O transtorno do pânico (TP) é um transtorno de ansiedade caracterizado por ataques de pânico recorrentes e inesperados, com um prognóstico crônico. Entre as drogas utilizadas no tratamento do TP, os benzodiazepínicos (BZs) de alta potência, como o alprazolam e o clonazepam, apresentam a vantagem de serem eficazes logo no início do tratamento. Assim como outras drogas BZs, tais como o diazepam e o flurazepam, estes compostos também são empregados como ansiolíticos no tratamento de pacientes com transtorno de ansiedade generalizada. O mecanismo da ação primária dessas drogas ocorre pela interação com os sítios de ligação BZs presentes nos receptores do ácido gama-aminobutírico do tipo A (GABAA), facilitando a neutotransmissão GABAérgica. Entretanto, ainda permanecem desconhecidos os substratos neurais envolvidos no efeito panicolítico causado pelos BZs. Dentre os substratos em potencial, a substância cinzenta periaquedutal dorsal (SCPD), uma estrutura mesencefálica criticamente relacionada à fisiopatogênica do TP, apresenta alta densidade de receptores GABAA e de sítios de ligação BZs. Neste trabalho avaliamos o envolvimento do complexo receptor GABAA/BZ presente na SCPD no efeito panicolítico promovido pela administração sistêmica de alprazolam em ratos Wistar. Para isso, empregamos o labirinto em T elevado (LTE), que além da resposta de fuga, que é associada ao pânico, também permite avaliar a resposta de esquiva inibitória, associada à ansiedade. Neste modelo, o alprazolam inibe a expressão da resposta de fuga, indicando efeito panicolítico e inibe a aquisição da esquiva inibitória, sugestivo de efeito ansiolítico. Além do LTE, também empregamos os modelos experimentais da hipóxia e o de Vogel, associados ao pânico e a ansiedade, respectivamente. Os resultados obtidos mostraram que o efeito panicolítico promovido pela administração sistêmica de alprazolam, observado na resposta de fuga do LTE, foi bloqueado pela administração intra-SCPD de flumazenil, antagonista dos sítios de ligação BZs, ou de bicuculina, antagonista dos receptores 10 GABAA. No teste da hipóxia, o efeito panicolítico causado pela administração sistêmica de alprazolam foi inibido, porém não significativamente bloqueado, pela administração intra-SCPD de bicuculina. Já o efeito ansiolítico, observado na resposta de esquiva do LTE e no teste do beber punido de Vogel, não foi bloqueado pela administração intra-SCPD de flumazenil ou de bicuculina. No conjunto, nossos resultados sugerem que o complexo receptor GABAA/BZ da SCPD está envolvido no efeito panicolítico, mas não ansiolítico, promovido pela administração sistêmica de alprazolam. / Panic Disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks with a chronic prognosis. Among the drugs used to treat PD, highpotency benzodiazepines (BZs), such as alprazolam and clonazepam, have the advantage of causing significant effects early in the treatment. Like others BZs, such as diazepam and flurazepam, these compounds are also used as anxiolytics in the treatment of patients with generalized anxiety disorder. The primary mechanism of action of these drugs is the interaction with BZs binding sites present at gammaaminobutyric acid type A receptors (GABAA), facilitating GABAergic neurotransmission. However, it remains yet unknown the neural substrates involved in the panicolytic-like action caused by BZs. Among the potential substrates, the dorsal periaqueductal gray matter (DPAG), a mesencephalic structure critically associated with the physiopathology of PD, presents a high density of GABAA receptors and of BZs binding sites. In this work, we evaluated the participation of the GABAA/BZ receptor complex present in the DPAG in the panicolytic-like effect caused by systemic administration of alprazolam in Wistar rats. For this, we use the elevated T-maze (ETM), that besides the escape response which is associated with panic, also allows the measurement of inhibitory avoidance acquisition, which has been related to anxiety. In this model, alprazolam inhibits the expression of escape, indicating a panicolytic-like effect and inhibits the acquisition of inhibitory avoidance, suggestive of an anxiolytic effect. In addition to the ETM, animals were also tested in the hypoxia and Vogel\'s conflict tests, which have been associated with panic and anxiety, respectively. The results showed that the panicolytic-like effect caused by alprazolam in ETM\'s escape response was blocked by intra-DPAG injection of flumazenil, a BZs binding site antagonist, or bicuculline, a GABAA receptor antagonist. In the hypoxia test, the panicolytic-like effect caused by alprazolam was inhibited, but not significantly blocked, by intra-DPAG injection of bicuculline. The anxiolytic effect observed in the 12 ETM\'s avoidance task or in the Vogel\'s conflict test was not blocked by intra-DPAG injection of flumazenil or bicuculline. Taken together, our results suggest that the GABAA/BZ receptor complex located in the DPAG is involved in the panicolytic, but not anxiolytic, effect caused by systemic administration of alprazolam.

