Orientador: José de Anchieta de Castro e Horta Júnior / Resumo: A associação do baixo peso ao nascer com alto risco de doenças como obesidade, diabete tipo 2 e doenças cardiovasculares na vida adulta levaram à hipótese da “Origem Desenvolvimentista da Saúde e Doença” (DOHaD). Nessa hipótese, Programação se refere às adaptações executadas pelo organismo frente a insultos ocorridos durante seu desenvolvimento, gerando efeitos permanentes ou não na estrutura e função de órgãos. A nutrição materna durante o desenvolvimento do indivíduo é considerada um importante indutor de Programação, visto que a deficiência de nutrientes, durante a prenhez e a lactação, provoca alterações significativas no peso corpóreo, no balanço energético, na ingestão alimentar e na expressão de neuropeptídeos. O hormônio concentrador de melanina (MCH) e o transcrito regulado pela cocaína e anfetamina (CART) são neuropeptídeos expressos na área hipotalâmica lateral (LHA), que participam da regulação do balanço energético e do comportamento alimentar, nos quais o MCH desempenha papel orexígeno e o CART, anorexígeno. Nosso objetivo foi analisar o número e a distribuição de neurônios MCH e CART e sua ultraestrutura na LHA de ratos cujas mães foram submetidas à restrição alimentar durante a prenhez e lactação. Fêmeas prenhes Wistar foram separadas em dois grupos experimentais: grupo controle (GC), dieta padrão ad libitum, e grupo restrição calórica (GR), dieta de 50% de restrição em relação ao grupo controle durante os períodos de prenhez e lactação. Foram avaliados o núme... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The association between lower birth weight and an increased risk of obesity, diabetes type 2 and cardiovascular diseases in adult life led to Developmantal Origins of Health and Disease (DOHaD) hypothesis. In this hypothesis, programming is related to the adjustments performed by the organism to insults occurring at key stages of their development, which may lead to long-lasting effects in the organs structure and function. Maternal nutrition during critical periods of individual development is considered an important Programming inductor, since the nutrient deficiency during pregnancy and lactation causes significant changes in body weight, energy balance, food intake and neuropeptides expression. The melanin-concentrating hormone (MCH) and the cocaine- and amphetamine-regulated transcript (CART) are neuropeptides expressed in the lateral hypothalamic area (LHA) that are involved in the regulation of energy balance and feeding behavior in which MCH plays an orexigenic role and CART an anorexigenic one. Thus, our aim was to analyze the number and the distribution of MCH and CART and the ultrastructure of these neurons in the LHA of rats whose mothers were subjected to food restriction during pregnancy and lactation. After pregnancy confirmation, female Wistar rats were divided in two groups: control group (CG), ad libitum standard diet, and caloric restriction group (RG), 50% diet restriction compared to the control group during pregnancy and lactation. After birth, the numbe... (Complete abstract click electronic access below) / Doutor

O neuropeptídeo urocortina 1 (UCN 1) tem entre os seus principais locais de expressão o núcleo de Edinger-Westphal (EW) e o núcleo lateral superior da oliva. Após sua descoberta, sugeriu-se que o EW e o núcleo paraventricular do hipotálamo (PVH) possuíssem papéis complementares e opostos na resposta ao estresse, porém, não existem trabalhos que relacionam anatomicamente núcleos hipotalâmicos e o EW. A fim de contribuir para esta área foi proposto o mapeamento das aferências hipotalâmicas do EW, através da injeção de Fluoro-Gold neste núcleo e posterior mapeamento de suas aferências. Os resultados encontrados foram: PVH, área hipotalâmica lateral (LHA) e o núcleo posterior do hipotálamo (PH) e outras regiões do sistema nervoso central. Para controle, o traçador anterógrado Amina Dextrana Biotinilada, foi injetado nos núcleos/áreas hipotalâmicas PVH, LHA e PH sendo encontradas fibras próximas as células urocortinérgicas do EW. Nossos dados mostram um possível envolvimento das células UCN 1 do EW com o controle de funções autonômicas e neuroendócrinas. / The neuropeptide urocortin 1 (UCN 1) has its main sites of expression at the Edinger-Westphal nucleus (EW) and the lateral superior olivary nucleus. After its discovery has suggested that EW and paraventricular nucleus of hypothalamus (PVH) have complementary and opposing roles in the stress response. However, there are no works relating anatomically the hypothalamic nuclei and EW. To contribute to this area we proposed mapping the hypothalamic afferents of the EW. We have used the Fluoro-Gold injected in the EW as a result of we have found retrogradely labeled cells in the following nuclei: PVH, lateral hypothalamic area (LHA), posterior hypothalamic nucleus (PH) and other regions of the central nervous system. For control, the anterograde tracer biotinylated dextran amine was injected into the nuclei/areas hypothalamic PVH, LHA, and PH we have found anterogradely labeled fibers in a very close apposition over urocortinergic cells at EW. Based on these data we are suggesting a involvement of cells with UCN 1 EW control of autonomic and neuroendocrine functions.

