are activated by CO2. However, in OVX+E2 group, estradiol reduced the immunoreactivity compared to OVX group during normocapnia and hypercapnia. Additionally, LC noradrenergic neurons play role in hypercapnic ventilatory response in females but do not affect temperature regulation during normocapnic and hypercapnic conditions. / O Locus coeruleus (LC) é uma área quimiossensível ao CO2 em mamíferos. A maioria dos estudos envolvendo a participação do LC na resposta ventilatória a hipercapnia é realizada em machos. Visto que esteróides ovarianos modulam a atividade de neurônios do LC e fêmeas apresentam uma resposta respiratória ao CO2 diferente de machos, nós avaliamos a atividade dos neurônios noradrenérgicos do LC durante normocapnia e hipercapnia em ratas ciclando em diestro, ovariectomizadas (OVX; 0,2 mL/rata de óleo de milho, s.c., por 3 dias) e ovariectomizadas tratadas com estradiol (OVX+E2; 10 μg/0,2 mL/rata, s.c., por 3 dias) e em ratos intactos, orquidectomizados (ORX; 0,2 mL/rato de óleo de milho, s.c., por 7 dias), orquidectomizados tratados com testosterona (ORX+T; 0,25 mg/0,2 mL/rato, s.c., por 7 dias) e tratados com estradiol (ORX+E2; 10 μg/0,2 mL/rato, s.c., por 3 dias) usando dupla-marcação imunoistoquímica para c-Fos/TH. Adicionalmente, nós avaliamos a participação dos neurônios noradrenérgicos do LC em fêmeas OVX e OVX+E2 na resposta respiratória a hipercapnia usando a neurotoxina 6-hidroxidopamina. A hipercapnia (7% CO2) aumentou a dupla marcação (c-Fos/TH-ir) nos neurônios do LC em todos os grupos comparados a normocapnia. No grupo OVX+E2 houve uma atenuação da expressão de c-Fos no LC em normocapnia e hipercapnia. A hipercapnia causou aumento na ventilação nos grupos OVX e OVX+E2, o qual resultou do aumento da frequência respiratória (fR) e volume corrente (VT) nos grupos controle e lesados. A resposta ventilatória a hipercapnia foi significativamente atenuada no grupo lesado comparado ao grupo controle (29,4% no grupo OVX e 28,7% no grupo OVX+E2) devido à queda no VT no grupo OVX+E2 e no grupo OVX foi devido a queda no VT e na fR. Observamos uma redução de neurônios noradrenérgicos (~61% nos grupos OVX e OVX+E2) sete dias após microinjeções de 6-OHDA no LC. A lesão química do LC e o 8 estradiol não afetaram a Tc. Entretanto, a hipercapnia promoveu redução na temperatura dos grupos sham (OVX e OVX+E2) e lesado. Assim, nós podemos concluir que os neurônios noradrenérgicos do LC de fêmeas e machos são ativados por CO2. Entretanto, no grupo OVX+E2, o estradiol reduziu a imunorreatividade comparado ao grupo OVX durante normocapnia e hipercapnia. Adicionalmente, os neurônios noradrenérgicos do LC de fêmeas participam da resposta ventilatória a hipercapnia, mas não participam da regulação da temperatura durante condições normocápnicas e hipercápnicas.

Submitted by Viviane Lima da Cunha (viviane@biblioteca.ufpb.br) on 2016-01-26T13:19:09Z No. of bitstreams: 1 arquivototal.pdf: 2866873 bytes, checksum: d719d963c473f40750c279e2b5305270 (MD5) / Made available in DSpace on 2016-01-26T13:19:09Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2866873 bytes, checksum: d719d963c473f40750c279e2b5305270 (MD5) Previous issue date: 2015-04-24 / Episodic-like memory is a subtype of declarative memory that refers recall an integration of where and when a certain event (what) happened. The hippocampus –subregions function in pattern separation process are key to mediating of episodic memory recall. Glutamatergic neurotransmission, particularly AMPA and NMDA receptors, have been characterized as essential in neuroplastic processes. Ketamine is a non-competitive NMDA antagonist available at clinical practice with effect on cognitive performance and plasticity. This study’s goal was to evaluate the acute action of ketamine on behavioral and neurochemical aspects of episodic-like memory through immediate-early gene expression (IEG), c-Fos. The experimental procedure was done at a circular arena, and consists of two training sessions and a test of five minutes each. In the first training, the animal was placed in a circular open field to explore four similar objects (A), after a 1 hour, the rats start a second sample with four other objects (B), two of those appear in different spatial locations relative for the first sample. In the test, four objects are shown, two recent-familiar (B) and two old-familiar (A), two displaced (A2, B2) and two stationary (A1 and B1). Forty-six 3-month-old male Wistar rats were separated in five groups. The home cage group (n=6; without apparatus exposure) was used to measure IEG basal expression. The other four groups, with 10 rats each, went through the behavioral test. One of them received saline 0.9% and the other two received 8 mg/kg or 15 mg/kg ketamine ip immediately after the second sample, while the control group received no treatment. All objects and spatial location in this protocol were randomized among groups. The analyses were blinded for groups and the behavioral measures were distance, speed and time of exploration in all sessions. The exploration ratio and discrimination ratio of the four objects in the test session were calculated. Wilcoxon test showed statistically significant differences between these pairs of objects in the control group: A1> A2, B2> B1 and A1> B1. The data indicate that these rats could integrate the three elements of episodic-like memory. The saline group demonstrated the same exploration pattern of control group for comparisons between A1>A2 and B2>B1, but statistical differences were not found between A1and B1. The Welch’s analysis showed a difference of c-Fos expression in all hippocampal sub-regions. The control group had the highest c-Fos expression in the dentate gyrus when compared to the other groups, suggesting the role of this sub-region for integration of episodic-like memory. The two sub-anesthetic doses of ketamine induced a deficit for this type of memory. The highest dose demonstrated a possible hypolocomotion