Após o parto, a mãe deve optar por buscar por comida ou cuidar da prole sendo que a substância cinzenta periaquedutal (PAG) é uma área central importante de regulação, seleção e um sítio de ação de opióides. Ainda não se sabe a importância funcional de cada um dos receptores opióides na PAG sobre a expressão dos comportamentos materno e predatório. Foram utilizadas ratas com cânula unilateral implantada na PAG e divididas em dois experimentos: Experimento 1, onde as ratas receberam injeções de agonista m, ou o agonista k, ou sulfato de morfina, ou veículo; Experimento 2, onde receberam antagonista m seguido de sulfato de morfina, ou antagonista k seguido de sulfato de morfina, ou sulfato de morfina, ou veículo. Os animais foram avaliados no teste de comportamento materno versus predatório. Os resultados sugerem que o tônus opióide endógeno é importante para a expressão do comportamento predatório e há possibilidade da morfina agir em mais de um tipo de receptor opióide simultaneamente para promover a inibição do comportamento materno nesse contexto. / After giving birth, a mother must both provide subsistence and care for her young. Periaqueductal gray (PAG) is an important area for behavioral selection and a site of opioid action. The functional role of PAG opioid receptors in the expression of maternal and predatory behaviors is not clear. Rats with unilateral guide cannulae implanted in the PAG were separated into two experiments: Experiment 1 where the animals received injectios of m receptor agonist, or k receptor agonist, or morphine sulfate, or vehicle; Experiment 2, where they received m receptor antagonist followed by morphine sulfate, or k receptor antagonist before morphine sulfate, or morphine sulfate, or vehicle. The animals were then tested for maternal behavior vs. predatory hunting. The results suggest that endogenous opioid tone is important for the expression of predatory behavior. The results further raise the possibility that morphine acts at more than one type of opioid receptor simultaneously to inhibit maternal behavior in this context.

O córtex pré-frontal (PFC) participa do controle do comportamento de busca por droga e se projeta para a coluna rostrolateral da substância cinzenta periaquedutal (PAGrl) que por sua vez se projeta para o sistema orexinérgico da área hipotalâmica lateral (LHA) que controla comportamentos que oferecem recompensa através de projeções para o sistema dopaminérgico mesolímbico. O objetivo do trabalho é investigar a participação da PAGrl e a sua relação com o PFC e com o sistema orexinérgico da LHA na expressão do comportamento de busca por droga. Submetemos ratos Wistar ao condicionamento de preferência por lugar para sulfato de morfina e notamos que o PFC, a PAGrl e a LHA estão ativados em animais que expressaram tal comportamento. Após, realizamos lesões neuroquímicas bilaterais no PFC e notamos a ausência da busca pela droga nestes animais e da diminuição da ativação da PAGrl e do sistema orexinérgico da LHA. Posteriormente realizarmos lesões neuroquímicas por NMDA na PAGrl e notamos a ausência do comportamento e diminuição de duplas marcações para Fos e orexina na LHA. Os resultados indicam que a PAGrl exerceria um papel crítico para o comportamento de busca por droga, integrando aferências provenientes do PFC para modular os neurônios orexinérgicos da LHA. / The prefrontal cortex (PFC) is involved with planning of the drug seeking behavior and projects itself to the rostrolateral periaqueductal gray (PAGrl) that through projections for the orexin neurons in the lateral hypothalamic area (LHA), participates in the control of behavior that offer rewards. The LHA controls drug reward through projections for the mesolimbic dopaminergic system. This study aims to investigate the relationship between the PFC, PAGrl and orexin neurons in the LHA in drug seeking behavior. We did a morphine conditioned place preference (CPP) procedure in intact, bilateral PAGrl-lesioned and bilateral PFC-lesioned Wistar rats and investigated the pattern of Fos expression. The intact animals displayed such behavior and presented an increase in Fos activation in the PFC, rlPAG and LHA orexinergic neurons. Conversely, PAGrl-lesioned and PFC-lesioned animals did not display this behavior and reduced the activation of orexin neurons in the LHA. PFC-lesioned animals presented a reduction of the Fos activation in the rlPAG. The results suggest a pathway involving the PFC, PAGrl and LHA orexinergic cell group underlying the CCP, where the rlPAG would integrate inputs from the PFC to control the LHA orexinergic cell group.

