Os Transtornos por Uso de Substâncias (TUS) são propostos pela Associação Norte-Americana de Psiquiatria e englobam diversas dependências químicas, incluindo o tabagismo e a dependência de crack. O uso de crack tem aumentado consideravelmente nos últimos anos, segundo dados de levantamentos brasileiros e mundiais. Com mecanismo de ação semelhante ao da cocaína, porém com efeito mais rápido, o crack é uma droga que causa grave prejuízo a seus usuários e conduz à dependência em pouco tempo. O tabagismo também é uma condição bastante prevalente no mundo inteiro, sendo que os prejuízos relacionados a esse transtorno envolvem principalmente o desenvolvimento de doenças respiratórias e câncer. Diversos trabalhos têm buscado identificar fatores de suscetibilidade a esses transtornos, sendo que estudos de associação envolvendo genes do sistema de resposta a estresse vêm ganhando importância. O eixo Hipotálamo- Pituitária-Adrenal (HPA) é o sistema de resposta a estresse mais conhecido em humanos e alvo do presente trabalho, uma vez que o funcionamento dessa cascata de sinalização da produção de cortisol pode desempenhar um papel relevante no desenvolvimento de psicopatologias. Além disso, o eixo HPA pode ser considerado um mediador da relação entre situações adversas na infância e o surgimento de TUS. O objetivo desse trabalho, portanto, é investigar o papel de polimorfismos no gene CRHR1 (que codifica o receptor tipo 1 do hormônio liberador de corticotrofina – CRH, hormônio inicial do eixo HPA) sobre o desenvolvimento e características clínicas da dependência química. Para isso, foram realizados dois estudos, envolvendo amostras de mulheres. No primeiro artigo, a partir de três amostras – (1) 136 usuárias de crack, (2) 55 tabagistas e (3) 262 voluntárias saudáveis – foram identificadas diferenças de freqüências alélicas e genotípicas do SNP rs12944712; além disso, a análise de haplótipos envolvendo tal SNP e o rs110402 revelou maior frequência do haplótipo contendo o alelo G nos dois polimorfismos nos grupos de usuárias de crack e tabagistas. No segundo artigo, foi avaliado o efeito da interação geneambiente envolvendo os mesmos polimorfismos e situações adversas na infância – estimada pela escala Childhood Trauma Questionnaire (CTQ) –sobre características clínicas da amostra de usuárias de crack, como craving e gravidade da dependência – estimados, respectivamente, pelas escalas Cocaine Selective Severity Assessment (CSSA) e Addiction Severity Index (ASI6). A análise não revelou uma interação significativa. A presente dissertação, portanto, revela um efeito do gene CRHR1 sobre o desenvolvimento de TUS, embora esse efeito pareça não se manifestar sobre a gravidade. Mais estudos são necessários visando esclarecer o real efeito do gene e do eixo HPA como um todo sobre os fenótipos e comportamentos aditivos, bem como os mecanismos subjacentes a essa relação. / The Substance Use Disorders (SUD) are proposed by the American Psychiatric Association and comprise several addictions, including tobacco and crack cocaine smoking. The prevalence of crack cocaine dependence has grown considerably, according to survey data from Brazil and worldwide. With mechanism of action similar to cocaine but with faster effect, crack is a drug that causes severe impairments to its users and leads to dependence in a short time. Tobacco smoking is also a highly prevalent condition worldwide, and the impact related to this disorder includes cancer and respiratory diseases. Several studies have attempted the identification of susceptibility factors to these disorders, and association studies involving stress response system genes have been performed. The Hypothalamic-Pituitary-Adrenal (HPA) axis is the best known stress response system, and the signaling cascade production of cortisol may play a role in the development of psychopathology. In addition, HPA axis can be considered a mediator of the relationship between early life adversity and SUD. The aim of this study is to investigate the role of polymorphisms in CRHR1 gene (encoding the corticotrophin releasing factor – CRH – receptor type 1, an initial factor in HPA axis response) on the development and clinical traits of drug dependence. Two studies were conducted on women samples. In the first article, three groups were compared - (1) 136 crack smokers, (2) 55 tobacco smokers and (3) 262 healthy volunteers. Differences in allele and genotype frequencies of the SNP rs12944712 were identified; in addition, the haplotype analysis involving this SNP and rs110402 revealed a higher frequency of the haplotype containing G allele in both polymorphisms in the groups of nicotine dependents and crack smokers. In the second article, we evaluated the effect of a gene-environment interaction involving the same polymorphisms and childhood adversity - estimated by Childhood Trauma Questionnaire (CTQ) scale – on clinical characteristics of the sample of crack users, such as craving and severity of dependence - estimated respectively by the Cocaine Selective Severity Assessment (CSSA) and Addiction Severity Index (ASI6) scales. The analysis did not reveal a significant interaction. This dissertation thus shows an effect of CRHR1 genepolymorphism on the development of SUD, although this effect does not seem to impact disorder severity. More studies are needed in order to clarify the actual effect of the gene and of the HPA axis as a whole on addictive behaviors.