effect, characterized by decreasing of total distance traveled and speed, compared to the other groups at the test session. In short, the deficit of episodic-like memory was characterized both as amnesic effect of ketamine and as decrease of c-Fos in the dentate gyrus of those groups, suggesting a possible role of this field in episodic-like memory formation. / A memória similar à episódica é um subtipo de memória declarativa que se refere à recordação, de forma integrada, de onde e quando um determinado evento (o quê) aconteceu. A funcionalidade das sub-regiões do hipocampo dorsal no processo de separação de padrões apresenta-se como mediadora chave da recordação episódica. A neurotransmissão glutamatérgica, em especial dos receptores AMPA e NMDA, caracteriza-se como essencial em processos neuroplásticos. A Cetamina é um dos poucos antagonistas não competitivos NMDA disponíveis na prática clínica com efeitos no desempenho cognitivo e na plasticidade. O objetivo do presente estudo foi avaliar a ação aguda da Cetamina no comportamento da memória do tipo episódica e a funcionalidade das sub-regiões hipocampais (CA1, CA3 (ab e c) e GD), através da expressão do gene imediato (IEG), c-Fos. O procedimento experimental, realizado em uma arena circular, consistiu em duas sessões de treino e uma de teste com duração de cinco minutos cada. No primeiro treino, o animal é colocado em um campo aberto circular para explorar quatro objetos iguais (A), após o intervalo de 1 hora, o rato inicia o segundo treino com outros quatro objetos (B), destes dois aparecem em disposições espaciais não alocadas na primeira sessão. Na etapa do teste são apresentados quatro objetos, sendo dois recentes (B) e dois antigos (A), dois deslocados (A2 e B2) e dois estacionários (A1 e B1). Neste estudo, 46 ratos Wistar machos adultos foram divididos em cinco grupos. O grupo home cage foi escolhido como controle para a avaliação basal dos IEGs nas sub-regiões do hipocampo dorsal. Quatro grupos, contendo 10 animais cada, realizaram o procedimento comportamental, sendo um grupo controle e três grupos que passaram por intervenção farmacológica: um grupo que recebeu Salina 0.9% (i.p.) e os outros dois receberam a Cetamina (i.p.), nas doses de 8mg/kg e 15 mg/kg, imediatamente após o segundo treino. As análises do estudo foram duplo-cego e os objetos e suas localizações espaciais foram randomizadas entre os grupos. As medidas comportamentais utilizadas foram a “distância total percorrida”, a “velocidade” e o “tempo de exploração” para todas as sessões. Na sessão de teste também foram calculadas a “taxa de exploração” e a “taxa de discriminação” dos objetos. No teste de Wilcoxon o grupo controle apresentou o desempenho padrão estatisticamente significativo: A1>A2, B2>B1 e A1>B1. Integrando os três elementos da memória episódica, seguido pelo grupo salina que apresentou o mesmo perfil de exploração entre os objetos antigos e recentes, A1>A2, B2>B1. A análise do Welch mostrou diferenças neuroquímicas em todas as sub-regiões do hipocampo, destacando um aumento de c-Fos no giro denteado (GD) dos animais controles quando comparado aos outros grupos, sugerindo o papel desta sub-região para a integração da memória tipo episódica. As duas doses sub-anestésicas da Cetamina induziram um déficit para este tipo de memória. A dose mais elevada demonstrou um possível efeito hipolocomotor, caracterizado pela redução na distância total percorrida e na velocidade, em comparação com os outros grupos, na sessão de teste. Em suma, o déficit de memória tipo episódica foi caracterizado tanto pelo efeito amnésico de Cetamina quanto pela redução de c-Fos no GD desses grupos, sugerindo um possível papel deste campo na formação desse tipo de memória.

The brain and spinal cord make up the central nervous system (CNS), and as an immune-privileged site, it requires special immune surveillance and regulation. The complement system is a component of innate immunity produced locally in the CNS, since size restrictions from the blood brain barrier prevent complement proteins from easily passing through from the rest of the body. The complement pathway contributes to inflammatory cell recruitment, cell lysis, and opsonization, and thus requires regulation to avoid inappropriate activation. Despite its important role in innate immunity, very little is known about complement production, regulation, and function in the CNS of healthy or diseased individuals. For this dissertation, the central goal was to investigate and characterize the regulation of complement factor H (CFH), a regulator of the alternative pathway of complement activation. CFH polymorphisms have been associated with a number of diseases including atypical hemolytic syndrome, age-related macular degeneration, and Alzheimer's disease, but the regulation of CFH is not well understood, especially in the CNS. To investigate the role of CFH in the CNS, mRNA and protein production in glial cells was first established. The murine CFH (mCFH) promoter was cloned and the transcription start site was identified in astrocytes, microglia, and liver tissue. The mCFH promoter was truncated and different regions were investigated for enhancer or silencer activity. Database mining identified potential transcription factor binding sites, and mutagenesis studies and binding assays identified transcription factor binding candidates. Specifically, the activating protein-1 (AP-1) transcription factors c-Jun and c-Fos bound to a region of the mCFH promoter between – 416 base pairs (bp) and – 175 bp in an electrophoretic mobility supershift assay. Cytokine stimulation increased mCFH mRNA and protein production, as well as the mRNA production of c-Jun and c-Fos and the protein production of c-Jun. These results suggest a relationship between cell cycle and complement regulation, and the investigation of how these transcription factors and CFH affect disease will be a valuable area of research for CNS immune regulation.