The work presented in this thesis investigates whether primitive pallial brain circuits such as those found in teleost fish may also encode complex information such as spatial memory despite its circuitry being “simpler” than those found in species with much larger brains such as primates and rodents. Previous behavioral studies have already shown that most teleost fish are capable of spatially orienting themselves and remembering past food locations. Behavioral studies combined with selective brain lesions and related anatomical studies have identified a hippocampal-like region in the fish’s pallium; however, it is unknown whether the neurons located in this structure can also perform cortical-like computations as those found in the mammalian hippocampus. Consequently, this thesis will first present an anatomical characterization of the intrinsic circuitry of this hippocampal-like structure, followed by an in vitro electrophysiological characterization of its constituent neurons. Surprisingly, we have found that this hippocampal-like structure possesses many features reminiscent of the mammalian cortex, including recurrent local connectivity as well as a laminar/columnar-like organization. Furthermore, we have also identified many biophysical properties which would describe these hippocampal-like neurons as sparse coders, including a prominent after-hyperpolarizing potential and an adapting spike threshold with slow recovery. Since this particular dynamic spike threshold mechanism has not been thoroughly characterized in the mammalian hippocampus, we have further investigated the dynamic threshold in the major rodent hippocampal cell types. We have found that only a subset of excitatory neurons displayed this dynamic spike threshold on the time scale that was observed in teleost pallial cells, which allowed us to discuss its potential role in encoding spatial information in both species. Nevertheless, the fact that this teleost hippocampal homologue possesses characteristics that are both akin to the cortex and hippocampus suggest that it may perform computations that, in a mammalian brain, would require both structures and makes this ancestral structure a very interesting candidate to study the mechanism(s) underlying spatial memory.

Rationale: Cardiac function is under exquisite intrinsic cardiac neural control. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Objective: Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node (SAN) as an initial discovery step. Methods and Results: We report an in-depth, multiscale structural and functional characterization of the innervation of the SAN by the right atrial ganglionated plexus (RAGP) in porcine and human hearts. Combining intersectional strategies, including tissue clearing, immunohistochemical, and ultrastructural techniques, we have delineated a comprehensive neuroanatomic atlas of the RAGP-SAN complex. The RAGP shows significant phenotypic diversity of neurons while maintaining predominant cholinergic innervation. Cellular and tissue-level electrophysiological mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular conduction, and left ventricular contractility. Using this approach, we comprehensively demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. Conclusions: This report provides an experimental demonstration of a discrete neuronal population controlling a specific geographic region of the heart (SAN) that can serve as a framework for further exploration of other parts of the intrinsic cardiac nervous system (ICNS) in mammalian hearts and for developing targeted therapies.

No description available.

No description available.

Having an appropriate understanding of the behavioral and physiological impact of a disease requires thoroughly fielded tests and wide-ranging animal models to properly deduce generalized impacts of the disease under investigation. Through novel animal models, we acquire diverse insights into the mechanisms at play so that we may approach the problem at hand with fresh perspective and renewed vigor. Using the naked mole-rat (Heterocephalus glaber), a species becoming increasingly common in the medical sciences, my dissertation aimed to accomplish the aforementioned goals in two parts: 1) take the naked mole-rat through a battery of behavioral tasks to bolster our capabilities of using this animal model in medical research; and 2) introduce the naked mole-rat as an alternative model for the investigation of how loss of dental sensation alters behavior and neuroanatomy. Chapter two describes the many methods with which I tested the naked mole-rat across a variety of typical behavioral tasks for social dominance, learning and memory, anxiety, depression, and sociability. Included herein were tests to determine appropriate motivators for this subterranean species to perform such tasks. Additionally, due to the naked mole-rat’s unique disposition for biting, I measured their biting behaviors and compared them across rodent and other mammalian species. The results show that naked mole-rats exhibit large evolutionary divergence in their sensory capabilities and great consideration needs to be given to the proper behavioral tasks and subsequent evaluations of these behavioral paradigms. In chapter three, I evaluated the impact of tooth extraction on affective behaviors, learning and memory, and sociability. Chapter four sought to uncover underlying neuroplasticity associated with the behavioral tasks performed in chapter three. Additionally, in chapter four, I investigated plasticity of the traditional somatosensory pathway for tooth sensation. Tooth loss decreased neuronal density of contralateral ventral posteromedial nucleus of the thalamus and increased the neuronal density of the contralateral ventral dentate gyrus, indicating that tooth-loss induced neuronal plasticity may be more related to plasticity of pain circuitry or resultant from alterations in the muscles of mastication following tooth loss. Though no significant changes in the hippocampus arose from one year of living with no right incisor, I theorized as to which of the physiological idiosyncrasies exhibited by Heterocephalus glaber may have inhibited any observable plasticity due to tooth loss.