Em função da categoria dos estressores, vias neurais específicas são envolvidas e respostas distintas podem ser induzidas. A literatura tem reportado que o estrógeno (E 2 ) através de seus receptores de tipos (ER) e (ER) influencia a atividade do eixo hipotálamo hipófise adrenal (HPA). Além disso, há evidências de que o E2 exerça efeitos protetores em situação de choque hemorrágico. O objetivo deste trabalho foi verificar a participação dos receptores ER e ER na atividade do eixo HPA durante estresse hemorrágico. Foram utilizadas ratas Wistar ovariectomizadas que receberam injeções s.c. de DMSO (veículo), PPT (agonista ER) ou DPN (agonista ER), durante 3 dias. No segundo dia, as ratas foram canuladas para coleta seriada de sangue na manhã seguinte. Os animais receberam (controle) ou não (hemorrágicos) reposição imediata com salina. Os hormônios corticosterona (CORT), ocitocina (OT) e vasopressina (AVP) foram dosados por radioimunoensaio. Ao final do experimento, os ratos foram perfundidos e os cérebros processados para imuno-histoquímica de FOS, tirosina hidroxilase (TH) e hormônio liberador de corticotrofina (CRH). Nos animais tratados com veículo, a hemorragia gradual moderada aumentou a secreção de CORT, OT e AVP, a expressão de neurônios TH ativados na região A1C1 e de FOS no mpPVN. O PPT reduziu a secreção de CORT, na situação controle atuando no LC e mpPVN; e também após hemorragia atuando no LC, NTS, A1C1 e mpPVN. O DPN reduziu a secreção de CORT apenas após estresse hemorrágico atuando no LC, A1C1 e mpPVN. O PPT bloqueou o aumento da secreção de OT e aumentou a secreção de AVP, após hemorragia. O DPN, por sua vez, reduziu a concentração plasmática de OT e aumentou a concentração plasmática de AVP, independentemente da hemorragia. Em conclusão: o estrógeno pode exercer uma ação inibitória sobre a secreção basal de CORT somente através da ação do ER sobre o LC e mpPVN; a secreção de CORT aumenta em resposta à hemorragia gradual moderada e o estrógeno pode exercer um controle inibitório nessa resposta através de ER atuando sobre LC, NTS, A1C1 e mpPVN, bem como através de ER atuando sobre LC, A1C1 e mpPVN. / Depending on the stressors category, specific neural pathways are involved and different responses can be selected. It has been reported in the literature that estrogen (E2 ) can affect hypothalamus pituitary adrenal (HPA) axis activity through its receptors type (ER) and (ER). Moreover, there is evidence that E 2 has protecting properties after hemorrhagic shock. The aim of this work was to assess the participation of ER and ER on HPA axis activity during hemorrhagic stress. It was used ovariectomized Wistar rats that received s.c. injections of: DMSO (vehicle), PPT (ER agonist) or DPN (ER agonist), during 3 days. In the second day the rats were catheterized for serial blood collect in the next morning. Animals received (control) or not (hemorrhagic) immediate reposition with same volume of isotonic saline. The hormones corticosterone (CORT), oxytocin (OT) and vasopressin (AVP) were measured by radioimmunoassay. At the end of the experiment, animals were perfused and their brains were processed for immuno-histochemistry for FOS, tyrosine hydroxylase (TH) and corticotropin releasing hormone (CRH). In vehicle treated animals, the gradual hemorrhage enhanced CORT, OT and AVP secretion, TH activated neurons expression in A1C1 and FOS expression in mpPVN. PPT decreased plasma CORT in control situation acting on LC and mpPVN, and also after hemorrhage acting on LC, NTS, A1C1 and mpPVN. DPN reduced plasma CORT only after hemorrhagic stress acting on LC, A1C1 and mpPVN. PPT blocked the increase of OT secretion and increased AVP secretion, after hemorrhage. The agonist DPN reduced OT and increased AVP levels, despite hemorrhage. In conclusion: E2 can exert an inhibitory effect on CORT basal secretion only through ER action on LC and mpPVN; CORT secretion increases after gradual moderate hemorrhage and E2 inhibit this secretion through ER action on LC, NTS, A1C1 and mpPVN, as well through ER action on LC, A1C1 and mpPVN.