Etologicamente, os animais expressam repostas de medo frente a um predador ou a um co-especifico e a organização neural de respostas defensivas intraespecíficas são pouco conhecidas. Assim, o objetivo deste trabalho foi estudar o papel hipotalâmico na organização da defesa intraespecífica. Observamos que o núcleo pré-mamilar dorsal do hipotálamo também está ativo durante nesse tipo de defesa, porém porções distintas do mesmo. A lesão desse núcleo em ratos expostos a derrota social levou a importantes alterações comportamentais, praticamente abolindo comportamentos de defesa passiva. Notamos que regiões do hipotálamo lateral são as principais projeções aferentes do núcleo pré-mamilar dorsal e o principal alvo eferente é a coluna dorsomedial da matéria cinzenta periaquedutal. Concluímos que o hipotálamo é fundamental para a organização da defesa intraespecífica e que comportamentos defensivos inter e intra-específicos se utilizam de caminhos neurais distintos. / In nature, animals express fear responses toward a predator or a co-specific and not much is known about the neural organization of intra-specific defense. Therefore, the aim of this work was to analyze the role that the hypothalamus plays during the intra-specific defense expression. We observed that the dorsal premammilary nucleus is also mobilized during the agonistic encounter, but a different portion. Dorsal premammilary nucleus lesioned intruders led to important defense alterations, almost abolishing passive forms of defensive behavior. Notably, regions in lateral hypothalamus are particularly important for activating the dorsal premammilary nucleus and its efferent projection to the dorsomedial column of periaqueductal gray matter is the most important outcome for the defensive behavior expression. Concluding, the hypothalamus is fundamental for the neural organization of intra-specific defense and inter and intra-specific defensive behaviors are organized by distinct neural pathways.

Introdução: O Transtorno Afetivo Bipolar (TAB) e o Transtorno de Personalidade Borderline (TPB) apresentam características clínicas em comum que frequentemente tornam difícil seu diagnóstico diferencial, podendo implicar em indicações terapêuticas inadequadas. Assim, é importante ampliar o conhecimento diagnóstico sobre esses transtornos mentais buscando identificar marcadores que auxiliem sua diferenciação. A história de estresse precoce, associada à vulnerabilidade individual no desenvolvimento de transtornos mentais relatada na literatura, pode representar um fator de diferenciação entre TAB e TPB, assim como sua associação com manifestações clínicas e respostas neuroendócrinas específicas a cada um desses diagnósticos. Objetivo: Avaliação e comparação de pacientes com diagnóstico de TAB e TPB buscando indicadores de seu diagnóstico diferencial, relacionados a fatores associados a sua sintomatologia, etiopatogênese e marcadores neuroendócrinos. Metodologia: A amostra do estudo foi composta por 51 mulheres, distribuídas em 3 grupos constituídos por pacientes com diagnóstico clínico de TAB (n=16) e TPB (n=20), e controles saudáveis (n=15). Para sua avaliação, foram utilizados instrumentos para confirmação diagnóstica e entrevista semiestruturada para delineamento do perfil sócio-demográfico e clínico. A gravidade da sintomatologia psiquiátrica foi avaliada através dos instrumentos de Beck para avaliação de ansiedade, depressão, desesperança e ideação suicida, além de escalas de avaliação de sintomas maníacos e impulsividade. A história de estresse precoce foi investigada pelo Questionário de Traumas na Infância (CTQ), e classificada segundo os subtipos abuso emocional, abuso físico, abuso sexual, negligência emocional e negligência física. O funcionamento do eixo hipotálamo- hipófise-adrenal (HHA) foi avaliado pela dosagem de cortisol basal plasmático. Os resultados das avaliações foram analisados em um segundo momento de acordo com a presença ou ausência de estresse precoce. Resultados: A amostra de pacientes com diagnósticos de TAB e TPB analisadas apresentaram diferenças significativas em relação à idade e tempo de tratamento, maiores no grupo TAB. A análise da sintomatologia psiquiátrica indica maior gravidade de ansiedade, impulsividade, depressão, desesperança e ideação suicida no grupo TPB. A história de estresse precoce foi