This cross-sectional study examined neurobiologic correlates of depression in ischemic stroke patients. Depression severity was measured with a standardized scale (Center for Epidemiologic Studies Depression Scale; CES-D). Eighty-two patients (53.1% male, mean (± SD) age 71.9 ± 14.2 years, mean (± SD) National Institutes of Health Stroke Scale (NIHSS) score 4.6±4.7, mean (± SD) CES-D score 12.6 ± 10.8) were recruited. A linear regression controlling for age and stroke severity (NIHSS) determined that the kynurenine to tryptophan ratio (β= -0.105, p=0.369) was not significantly associated with CES-D (primary hypothesis) (overall model R2=0.069, F3,73=1.805, p=0.154). Secondary analyses suggested one instance of cytokines favouring inflammatory states in mild depressive symptomatology; IFN-Ɣ/IL-10 (OR, 2.17; 95% CI, 1.02-4.64, p=0.045). For the most part however, inclusion of cytokines and neuroimaging correlates such as atrophy, lesion location and white matter changes were non-significant. Longitudinal studies are necessary to identify the possible neurobiologic correlates of depressive symptoms post-stroke.

This cross-sectional study examined neurobiologic correlates of depression in ischemic stroke patients. Depression severity was measured with a standardized scale (Center for Epidemiologic Studies Depression Scale; CES-D). Eighty-two patients (53.1% male, mean (± SD) age 71.9 ± 14.2 years, mean (± SD) National Institutes of Health Stroke Scale (NIHSS) score 4.6±4.7, mean (± SD) CES-D score 12.6 ± 10.8) were recruited. A linear regression controlling for age and stroke severity (NIHSS) determined that the kynurenine to tryptophan ratio (β= -0.105, p=0.369) was not significantly associated with CES-D (primary hypothesis) (overall model R2=0.069, F3,73=1.805, p=0.154). Secondary analyses suggested one instance of cytokines favouring inflammatory states in mild depressive symptomatology; IFN-Ɣ/IL-10 (OR, 2.17; 95% CI, 1.02-4.64, p=0.045). For the most part however, inclusion of cytokines and neuroimaging correlates such as atrophy, lesion location and white matter changes were non-significant. Longitudinal studies are necessary to identify the possible neurobiologic correlates of depressive symptoms post-stroke.