With increasing strain on the civil aviation industry to meet strict targets to reduce the adverse effects aviation has on the environment by 2050, significant advances in aircraft design and research are required. Aerodynamic improvements have been a focus for several decades now, however, current and future civil transport aircraft are based on traditional designs originating from the 1950s. Optimisation of aircraft external geometry for aerodynamic gain is reaching maturity and is becoming increasingly non-cost-effective. New advances in sensor and actuator technology has allowed for the development of active flow control (AFC) devices that have shown promising results in laboratory and even full-scale flight conditions, as seen by the joint NASA-Boeing ecoDemonstrator. One such device is the synthetic jet actuator (SJA), that synthesises periodic jets without the requirement for external air supply, while adding momentum to the surrounding flow. For this reason, SJAs are also referred to as zero-net-mass-flux actuators. There exists extensive work on the use of these devices for flow control applications in a laboratory setting. One of the key issues that remains unresolved, hindering successful aircraft application to-date, is the actuator self-noise generated. The noise level of SJAs can be so severe that they were rejected for application on the ecoDemonstrator in favour of a higher authority, quieter AFC device. SJAs were only considered for use in emergency situations on aircraft. Furthermore, the actuators were also not permitted to operate simultaneously at full power, which may severely limit scope for flow control on aircraft. Other applications that would benefit from SJAs include heat transfer for cooling in electronic devices. Studies in this field identify the same problem with noise levels of up to 73 dB reported. It is clear that work towards the self-noise reduction of SJAs is required to harness the full potential of this actuator technology. In the work presented, passive and active noise control measures in the form of lobed orifices and antiphase operation of two jets, respectively, on the noise reduction of SJAs are ii investigated. Noise sources of synthetic jet actuators include mechanical (diaphragm) and jet induced noise, where the focus of this work is on the latter type. Tests were conducted in quiescent conditions using jet velocity measurements, acoustic measurements, and flow visualisation. Tests were carried out using a single chamber SJA with variable cavity height and both circular and lobed orifices. These tests helped identify a SJA self-noise generation mechanism when using a circular orifice. This mechanism is characterised by a constant frequency behaviour visible in acoustic spectra for a specific jet Reynolds number range of 600 < Rej < 750 and Strouhal number range of 0.22 < St < 0.50. The geometries of the lobed orifices used in this work differ in lobe count and penetration. It was shown that a broadband noise reduction is possible with such orifices, with a maximum noise reduction of 14 dB at particular frequencies. The results indicate that a high number of lobes and penetration are preferred for noise reduction, however, at the expense of quickly dissipating downstream jet velocity. Flow visualisation reveals that this adverse effect is caused by enhanced mixing of lobed jets with ambient air that leads to earlier and more aggressive breakup of flow structures. A double chamber SJA is also used to demonstrate the noise attenuation through the antiphase operation of two cavities, caused by the interference pattern of the sound field of each source. The maximum reduction measured using this actuator configuration is 14 dB, depending on directivity.