identificada como mais prevalente e significativamente mais grave nas pacientes do que em controles saudáveis, nos escores de CTQ total, abuso emocional, negligência emocional e negligência física, que também diferenciaram os grupos diagnósticos, sendo maiores no TPB comparado ao TAB. A partir da presença do estresse precoce em níveis de moderado a extremo, o subtipo negligência física diferenciou significativamente os diagnósticos, indicando ser mais grave quando associado ao TPB. A avaliação endócrina indicou diferenças entre os diagnósticos TAB e TPB em relação aos controles saudáveis, com níveis mais baixos de cortisol apresentados pelas pacientes. A presença de estresse precoce em pacientes com TAB demonstrou diferença significativa com menores níveis de cortisol em relação aos controles. O cortisol mensurado nas pacientes com TPB foi significativamente menor comparado ao dos controles na presença de negligência emocional e negligência física. O cortisol apresentou correlações significativas e opostas nos grupos diagnósticos com o abuso sexual, sendo uma correlação de Pearson negativa no TAB e positiva no TPB. A presença de estresse precoce associada ao diagnóstico de TPB revelou ainda correlação significativa negativa do cortisol com a negligência física. Discussão: Considerando a necessidade de uma análise multifatorial, o diagnóstico diferencial entre TAB e TPB pode ser facilitado pela análise dos sintomas psiquiátricos e da história de estresse precoce. O diagnóstico de TPB se associa a sintomatologia mais grave de ansiedade, impulsividade, depressão, desesperança e ideação suicida; assim como, a maior prevalência e gravidade da história de estresse precoce em geral e em relação aos subtipos abuso emocional, negligência emocional e, especialmente, negligência física quando presente em maior gravidade. O funcionamento do eixo HHA avaliado pelo cortisol sugere diferenciar-se em ambos os diagnósticos, na associação com experiências estressantes precoces no TAB e, especialmente, com história de negligência física no TPB. Conclusão: Assim, a análise integrada dos parâmetros relacionados a psicopatologia, ao estresse precoce e funcionamento neuroendócrino fornecem indicadores úteis na diferenciação entre os diagnósticos de TAB e TPB, mas que necessitam ser melhor explorados e compreendidos através de futuros estudos. / Introduction: Bipolar Disorder (BD) and Borderline Personality Disorder (BPD) have clinical features in common that often make it difficult differential diagnosis , and may result in inadequate therapeutic indications. Thus , it is important to expand knowledge diagnosis on these mental disorders in order to identify markers that make clear the differences. The history of early stress associated with individual vulnerability to develop mental disorders can be a difference factors between BD and BPD , as its association with clinical and neuroendocrine responses. Objective: To assess and compare patients with BD and BPD seeking indicators of differential diagnosis, related to factors associated with its etiology and pathogenesis, symptoms and neuroendocrine markers. Methodology: The study sample consisted of 51 women , distributed in 3 groups: patients diagnosed with BD (n=16) and BPD (n=20) and healthy controls (n=15). We confirm the diagnosis with SCID I and SCID II; and semi-structured interview for delineating the socio-demographic and clinical features. Severity of psychiatric symptoms was assessed using the Beck instruments for assessment of anxiety , depression , hopelessness and suicidal ideation, as scales of impulsivity and manic symptoms. The history of early stress was investigated by the Childhood Trauma Questionnaire (CTQ), and classified according to subtypes emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect. The functioning of the hypothalamic- pituitary- adrenal (HPA) axis was evaluated by measurement of basal plasma cortisol. Results were analyzed in a second time according to the presence or absence of early stress. Results: A sample of patients with diagnoses of BD and BPD were analyzed and showed significant differences in relation to age and treatment time , higher in BD. The analysis of psychiatric symptoms indicating greater severity of anxiety, impulsivity, depression, hopelessness and suicidal ideation in the group BPD. The history