INTRODUÇÃO: Embora a craniotomia pterional e suas variantes sejam os acessos mais utilizados em neurocirurgia, poucos estudos analisaram de forma quantitativa a exposição fornecida em cada uma delas. OBJETIVOS: Neste estudo, realizou-se avaliação comparativa das exposições cirúrgicas fornecidas pelas craniotomias pterional (PT), pré-temporal (PreT) e orbitozigomática (OZ) por meio de medidas quantitativas da área de exposição cirúrgica ao redor círculo arterial do cérebro, exposição angular e exposição linear da artéria basilar na fossa interpeduncular e cisterna pré-pontina. MÉTODOS: Oito cadáveres adultos frescos, com tempo máximo de 24 horas após a morte, foram utilizados no estudo. As craniotomias foram realizadas sequencialmente no mesmo cadáver, em um único lado, iniciando-se com a PT, seguido da PreT e terminando com a OZ. Após cada craniotomia, calculou-se a área de exposição cirúrgica, delimitada pelos seguintes pontos: (1) ponto mais lateral da fissura orbitária superior ipsilateral; (2) bifurcação da artéria cerebral média (ACM) ipsilateral; (3) ponto mais distal da artéria cerebral posterior (ACP) ipsilateral; (4) ponto mais distal da ACP contralateral; (5) ponto mais distal da ACM contralateral; (6) ponto mais lateral na asa menor do esfenoide contralateral. Calculou-se ainda, após cada craniotomia, a exposição angular nos eixos horizontal e vertical das seguintes estruturas vasculares: (1) bifurcação da ACM ipsilateral; (2) bifurcação da artéria carótida interna (ACI) ipsilateral; (3) topo da artéria basilar; (4) ponto médio da artéria comunicante anterior; (5) bifurcação da ACI contralateral; (6) ponto mais distal da ACM contralateral. Por fim, após cada craniotomia, mediu-se a exposição linear da artéria basilar na fossa interpeduncular e cisterna pré-pontina. Todas as aferições foram feitas utilizando-se um sistema de neuronavegação computadorizado. RESULTADOS: A OZ apresentou maior exposição cirúrgica em torno do círculo arterial do cérebro (PT = 844,7 ± 233,3 mm2; PreT = 1.134 ± 223,3 mm2; OZ = 1.301,3 ± 215,9 mm2) com aumento de 456,7 mm2 em relação à PT (p < 0,01) e de 167,4 mm2 comparado com a PreT (p < 0,05). A exposição linear da artéria basilar aumentou significativamente com a extensão da craniotomia PT para a PreT e sequencialmente para a OZ. A extensão da PT para PreT e OZ aumentou a exposição angular em todas as medições. Ao compararmos as craniotomias PreT e OZ encontramos um aumento na exposição angular horizontal do topo da artéria basilar (p = 0,02) e bifurcação da artéria carótida interna contralateral (p = 0,048). CONCLUSÕES: A craniotomia OZ oferece vantagens cirúrgicas significativas em relação à PT e PreT, no que diz respeito à área de exposição cirúrgica e exposição linear da artéria basilar. A remoção de parte da margem orbital e do arco zigomático forneceu aumento significativo da exposição angular, proporcionando maior liberdade cirúrgica para acessar estruturas da fossa interpeduncular, cisterna pré-pontina e cisternas subaracnóideas contralaterais. Os dados apresentados no estudo, somados à experiência do cirurgião podem auxiliar na escolha do melhor acesso cirúrgico para cada lesão a ser tratada / INTRODUCTION: Although pterional craniotomy and its variants are the most used approaches in neurosurgery, few studies have analyzed quantitatively the exposure provided by each of them. OBJECTIVES: In this study we compared the surgical exposures provided by pterional (PT), pretemporal (PreT) and orbitozygomatic (OZ) approaches through quantitative measurements of area of surgical exposure around the circle of Willis, angular exposures, and linear exposure of basilar artery in the interpeduncular fossa and prepontine cistern. METHODS: Eight adult fresh cadavers were used within 24 hours after death. The craniotomies were sequentially performed in the same cadaver, first starting with the PT, followed by the PreT, ending up with the OZ. After each craniotomy the area of surgical exposure was calculated, delimited by the following points: (1) lateral aspect of the superior orbital fissure in the ipsilateral sphenoid wing; (2) bifurcation of ipsilateral middle cerebral artery (MCA); (3) most posterior visible point of the ipsilateral posterior cerebral artery (PCA); (4) most posterior visible point of the contralateral PCA; (5) most distal visible point of the contralateral MCA; (6) most lateral visible point of the contralateral lesser sphenoid wing. After each craniotomy, the angular exposure in the horizontal and vertical axes of the following vascular structures was calculated: (1) bifurcation of the ipsilateral MCA; (2) bifurcation of the ipsilateral internal carotid artery (ICA); (3) basilar artery tip; (4) middle point of anterior communicating artery; (5) bifurcation of the contralateral ICA; (6) most distal point of the contralateral MCA. Finally, after each craniotomy, linear exposure of the basilar artery was measured in the interpeduncular fossa and prepontine cistern. All measurements were performed using a computerized neuronavigation system. RESULTS: OZ presented a wider surgical exposure of the circle of Willis (PT = 844.7 ± 233.3 mm2; PreT = 1134 ± 223.3 mm2; OZ = 1301.3 ± 215.9 mm2) with an increase of 456.7 mm2 in relation to the PT (p < 0.01) and of 167.4 mm2 to the PreT (p < 0.05). The linear exposure of the basilar artery significantly increased with the craniotomy extension to the PreT and then to OZ. The extension from PT to PreT and OZ increases angles in all measurements. When comparing the PreT and OZ we found an increase in the horizontal angular exposure to the basilar tip (p = 0.02) and contralateral ICA bifurcation (p = 0.048). CONCLUSIONS: The OZ approach offered significant surgical advantages compared to the traditional PT and PreT regarding to the area of exposure and linear exposure to basilar artery. With regards to the angular exposure, the orbital rim and zygomatic arch removal provided greater surgical freedom to access structures of the interpeduncular fossa, prepontine cistern, and contralateral subarachnoid cisterns. The data presented in the study added to the experience of the surgeon can help in choosing the best individualized surgical approach