Essa tese aborda a consolidação do eixo territorial Rio de Janeiro - São Paulo como núcleo principal do desenvolvimento nacional, através do planejamento econômico e da ação direta do Estado. Ao enfocar o período do 1o Ciclo Desenvolvimentista, de1930 a 1964, evidencia a opção pela industrialização como caminho para o desenvolvimento. Como consequência da subordinação do país à condição de periferia do sistema capitalista internacional, apesar da transformação estrutural do sistema de produção, de nação agroexportadora para urbano-industrial, há continuidade na reprodução das desigualdades, de regionais a intraurbanas.O eixo territorial se estrutura na base de seus vetores lineares, entrelaçando relações de seus núcleos urbanos articulados por uma malha de caminhos e percursos que remontam historicamente à forma de ocupação dos nativos indígenas. As relações entre as Capitais do Rio de Janeiro e de São Paulo, as cidades que se fundam ao longo da história do Vale do Paraíba do Sul e os diversos ciclos econômicos que prevaleceram em determinados momentos forjaram o espaço regional.A tese verifica a hipótese de que a lógica da materialização da produção social do espaço urbano e a dos desequilíbrios dos processos de urbanização brasileiros foram fundamentalmente consolidadas nesse período histórico, a partir de definições determinadas no plano econômico e não por planos urbanísticos concebidos no sentido da organização do meio urbano. Estes, por sua vez, reproduziram modelos para apoiar a construção da imagem de uma sociedade modernizada e assumiriam papel coadjuvante nos processos de urbanização. / This thesis concerns the consolidation of the Rio de Janeiro - Sao Paulo territorial axis as main core of Brazil\'s national development, through economic planning and the direct action of the State. Focusing the period of the 1st Developmental Cycle, from 1930 to 1964, and on the option for industrialization as the path to development. As a consequence of the country\'s subordination to a peripheral condition in the international capitalistic system, though there was structural change in the production system, from agro exporter to urban industrial, there was continuity on the reproduction of inequalities, from regional to intra urban. The territorial axis structures itself on the basis of linear vectors, interweaving relationships of its urban centers articulated by a network of paths and trails that date back to the native indians\' occupation. The relationships between the Capitals cities of Rio de Janeiro and Sao Paulo, the cities that were founded along the Paraiba do Sul Valley\'s history and the several economic cycles that prevailed in determined moments shaped the regional space. The thesis finds support for the hypothesis that the logic of materialization of the social production of the urban space and the unbalanced Brazilian urbanization processes were fundamentally consolidated in this historical period, based on definitions determined by economic, rather than urbanistic plans, conceived in the sense of urban means arrangements. These, in turn, reproduced models to stand the construction of the image of a modernized society and assumed a supporting role in the urbanization processes.

Corticotroph cells from the anterior pituitary are an integral component of the hypothalamic-pituitary-adrenal (HPA) axis, which controls the neuroendocrine response to stress. Following stressful stimuli, corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus act synergistically to stimulate adrenocortiotrophin hormone (ACTH) secretion from corticotroph cells. ACTH is released into the circulation where it stimulates the secretion of glucocorticoids from the adrenal cortex. The HPA axis is kept in fine balance through an elegant negative feedback system where elevation of plasma glucocorticoids results in inhibition at the level of both the pituitary and the hypothalamus. During acute stress, glucocorticoids can be beneficial however chronic elevation of glucocorticoids can have many adverse effects on health. Corticotroph cells are electrically excitable and have been shown to fire single-spike action potentials as well as complex bursting patterns. Stimulation of corticotrophs with physiological concentrations of CRH/AVP results in a robust increase in firing frequency and a transition from spiking to bursting. Intracellular Ca2+ increases to a greater extent during bursting which has been proposed to drive hormone secretion. There is evidence to suggest that large conductance calcium- and voltage-gated potassium (BK) channels promote bursting behaviour in anterior pituitary cells. Glucocorticoids have been shown to regulate ACTH secretion and also modulate BK channel activity. However, the effects of glucocorticoids on native corticotroph excitability are currently unknown. The aim of this study was to first characterise the electrical properties of corticotrophs under basal conditions and following exposure to CRH/AVP. Secondly, to investigate the regulation of corticotroph excitability by glucocorticoids. Finally, establish the role of the BK channel in regulating bursting behaviour and CORT regulation in corticotroph cells. Corticotroph cells were acutely isolated by trypsin digestion from mice aged 2-5 months constitutively expressing GFP under control of the POMC promoter (POMC-GFP). Mice used for pituitary cell culture were male unless otherwise