of early life stress has been identified as the most prevalent and significantly worse in patients than in healthy controls, in scores of CTQ total emotional abuse, emotional neglect and physical neglect, which also differentiated the diagnostic groups and were higher BPD compared BD. From the presence of early life stress the subtypes physical neglect differed significantly , indicating higher severity when associated with the BPD. The endocrine evaluation indicated differences between diagnoses BD and BPD compared to healthy controls , with lower levels of cortisol presented by patients. The presence of early stress in patients with BD showed significant difference with lower cortisol levels compared to controls. Cortisol measured in patients with BPD was significantly lower compared to controls in the presence of emotional neglect and physical neglect. Cortisol was significantly correlated and opposite in diagnostic groups with sexual abuse , being a Pearson correlation negative in BD, and positive BPD. The presence of early stress associated with the diagnosis of BPD also showed a significant negative correlation of cortisol with physical neglect. Discussion: Considering the need for a multifactorial analysis, differential diagnosis between BD and BPD can be facilitated by analysis of psychiatric symptoms and history of early life stress. The diagnosis of BPD is associated with more severe symptoms of anxiety, impulsivity, depression, hopelessness and suicidal ideation, as well as the increased prevalence and severity of history of early life stress in general and in relation to subtypes emotional abuse, emotional neglect, and especially , physical neglect when present in greater severity . The functioning of the HPA axis measured by cortisol suggests differentiate the diagnosis and association with early stressful experiences in BD and particularly with a history of physical neglect in BPD. Conclusion: Thus, the integrated analysis of the parameters related to psychopathology, stress and neuroendocrine function provide early indicators useful in differentiating between diagnoses of BD and BPD, but these need to be better explored and understood by future studies.

Neste trabalho investigamos a interação entre ATP-glutamato na modulação de potenciais de ação e atividade sináptica de neurônios PVN-RVLM, além de avaliar se esta interação induziria mudanças na atividade simpática lombar (ANSL) por estímulo osmótico. Utilizamos de técnicas de imunohistoquímica, whole-cell patch clamp e registro eletroneurográfico. Observou-se que o ATP aumenta a frequência de potenciais de ação em neurônios PVN-RVLM, efeito bloqueado por acido quinurênico (KYN) e PPADS. A injeção de ATP no PVN aumenta a ANSL (25 nmol: 72%), um efeito atenuado por PPADS e/ou KYN, e também por CNQX. O ATP não afeta a função sináptica, mas aumenta correntes glutamatérgicas induzidas por aplicação AMPA em 52%, a qual foi bloqueada por PPADS ou por quelação de Ca2+ intracelular. Além disso, o estímulo osmótico ativa neurônios do PVN que expressam receptores P2X2 e potencia as correntes mediadas por AMPA (53%), um efeito bloqueado por PPADS. Finalmente, demonstrou-se que receptores P2 no PVN são importantes na simpatoexcitação induzida por estímulo osmótico agudo. / In the present study we investigate the interaction of ATP-glutamate on the firing activity and synaptic function in PVN-RVLM neurons, besides whether that interaction would be translated in changes on sympathetic nerve activity (SNA) induced by osmotic stimulus. Immunohistochemistry, whole-cell patch clamp and electroneurography technical approaches were used. Our data have shown that ATP increases firing rate of PVN-RVLM neurons, an effect blocked by kynurenic acid (KYN) or PPADS. ATP injection into the PVN enhanced SNA (72%), which was attenuated by PPADS and/or KYN, or CNQX. ATP did not affect synaptic function but, glutamatergic currents evoked by AMPA application were augmented with ATP (AMPA area: 52%), blocked by PPADS and chelation of intracellular Ca2+. In addition, we observed that acute osmotic stimulus activates P2X2 expressing neurons in the PVN. Moreover, an osmotic challenge potentiated AMPA responses (53%), an effect blocked by PPADS. Finally, we demonstrated that P2 receptors in the PVN are important for osmotically-driven sympathoexcitation.