Estudos apontam a substância cinzenta periaquedutal (PAG) como um sítio crítico para a expressão de vários comportamentos motivados. A porção rostrolateral da PAG (PAGrl), tem um papel chave na regulação da motivação na caça predatória, e modularia mecanismos de recompensa associados ao comportamento alimentar e busca por droga, a partir de projeções para área tegmental ventral e núcleo acumbens; o que dependeria da ligação com neurônios orexinérgicos da área hipotalâmica lateral (LHA). A PAGrl, está mobilizada nos comportamentos de busca por droga assim como na caça predatória. As principais regiões que aferentam a PAGrl são áreas do córtex pré-frontal medial (mPFC) onde a PAGrl integraria tais aferencias e modularia a LHA. Os resultados corroboram com a hipótese, pois lesões no mPFC diminuíram a busca por droga e vimos que neurônios da PAGrl mobilizados no comportamento, que recebem aferências do mPFC, seriam os mesmos que se projetam para LHA e que a PAGrl teria papel crítico na promoção do comportamento de busca por droga no CPP para sulfato de morfina. / Studies show a periaqueductal gray (PAG) as a critical place for an expression of motivated behaviors. The rostrolateral portion of PAG (PAGrl), is a key role in the regulation of motivation in predatory hunting, and modulates, reward mechanisms associated with drug and food seeking, through projections to ventral tegmental area and the nucleus accumbens; what would depend on the connection with orexin neurons of the lateral hypothalamic area (LHA). The PAGrl, is mobilized in predatory hunting as drug seeking. The main region that sends projections to PAGrl is the medial prefrontal cortex (mPFC), where PAGrl integrate such afferent and modulates the LHA. Our results corroborate the hypothesis, because mPFC injuries, decreased drug seeking and we observed that PAGrl neurons mobilized in behavior, and also receive afferents from mPFC, would be the same as projecting to LHA, thus PAGrl had critical role in promotion of drug seeking behavior during the CPP for morphine sulfate.

O medo e a ansiedade são emoções que apresentam claro valor adaptativo, e que tem suas origens nas reações de defesa que os animais exibem em resposta a situações de ameaça que podem comprometer sua integridade física ou sobrevivência. Recentes estudos têm indicado que a matéria cinzenta periaquedutal dorsal (MCPD) está envolvida na organização e expressão de comportamentos intempestivos do tipo fuga e luta, os quais são relacionados ao estado de medo, e também participa, juntamente com estruturas prosencefálicas (ex. córtex pré-frontal, sistema septo-hipocampal e amígdala), do controle de comportamentos defensivos mais elaborados e orientados relacionados à ansiedade. O presente estudo investigou a participação da MCPD na modulação de diferentes comportamentos defensivos (p. ex. fuga, esquiva e avaliação de risco) induzidos por métodos artificial (estimulação química) e naturalístico (exposição ao predador) em camundongos. Na primeira etapa, investigamos o padrão de resposta comportamental induzida pela infusão do ácido D,L-homocistéico (DLH, estímulo aversivo químico) na MCPD em diferentes situações ou ambientes, com e sem grande disponibilidade de espaço - o Mouse Defense Test Battery (MDTB) e a Arena (Experimento 1), respectivamente. Além disso, o presente estudo avaliou a habilidade dos animais de reagirem a estímulos aversivos (predador) durante o período inicial (nos 60 s iniciais) do efeito do ácido DLH (fuga explosiva) (Experimento 3), e imediatamente após esse período, no qual o animal apresente comportamento de congelamento ou imobilidade (Experimento 2). Nossos resultados indicaram que a fuga desencadeada pela estimulação química é a resposta predominante de camundongos e que sua exibição depende da disponibilidade de espaço, uma vez que a maioria dos saltos observados na arena está intimamente relacionada ao contato tátil do animal com as paredes do aparato. Esse perfil de respostas de fuga explosiva e saltos parece não representar o padrão comportamental defensivo natural, tal como acontece diante de uma ameaça proximal (ex. um predador), uma vez que durante a estimulação química os camundongos apresentaram um déficit na estratégia antipredador. A segunda etapa do estudo avaliou os efeitos da injeção intra-MCPD do agonista glutamatérgico ácido N-metil-D-aspártico (NMDA), do inibidor da enzima de síntese do óxido nítrico neuronial (NOSn), N?