stated. Cells were maintained in a serum free media and electrophysiological recordings obtained 24-96 hours post-isolation. Current clamp recordings were obtained from corticotrophs using the perforated patch technique. Although spontaneous activity of corticotroph cells was variable, they displayed predominantly single-spike action potentials under basal conditions. Stimulation with physiological concentrations of CRH and AVP (0.2 nM and 2 nM respectively) resulted in a membrane depolarisation accompanied by an increase in firing frequency and a transition to bursting. Individually, CRH and AVP were able to increase corticotroph excitability. However, only CRH was able to drive an increase in bursting suggesting that bursting is primarily regulated through the cAMP/PKA pathway. Experiments were performed to investigate the modulation of corticotroph activity by glucocorticoid negative feedback. Acute exposure (< 10 min) to corticosterone resulted in a decrease in spontaneous activity as well as shortening the response to CRH/AVP. Pretreatment of corticotrophs with 100 nM corticosterone (90 min) resulted in a membrane hyperpolarisation and a decrease in spontaneous firing frequency. Following corticosterone pretreatment, CRH/AVP failed to induce a significant transition from spiking to bursting. Increasing the pretreatment time to 150 minutes resulted in a further suppression of both spontaneous and CRH/AVPevoked activity. Fast activation of BK channels during the upstroke of an action potential has been proposed to promote bursting behaviour in other pituitary cells. Corticotrophs treated with a BK channel blocker (1 μM paxilline) or isolated from BK-/- mice showed no significant difference in basal activity but displayed a reduction in CRH/AVPevoked bursting activity. In both cases, bursting was significantly reduced but not completely abolished. Corticosterone treatment of BK-/- cells resulted in a further decrease in both firing frequency and bursting behaviour. Taken together, these results suggest that although BK channels play an important role in bursting, they are not the only component. Comparisons of male and female corticotrophs revealed subtle differences in their properties. Following CRH/AVP stimulation, male cells displayed a high degree of bursting activity whereas female cells exhibited predominantly an increase in singlespike action potential frequency. Treatment of female corticotrophs with corticosterone (150 min) resulted in a significant reduction in firing frequency but no measurable change in bursting behaviour. BK-/- cells from female mice showed no difference in bursting activity following CRH/AVP compared to wild types. This data suggests that modulation of firing frequency is the more important component in female corticotroph cells. In conclusion, CRH/AVP is proposed to drive ACTH secretion in male corticotroph cells through an increase in bursting activity. Corticosterone pretreatment suppresses both spontaneous and CRH/AVP-evoked activity. It is possible that corticosterone regulates corticotroph excitability through two mechanisms. Corticosterone suppresses bursting activity following CRH/AVP stimulation through multiple targets which might include the BK channel. Additionally, corticosterone reduces firing frequency through a mechanism independent of BK channels. It is important to further characterise the physiology of corticotroph cells and how ACTH secretion is regulated through their electrical excitability. This would lead to a greater understanding of the role of corticotrophs in the HPA axis. Further study of corticotrophs could potentially lead to pharmacological manipulation of the stress response and novel treatments for stress-related disorders.

Thesis (M.A.)--State University of New York at Binghamton, Psychology Department, 2006. / Includes bibliographical references.

<p>Examensarbetet är utfört på avdelningen för Fluida och mekatroniska system vid Linköpings universitet i uppdrag åt Sunfab Hydraulics AB.</p><p>Höga ljudnivåer är en stor nackdel vid användning av hydrauliska system. Ofta är det hydraulmaskiner av deplacementtyp som står för en stor del av ljudemissionerna. Eftersom maskinerna arbetar med stora tryckskillnader uppstår flödespulsationer vid in- och utlopp som fortplantar sig vidare i systemet. Dessa medför påfrestningar på maskinen som kan leda till läckage eller haveri. Flödespulsationer kan delas upp i två delar; kinematiska och kompressionsberoende. De kinematiska pulsationerna beror på det begränsade antalet cylindrar och kolvarnas varierande hastighet. På grund av oljans kompressibilitet uppstår pulsationer när cylindertrycket hastigt växlar mellan trycknivåerna.</p><p>Arbetet har resulterat i en modell i programmet HOPSAN som kan simulera flödesdynamiken i en axialkolvmaskin med fast deplacement av typen bent-axis. I modellen kan bland annat ventilskivans geometri förändras för att studera hur flödespulsationerna påverkas vid olika driftspunkter.</p><p>Simuleringsmodellen har med två-mikrofon metoden validerats för en maskin med deplacement 47.1 cm3/varv. Mätutrustningen som använts är anpassad för pumpar vilket innebär att vid mätningarna på motorlocket kördes maskinen som pump.</p><p>För att underlätta tillverkningen av krypspår borras små hål vid dess spets. Dessa finns implementerade i modellen för att undersöka hur flödespulsationerna påverkas. Simuleringar påvisar ett större läckflöde mellan njurarna vilket resulterar i en liten minskning av den volymetriska verkningsgraden vid låga varvtal. För att bättre kunna använda modellen till utveckling av befintliga maskiner borde Sunfab se över om hålen kan tas bort.</p><p>För- och nackdelar med stängd respektive öppen geometri kan undersökas i modellen. Den senare innebär att ett korsande flöde mellan hög- och lågtryckssidan tillåts. Simuleringar visar att vid låga varvtal är den volymetriska verkningsgraden lägre för motorlock med öppen geometri. Stängd geometri ger bättre startmoment på grund av frånvaron av läckflöde men ger däremot större flödespulsationer.</p><p>Optimering av krypspåren visar att maximala tvärsnittsarean kan justeras lite för att minska amplituden av flödespulsationerna.</p>