Uma nutrição maternal rica em lipídios pode causar prejuízos no desenvolvimento e na vida adulta dos descendentes, como elevado risco de desenvolver alterações metabólicas e obesidade, e também parece alterar a sinalização central por opióides. Porém, estudos realizados a fim de investigar a influência da dieta hiperlipídica (HF) materna sobre o comportamento materno e o desenvolvimento da prole não são conclusivos. Este trabalho investigou a influência da dieta HF sobre a interação mãe-filhote, em duas gerações, e os efeitos imediatos e tardios sobre a prole, relacionando-os ao sistema opióide. As mães HF apresentaram prejuízos na ejeção do leite e maior expressão dos receptores opióides no hipotálamo. No geral, os descendentes HF apresentaram elevados níveis de colesterol, baixa leptina plasmática, maior expressão de peptídeos relacionados à ingestão alimentar, e menor peso. Portanto, o consumo materno de dieta HF causou alterações metabólicas, comportamentais e na expressão gênica na mãe e nos descendentes, mesmo que esses animais não tenham se tornado obesos. / A maternal nutrition high in fat may impair offspring development and adulthood, increasing the risk to develop metabolic alterations and obesity, and may modify the opioids central signaling. However, studies investigating maternal high fat (HF) diet influences on maternal behavior and offspring development are inconclusive. This study aimed to evaluate the influences of a diet high in fat on mother-pup interaction, in two generations, and its early and late effects in the offspring, connecting them to the opioid system. HF dams show decreased milk ejections and higher expression of opioid receptors in the hypothalamus. Overall, HF offspring had higher cholesterol levels, less serum leptin, higher expression of peptides related to food intake, and were lighter. Therefore, maternal intake of HF diet promoted metabolic, behavioral and gene expression alterations in the mother and her offspring, even though these animals did not become obese.

Há evidências de que os endocanabinoides e os receptores CB1 estejam envolvidos em diversos transtornos emocionais, dentre eles a ansiedade e a depressão. A interação deste sistema endocanabinoide com outros neurotransmissores, como a serotonina (5-HT), tem sido alvo de diversos estudos, uma vez que o aumento na atividade deste sistema promove respostas ansiolíticas e antidepressivas. Alguns estudos mostraram que a porção ventromedial do hipotálamo modula algumas respostas defensivas, como fuga e a imobilidade tônica, respostas estas eliciadas pelos animais frente a situações de medo intenso, como ocorre em um confronto com um dado predador. Dentro desta perspectiva, o presente estudo teve por objetivos avaliar o efeito do tratamento crônico durante 21 dias com canabidiol (CBD) sobre as respostas defensivas em cobaias (Cavia porcellus), evocadas diante de um predador natural. Avaliamos, ainda, o efeito da microinjeção intradiencefálica de AM251 (antagonista de receptores CB1; 100pmol/0,2µl), de 6-I-CPS (antagonista de canais iônicos TRPV1; 9nmol/0,2µl), de WAY-100635 (antagonista 5-HT1A; 0,37nmol/0,2µl) e seus respectivos veículos em diferentes grupos de cobaias, após o tratamento crônico com canabidiol sobre as respostas defensivas evocadas diante do predador. Os resultados mostraram que, muito embora o tratamento crônico com CBD não tenha atenuado a resposta de imobilidade tônica (IT), devido ao fenômeno de habituação da resposta, diminuiu a expressão de outras respostas comportamentais, como a atenção defensiva e afuga orientada para a toca, promovendo, pois, um efeito anxiolítico e panicolítico. Ademais, a microinjeção de AM251 tendeu a abolir o efeito ansiolítico causado pelo tratamento crônico com CBD, potencializando as respostas defensivas diante de um predador natural. Tais resultados indicam que o CBD promove seu efeito farmacológico também mediante tratamento crônico, e que os receptores canabinoides do tipo CB1 do hipotálamo ventromedial parecem desmpenhar algum um papel nesse mecanismo de ação. / Evidence has shown that endocannabinoids and CB1 receptors are involved in several emotional disorders, including anxiety and depression. The endocannabinoid system and its interaction with other neurotransmitters