-propil-L-arginina (NPLA) (Experimento 4), e do agonista não seletivo de receptores do fator de liberação de corticotrofina (CRF), CRF ovino (oCRF) (Experimento 5), no comportamento defensivo de camundongos submetidos ao MDTB e ao teste de exposição ao rato (Rat Exposure Test; RET). Os resultados da segunda etapa demonstraram que a ativação de receptores NMDA na MCPD de camundongos intensifica comportamentos relacionados à esquiva do predador. De maneira interessante, essas alterações produzidas pelo NMDA foram consistentemente revertidas pelo inibidor da NOSn, previamente microinjetado no mesmo sítio. Além disso, efeitos intrínsecos do NPLA atenuaram as respostas de esquiva e de avaliação de risco em camundongos submetidos ao RET. Por fim, os resultados da segunda etapa também apontaram para um efeito proaversivo (nas respostas de salto e de esquiva) do agonista de receptores CRF, indicando uma participação dos sistemas glutamatérgico, nitrérgico e CRFérgico, localizados na MCPD, na modulação de diferentes estratégias defensivas (ex. esquiva, avaliação de risco e saltos) de camundongos submetidos ao confronto com o predador. Em conjunto, nossos resultados corroboram a hipótese de que a MPCD está envolvida tanto na organização e expressão de comportamentos intempestivos do tipo fuga e luta como também no controle de comportamentos defensivos mais elaborados e orientados, tais como a avaliação de risco e a esquiva. / The midbrain dorsal periaqueductal grey (DPAG) is part of the brain defensive system involved in active defense reactions to threatening stimuli. Many lines of evidence suggest that besides fundamentally controlling fear-like responses (fight and flight) the DPAG also controls responses related to anxiety, such as avoidance and risk assessment. This study investigated the role of DPAG on different defensive strategies (i.e. flight, avoidance and risk assessment) elicited by artificial (chemical stimulation, Experiments 1-3) and naturalistic (exposure to predator, Experiments 4 and 5) paradigms in mice. Firstly, D,L-Homocysteic acid (DLH) was infused into the DPAG and behavioral responses of mice were evaluated in two different situations, a rectangular novel chamber and a large oval runway, the Mouse Defense Test Battery (MDTB) apparatus (Exp. 1). We also investigated the ability of mice to react to a threatening stimulus (ex. a predator) during (Exp. 3) and immediately after (Exp. 2) the hyperactive responses (ex. jumping and running) induced by DLH injection. Our results indicated that running as opposed to jumping is the primary response in mice injected with DLH into the DPAG when the environment enables flight. However, mice did not react the predator during the flight reaction induced by chemical stimulation, suggesting the behavioral profile induced by DLH infusion into the DPAG is not related to a normal antipredator flight. In the Experiments 4 and 5, we evaluated the effects of three different compounds, N-methyl-D-Aspartate (NMDA), a NMDA receptor agonist, N?-propyl-L-arginine (NPLA), an neuronal nitric oxide synthase (nNOS) inhibitor as well as ovine CRF (oCRF), a nonspecific corticotropin-releasing factor (CRF) receptor agonist, injected into the DPAG of mice, in two predator-stress situations, the Mouse Defense Test Battery (MDTB), and the Rat Exposure Test (RET). Firstly, our results demonstrated that NMDA receptor activation into the mouse DPAG enhances antipredator reactivity (avoidance), an effect that was attenuated by prior infusion of NPLA into the same site. Moreover, the results from the Experiment 4 indicated that the NPLA treatment per se induces consistent anti-aversive effects on defensive behaviors (avoidance and risk assessment) of mice confronted by predator. Finally, our results pointed out a proaversive effect (e.g. increased jump escapes and avoidance behaviors) following intra-DPAG infusion of oCRF, suggesting an important role of glutamatergic, nitrergic and CRFergic systems into the DPAG on the defensive behaviors (risk assessment, avoidance and jumps) elicited by the confront to the predator. Taken together, present results are compatible with previous studies which have emphasized the role of the periaqueductal gray in the modulation of behavioral responses related to anxiety such as risk assessment and avoidance besides fundamentally controlling fear-like responses.