Na puberdade ocorrem mudanças significativas na organização de circuitos neurais com ajuda da ação dos hormônios esteroidais, levando a dimorfismos sexuais relevantes para a promoção de comportamentos adultos. A porção ventrolateral do núcleo ventromedial do hipotálamo (VMHvl) é o sítio neural que mais exerce controle do comportamento sexual feminino a partir da ação dos hormônios ovarianos. Dentre os núcleos que o aferentam, destaca-se o núcleo medial da amígdala (MEA), transmitindo informações essenciais para iniciar tal comportamento. Investigamos a densidade das projeções do núcleo MEA para o VMHvl, em ratas ooforectomizadas pré-ppuberes e em ratas controle. Foi feita a ooforectomia em ratas Sprague-Dawley com 35 dias de idade. Ao atingirem idade de 90 dias, injetamos por iontoforese o traçador anterógrado Phaseolus vulgaris no MEA. Sugerimos uma diferença na densidade de projeções e varicosidades do MEA para o VMHvl entre os grupos. Aparentemente, os hormônios ovarianos contribuem na organização das conexões do MEA com estruturas do circuito do comportamento sexual feminino. / During puberty, significant changes occur to organize neural circuits, with steroid hormones action, leading to significant sexual dimorphism to promote adults behaviors. The ventrolateral portion of the ventromedial nucleus of the hypothalamus (VMHvl) is the major neural site controlling this behavior with the ovarian hormones action. One of outputs to VMHvl, the medial amygdala nucleus (MEA) transmit essential information to start such behavior. We investigate the projections density of MEA to VMHvl, in ovariectomized rats at early puberty. We performed ovariectomy Sprague-Dawley rats with approximately 35 days of age, when they reach the age of 90 days, we perform unilateral iontophoretic injections of anterograde tracer Phaseolus vulgaris in MEA. Our results suggest a possible difference in projections density of the MEA to VMHvl, between ovariectomized rats the onset of puberty and control. Apparently, ovarian hormones are important factors that contribute to the organization of MEA connections with structures of the circuit of female sexual behavior during puberty.

A habenula lateral (LHb) inibe neurônios dopaminérgicos no mesencéfalo através de um nodo GABAérgico no tegmento mesopontino, o núcleo tegmental rostromedial (RMTg). Ambos a LHb e o RMTg também projetam para o núcleo dorsal da rafe (DR). A organização das projeções da LHb e do RMTg para o DR foi investigada através de injeções de um traçador anterógrado na LHb ou no RMTg e confirmada com injeções de traçadores retrógrados. Para identificar o fenótipo neuroquímico das projeções RMTg-DR, combinamos a hibridização in situ para mRNA de GAD67 com a detecção imunoistoquímica de traçadores retrógrados injetados no DR. Caracterizamos as subdivisões-alvo das projeções RMTg-DR através de dupla-imunofluorescência para o traçador anterógrado injetado no RMTg e serotonina ou o transportador vesicular de glutamato do tipo 3. Detectamos uma projeção focal direta da divisão medial da LHb para a parte caudal do DR. Em contraste, projeções GABAérgicas robustas do RMTg foram direcionadas para uma subdivisão central do DR enriquecida em neurônios presumidamente glutamatérgicos. / The lateral habenula (LHb) inhibits mesencephalic dopamine neurons through a mesopontine GABAergic node, the rostromedial tegmental nucleus (RMTg). Both LHb and RMTg also project to the dorsal raphe nucleus (DR). The organization of LHb and RMTg projections to the DR was investigated using anterograde tracer injections into the LHb or RMTg and confirmed with retrograde tracer injections. To identify the neurochemical phenotype of RMTg-DR projections, we associated in situ hybridization for GAD67 mRNA with immunohistochemical detection of retrograde tracers deposited in the DR. DR target regions of RMTg projections were characterized using double-imunofluorescence techniques for the anterograde tracer deposited into the RMTg and either serotonin or the type 3 vesicular glutamate transporter. We detected a focal direct projection from the medial LHb division to the caudal DR. In contrast the RMTg emits robust GABAergic projections to a central DR subdivision rich in presumptive glutamatergic neurons.