such as serotonin (5-HT) has been the subject of several studies, since the increase in the activity of this system promotes anxiolytic and antidepressant responses. Some studies have shown that the ventromedial division of the hypothalamus modulates some defensive responses such as flight and tonic immobility, elicited by preys experiencing intense fear-like reactions when facing dangerous situations, as confrontation with a given predator. From this perspective, this study aimed to evaluate the effect of chronic treatment for 21 days with cannabidiol (CBD) on the defensive responses displayed by guinea pigs (Cavia porcellus), in the presence of a natural predator. We also studied the effect of intradiencephalic microinjection of AM251 (a CB1 receptor antagonist; 100pmol / 0.2?L), 6-PSC-I (TRPV1 ion channel antagonist; 9nmol / 0.2?L), or WAY- 100635 (antagonist 5- HT1A; 0.37nmol / 0.2?L) and their respective controls in different groups of mice after chronic treatment with cannabidiol on the defensive responses evoked in the presence of the predator. The results showed that although the chronic treatment with CBD attenuated tonic immobility response (IT) and other behavioural responses, such as defensive attention and oriented escape behaviour, promoting a significant anxiolytic and panicolytic effect. In addition, intra-hypothalamic microinjection of AM251 exert a potential impairment of the antipanic effect caused by chronic treatment with CBD, increasing the defensive responses displayed in the presence of the predator. These results indicate that the CBD also promotes its pharmacological effect upon chronic treatment, and that medial hypothalamus CB1 receptors seem to play a role in its mechanism of action.

<p>The purpose of this investigation was to study sexual function in women with neurological disorders at fairly distinct and separate locations. The dissertation comprises descriptive, retrospective, quantitative studies on sexual functioning in women with hypothalamo-pituitary disorders (HPD) (<i>n</i>:48), multiple sclerosis (MS)(<i>n</i>:47), and insulin-dependent diabetes mellitus (IDDM) (<i>n</i>:42). The results werecompared with those in an age-matched control group (C) (<i>n</i>:42), and as reported by representative Swedish women (<i>n</i>:742) in the Swedish sex survey SiS). The studies were based on comprehensive interviews, neurological examinations, incl. Vibration Perception Thresholds (IDDM), concentrations of prolactin and testosterone in serum (HPD), and a checklist on life satisfaction (IDDM, C, and SiS).</p><p>Sexual dysfunction was prevalent in almost all women with HPD and MS, and in 40% of the IDDM group. The problem of insufficient vaginal lubrication was more common in those with neurological disorders than among women in the SiS group. Sexual problems caused by reduced libido and orgasmic difficulties were more commonin the HPD and MS groups than in the SiS group. In the HPD group, women with intrasellar adenomas had better sexual function than women having expansively growing pituitary adenomas with both intra- and suprasellar extension. Normal serum testosterone values correlated to masturbation activity. Amenorrhea and older age werecorrelated with sexual problems in all groups. In the MS group, symptoms of a weak pelvic floor and of bladder and bowel dysfunction were correlated with reduced lubrication and orgasmic ability. In the IDDM group, signs of autonomic neuropathy were correlated with sexual dysfunction. Concerning life satisfaction generally,proportionately fewer women with IDDM were satisfied or very satisfied, though differing significantly from the other two groups in only two domains of life: contacts with friends, and physical health.</p>