Em estudos anteriores do laboratório, mediante paradigma farmacológico de injeção sistêmica de morfina, foi examinada a influência dos opióides no desempenho do comportamento maternal em ratas. Foi verificado que injeções centrais de naloxona e de CCK na PAG rostral lateral (rPAGl) revertem a inibição opioidérgica desse comportamento. Dando continuidade ao estudo da ação da PAG no comportamento maternal, foi proposto investigar neste trabalho possíveis alterações dele por meio da administração local de morfina na rPAGl de ratas lactantes. Esse tem se mostrado um paradigma eficiente e capaz de fornecer pistas do arcabouço farmacológico e neurofisiológico que integram a intrincada rede neuroanatômica que o permeia. Assim, por meio de um método adequado como a estereotaxia, é possível avaliar em termos neuroanatômicos, de modo mais isolado e eficiente, a interação da PAG nesse comportamento. As ratas lactantes, da linhagem Wistar, que receberam injeções centrais de morfina apresentaram diferenças estatisticamente significantes nos parâmetros de prénutrição do comportamento maternal. A busca e agrupamento e a construção de ninho foram interrompidos por meio do tratamento opióide. Com esse mesmo tratamento, foi verificado também a alteração da latência, estatisticamente significante, nos parâmetros de forrageamento e de grooming de filhotes. Dessa maneira, o comportamento materno total (CMT) mostrouse inibido nas ratas tratadas com morfina. Tais resultados são interpretados como ação da rPAGl na modulação da decisão do comportamento, a qual é decorrente de interações neuroanatômicas com outros sítios cerebrais. Portanto, os dados sugerem que a rPAGl interfere em parâmetros comportamentais relacionados ao início ou ao estabelecimento do comportamento maternal, mas não afeta comportamentos reflexos de nutrição dos filhotes como a cifose. / By using pharmacologycal approaches such as systemic injections of morphine, it has been possible to reveal the inhibitory influence of opioids on rat maternal behavior (MB). Also, it has been reported that central infusions of naloxone or CCK into the rostral lateral PAG restore maternal behavior in lactating rats treated with morphine. This research investigates possible interferences of morphine in MB, through central infusions of this drug in rPAGl of lactating rats. This is an efficient paradigm to provide pharmacological and neurophysiological cues in the functional neuroanatomy of maternal behavior. Stereotaxical procedures were used to place cannulas directed to the PAG area, inject morphine into the PAG and evaluate its behavioral effects. Lactating Wistar rats received central infusions of morphine and showed significant differences in the various parameters. Retrieval and nest building were disrupted. This treatment alters latencies of foraging and pup grooming as well. Thus, full maternal behavior (FMB) was inhibited in the opioidergic treatment. The results suggest an involvement of a PAG role in opioidergicmodulation in maternal behavior. This modulation is provided for rPAGl, which have many neuroanatomical relations with another brain sites. These data suggest a role for rPAGl in ongoing of maternal behavior, but not in reflex nurturance behaviors like kyphosis.

Stress resilience in parenting depends on the parent's capacity to understand subjective experiences in self and child, namely intersubjectivity, which is intimately related to mimicking other's affective expressions (i. e., mirroring). Stress can worsen parenting by potentiating problems that can impair intersubjectivity, e.g., problems of “over-mentalizing” (misattribution of the child's behaviors) and “under-coupling” (inadequate child-oriented mirroring). Previously we have developed Mom Power (MP) parenting intervention to promote maternal intersubjectivity and reduce parenting stress. This study aimed to elucidate neural mechanisms underlying the effects of MP with a novel Child Face Mirroring Task (CFMT) in functional magnetic-resonance-imaging settings. In CFMT, the participants responded to own and other's child's facial pictures in three task conditions: (1) empathic mirroring (Join), (2) non-mirroring observing (Observe), and (3) voluntary responding (React). In each condition, each child's neutral, ambiguous, distressed, and joyful expressions were repeatedly displayed. We examined the CFMT-related neural responses in a sample of healthy mothers (n = 45) in Study 1, and MP effects on CFMT with a pre-intervention (T1) and post-intervention (T2) design in two groups, MP (n = 19) and Control (n = 17), in Study 2. We found that, from T1 to T2, MP (vs. Control) decreased parenting stress, decreased dorsomedial prefrontal cortex (dmPFC) during own-child-specific voluntary responding (React to Own vs. Other's Child), and increased activity in the frontoparietal cortices, midbrain, nucleus accumbens, and amygdala during own-child-specific empathic mirroring (Join vs. Observe of Own vs. Other's Child). We identified that MP effects on parenting stress were potentially mediated by T1-to-T2 changes in: (1) the left superior-temporal-gyrus differential responses in the contrast of Join vs. Observe of own (vs. other's) child, (2) the dmPFC-PAG (periaqueductal gray) differential functional connectivity in the same contrast, and (3) the left amygdala differential responses in the contrast of Join vs. Observe of own (vs. other's) child's joyful vs. distressed expressions. We discussed these results in support of the notion that MP reduces parenting stress via changing neural activities related to the problems of “over-mentalizing” and “under-coupling.” Additionally, we discussed theoretical relationships between parenting stress and intersubjectivity in a novel dyadic active inference framework in a two-agent system to guide future research.