Epidemiological studies in humans have revealed a relationship between altered development in utero and an increased incidence of pathophysiology during postnatal life. One of the mechanisms underlying this relationship is thought to be exposure to excess glucocorticoids during critical phases of brain development. The aim of the current set of studies was to determine the effects of prenatal stress during discrete developmental windows on behaviour and endocrine function in male and female guinea pig offspring. Guinea pigs were used as the model for these studies as they are a long-gestation species that give birth to neuroanatomically mature young and fetal brain development is well characterized. Pregnant guinea pigs were exposed to a high frequency strobe light during the period of rapid fetal brain growth or the period of rapid brain myelination. Pregnant guinea pigs were allowed to deliver normally and guinea pig offspring were tested for ambulatory activity, anxiety and hypothalamic-pituitary-adrenal (HPA) axis function. Male offspring whose mothers were exposed to stress during the period of rapid brain growth exhibited increased anxiety behaviour, increased basal plasma cortisol levels and decreased plasma testosterone levels. We found that replacing testosterone in these animals reversed the behavioural and endocrine differences. Male offspring whose mothers were exposed to stress during the period of rapid myelination exhibited an increased plasma cortisol response to activation of the HPA axis. Female offspring whose mothers were exposed to stress during the period of rapid brain myelination exhibited decreased ambulatory activity and a blunted salivary cortisol response to the stress of the strobe light, but only during the estrous phase of the reproductive cycle. Therefore, the current set of studies has demonstrated the effects of prenatal stress on behaviour and HPA axis activity are dependent on; 1) the timing of the prenatal stress and 2) the hypothalamic-pituitary-gonadal axis in both male and female offspring. These studies have begun to uncover the mechanisms underlying programming and provide the basis for continuing research in humans.

Axis Mundi - Ett examensarbete som undersöker om tvärvetenskap kan användas som alternativ process i skapandet av arkitektur. I arbetet formgavs en helig struktur efter den tvärvetenskapliga undersökningen, som sedan användes som en scenografi i en dansfilm.

Epidemiological studies in humans have revealed a relationship between altered development in utero and an increased incidence of pathophysiology during postnatal life. One of the mechanisms underlying this relationship is thought to be exposure to excess glucocorticoids during critical phases of brain development. The aim of the current set of studies was to determine the effects of prenatal stress during discrete developmental windows on behaviour and endocrine function in male and female guinea pig offspring. Guinea pigs were used as the model for these studies as they are a long-gestation species that give birth to neuroanatomically mature young and fetal brain development is well characterized. Pregnant guinea pigs were exposed to a high frequency strobe light during the period of rapid fetal brain growth or the period of rapid brain myelination. Pregnant guinea pigs were allowed to deliver normally and guinea pig offspring were tested for ambulatory activity, anxiety and hypothalamic-pituitary-adrenal (HPA) axis function. Male offspring whose mothers were exposed to stress during the period of rapid brain growth exhibited increased anxiety behaviour, increased basal plasma cortisol levels and decreased plasma testosterone levels. We found that replacing testosterone in these animals reversed the behavioural and endocrine differences. Male offspring whose mothers were exposed to stress during the period of rapid myelination exhibited an increased plasma cortisol response to activation of the HPA axis. Female offspring whose mothers were exposed to stress during the period of rapid brain myelination exhibited decreased ambulatory activity and a blunted salivary cortisol response to the stress of the strobe light, but only during the estrous phase of the reproductive cycle. Therefore, the current set of studies has demonstrated the effects of prenatal stress on behaviour and HPA axis activity are dependent on; 1) the timing of the prenatal stress and 2) the hypothalamic-pituitary-gonadal axis in both male and female offspring. These studies have begun to uncover the mechanisms underlying programming and provide the basis for continuing research in humans.