Artificial divergent selection of chickens for high and low body weight at 8 weeks of age has produced two lines: the high (HWS) and low (LWS) body weight chicken lines. In addition to the difference in body weight, the lines show extreme differences in feeding behaviour and body composition. The aim of this study was to uncover the genetic and molecular factors that contribute to and determine these differences, especially regarding body energy regulation and appetite. In papers I and II, genome-wide gene expression in a brain sample containing hypothalamus and in dissected hypothalamus was analysed using DNA microarray and qRT-PCR. We found that levels of differential expression were generally moderate, which was consistent with the idea that polygenic factors were involved in the establishment of the chicken lines. Genes associated with neural plasticity, lipid metabolism and body energy regulation were differentially expressed. This result indicated that the neural systems regulating feeding behaviour and body weight were altered in the chicken lines. However, genes that were involved in the central melanocortin system were not systematically differentially expressed. Interestingly, the biggest differences in expression between the lines found in endogenous retrovirus sequences of the ALV subgroup E. Thus, in paper III, we characterized the number of integrations, the expression of ALVE retroviral elements and their effects on body weight. A significant correlation between low body weight and high ALVE expression was observed in female F9 birds from an HWS x LWS advanced intercross line. This implied that ev-loci contributing to increased ALVE expression levels were genetically linked to loci influencing the low body weight of the pullets. In paper IV, the carnitine palmitoyltransferase-1b gene (CPT1B), which was highly differentially expressed in the hypothalami, was investigated. We mapped chicken CPT1B to the distal tip of chromosome 1p. The levels of CPT1B mRNA in the HWS line were higher in the hypothalamus and lower in muscle than in the LWS line. This pattern of differential expression indicates that this gene could contribute to the remarkable phenotypic differences between HWS and LWS chickens. However, comparison with quantitative trait loci data showed that the expression of CPT1B is a trans effect, rather than a direct causative locus. In conclusion, the data suggested that the long-term selection for body weight resulted in differential gene expression in the brains of the selected chicken lines. These results may have relevance for the poultry industry and will also contribute to increasing knowledge about human diseases such as obesity and anorexia.

Background: Subtle and inconsistent differences in hypothalamic-pituitary-adrenal (HPA) axis activity have been reported for patients with panic disorder. While these patients show little or no alterations in basal ACTH and cortisol levels, it has been hypothesized that HPA hyperresponsivity was a trait in panic patients when exposed to novel and uncontrollable stimulation. Methods: Thirty-four patients (23 females, mean age 35 yrs) diagnosed with panic disorder were compared to 34 healthy controls matched for age, gender, smoking status, and use of oral contraceptives. Both groups were exposed twice to a potent laboratory stress protocol, the Trier Social Stress Test (TSST) on consecutive days. Free salivary cortisol levels and heart rate responses were repeatedly measured before and following the TSST. In addition, the cortisol awakening response (CAR) was assessed to further investigate HPA reactivity in PD patients. Results: While the TSST induced similar heart rate stress responses in both groups, cortisol responses were clearly absent in the panic patients with normal responses in the controls (F(1.96, 66) = 20.16; p < 0.001). No differences in basal cortisol levels were observed in the extended baseline period. The same cortisol stress non-response patterns were observed when patients with/without comorbid depression, or with/without psychotropic medication were compared. In contrast to their non-response to the psychosocial stressor, panic patients showed a significant CAR. Conclusion: These findings provide strong evidence to suggest that PD patients present with a striking lack of cortisol responsivity to acute uncontrollable psychosocial stress under laboratory conditions. This unresponsiveness of the HPA axis appears to be rather specific, since a normal CAR in the morning could be documented in these patients. Thus, the present results do not support the hypothesis that PD patients show a trait HPA hyperresponsiveness to novel and uncontrollable stimulation. In contrast, the data provide support for a hyporesponsive HPA axis under emotional stress in PD patients.