No description available.

Deep brain stimulation (DBS) is a neurosurgical intervention now established for the treatment of movement disorders. For the treatment of chronic pain refractory to medical therapies, several prospective case series have been reported, but few centres worldwide have published findings from patients treated during the last decade using current standards of technology. This thesis seeks to survey the current clinical status of DBS for pain, investigate its mechanisms and their interactions with autonomic function, its clinical limitations and ablative alternatives. Presented first is a review of the current status of analgesic DBS including contemporary clinical studies. The historical background, scientific rationale, patient selection and assessment methods, surgical techniques and results are described. The clinical outcomes of DBS of the sensory thalamus and periventricular / periaqueductal grey (PAVG) matter in two centres are presented including results from several pain and quality of life measures. A series of translational investigations in human subjects receiving DBS for pain elucidating mechanisms of analgesic DBS and its effects upon autonomic function are then presented. Single photon emission tomography comparing PAVG, VP thalamus and dual target stimulation is described. Somatosensory and local field potential (LFP) recordings suggesting PAVG somatotopy are shown. ABPM results demonstrating changes with PAVG DBS are given and Portapres studies into heart rate variability changes with ventral PAVG DBS are detailed. Investigations using naloxone are then shown to hypothesise separate dorsal opioidergic and ventral parasympathetic analgesic streams in the PAVG. Finally, cingulotomy in lung cancer to relieve pain and dyspnoea results are discussed in the context of altering pain and autonomic function by functional neurosurgery. Pain and autonomic interactions and mechanisms in deep brain surgery for pain are then discussed alongside its limitations with proposals made for optimising treatment and improving outcomes.

This thesis is concerned with the neurocircuitry that underpins the cardiovascular response to exercise, which has thus far remained incompletely understood. Small animal studies have provided clues, but with the advent of functional neurosurgery, it has now been made possible to translate these findings to humans. Chapter One reviews the background to the studies in this thesis. Our current understanding of the cardiovascular response to exercise is considered, followed by a discussion on the anatomy and function of various brain nuclei. In particular, the rationale for targeting the periaqueductal grey (PAG) and the subthalamic nucleus (STN) is reviewed. Chapter Two reviews the use of deep brain stimulation (DBS), in which deep brain stimulating electrodes are implanted into various brain nuclei in humans, in order to treat chronic pain and movement disorders. This technique not only permits direct electrical stimulation of the human brain, but also gives the opportunity to record the neural activity from different brain regions during a variety of cardiovascular experiments. This chapter also gives a detailed methodological description of the experimental techniques performed in the studies in this thesis. Chapter Three identifies the cardiovascular neurocircuitry involved in the exercise pressor reflex in humans using functional neurosurgery. It shows for the first time in humans that the exercise pressor reflex is associated with significantly increased neural activity in the dorsal PAG. The other sites investigated, which had previously been identified as cardiovascular active in both animals and humans, seem not to have a role in the integration of this reflex. Chapter Four investigates whether changes in exercise intensity affect the neurocircuitry involved in the exercise pressor reflex. It demonstrates that the neural activity in the PAG is graded to increases in exercise intensity and corresponding increases in arterial blood pressure. This chapter also provides evidence to suggest that neural activity in the STN corresponds to the cardiovascular changes evoked by the remote ischaemic preconditioning stimulus in humans. Chapter Five identifies the cardiovascular neurocircuitry involved during changes in central command during isometric exercise at constant muscle tension using muscle vibration. It shows that, in humans, central command is associated with significantly decreased neural activity in the STN. Furthermore, the STN is graded to the perception of the exercise task, i.e. the degree of central command. The other sites investigated appear not to have as significant a role in the integration of central command during the light exercise task that was undertaken. Chapter Six studies the changes in muscle sympathetic nerve activity (MSNA) during stimulation of various brain nuclei in humans. Regrettably, the results presented in this chapter are not convincing enough to support the hypothesis that stimulation of particular subcortical structures corresponds to changes in MSNA. However, the cardiovascular changes that were recorded during stimulation of the different subcortical structures are congruous with previous studies in both animals and humans. Chapter Seven presents a brief summary of the findings in this thesis.