Orientador: Fernanda Klein Marcondes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-15T12:47:47Z (GMT). No. of bitstreams: 1 Costa_Rafaela_M.pdf: 755140 bytes, checksum: 92fa87f3ac79484f4ed67811cdc9d446 (MD5) Previous issue date: 2010 / Resumo: Problemas emocionais como ansiedade e depressão, relacionados ao estresse, estão cada vez mais presentes na sociedade moderna, e o suporte social, mais especificadamente suporte familiar, pode exercer um importante papel em atenuar os efeitos de diversos estressores. Em modelos animais o enriquecimento ambiental tem sido utilizado para melhora do bem estar animal. O objetivo deste estudo foi avaliar os efeitos do enriquecimento ambiental por meio da estimulação tátil em ratos submetidos ou não a estresse crônico. No Capítulo I, foi evidenciado que a estimulação tátil diminuiu a ansiedade e aumentou as respostas indicadoras de aprendizado e memória em ratos jovem-adultos. No Capítulo II, foram avaliados os efeitos do estresse crônico moderado e imprevisível e da estimulação tátil sobre respostas comportamentais (ansiedade, anedonia, aprendizado e memória) e sobre o perfil lipídico. O estresse aumentou a secreção de corticosterona avaliada quinze dias após o fim do estresse; induziu anedonia evidenciada pela diminuição da preferência pela sacarose 1%; aumentou a atividade locomotora; teve efeito negativo sobre o aprendizado e memória; e aumentou a concentração sérica de triglicerídeos, colesterol total e lipoproteína de baixa densidade (LDL). A manipulação diminuiu a ansiedade em animais submetidos ou não ao estresse crônico; diminuiu a secreção de corticosterona induzida pelo estresse e cancelou a redução do aprendizado e retenção de memória induzida pelo estresse crônico. Os resultados obtidos mostram que a estimulação tátil de ratos adultos jovens produziu efeitos comportamentais positivos que podem melhorar o bem-estar animal e diminuir efeitos deletérios induzidos pelo estresse crônico. / Abstract: Emotional problems such as stress related anxiety and depression, are becoming increasingly present in modern society, and social support, more specifically familiar support, can play an important role in attenuating the effects of various stressors. In animal models environmental enrichment has been used to improve animal welfare. The aim of this study was to evaluate the effects of environmental enrichment by handling, in rats submitted and those not submitted to chronic stress. In chapter 1 it was shown that handling diminished anxiety, and enhanced learning abilities and memory indicating response in young-adult rats. In chapter 2 the effects of handling on behavioral (anxiety, ahnedonia, learning and memory) and metabolic responses induced by chronic mild unpredictable stress. Whereas stress raised the corticosterone secretion evaluated fifteen days after the end of stress; induced ahnedonia evidenced by a 1% decrease in sucrose preference; increased locomotor activity; had negative effects on learning and memory; and raised the serum concentration of triglycerides, total cholesterol and low density lipoprotein (LDL). Handling reduced the anxiety in animals both when they were and were not submitted to chronic stress; diminished the corticosterone secretion induced by the stress and cancelled the reduction of learning and memory retention induced by the chronic stress. The results obtained showed that the handling of young-adult rats produced positive behavioral effects capable of improving the animal's welfare and diminishing the deleterious effects induced by chronic stress. / Mestrado / Fisiologia Oral / Mestre em Odontologia

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Seven rats were trained on Fixed Ratio 20 and two on Fixed Ratio 12 Escape Schedules until a stable baseline was established. Five of the subjects were administered gold thioglucose, three received gold thiomalate, and one was injected with gold, gold thioglucose, and gold thiomalate, allowing for an intrasubject comparison. Colloidal gold appeared to suppress response rate for one or two sessions, while gold thioglucose and gold thiomalate suppressed normal response rates from several to a number of sessions. This response rate suppression was often followed by gradual recovery, although in several subjects recovery of response rate could not be achieved prior to termination of the experiments. The drop in response rate was more consistent for the gold thiomalate-treated subjects than for the gold thioglucose group. A toxic effect of the injected compounds was manifest as a loss of weight, which was regularly associated with a drop in response rate. This weight reduction was greatest in the gold thiomalate-injected animals, indicating that gold thiomalate is probably more toxic than gold thioglucose to rats. Tolerance was developed for gold thioglucose and gold thiomalate, as indicated by smaller response rate decrements after repeated injections of the compound. As a consequence of repeated drug administrations, the animals demonstrated that they could tolerate a 1 milligram per gram of body weight dose of gold thioglucose if the dosage was increased gradually from a low-dosage initial injection. This dosage of 1 milligram per gram of body weight is double the amount required to produce demonstrable hypothalamic lesions in the rat. Previous investigations have failed to demonstrate this degree of tolerance in rats, primarily because the animals did not have the opportunity to adapt themselves to this treatment. Decrease in spontaneous activity on a balance beam apparatus was observed in several rats following administration of the larger gold thioglucose dosages (i.e., 0.5 milligrams per gram of body weight to 1.0 milligram per gram of body weight), as well as following the administration of gold thiomalate. Dosages of 20 milligrams to 50 milligrams of gold chloride were lethal to two rats. The heavy dosage of gold thioglucose administered to the female rat subjects at Utah State University (i.e., up to 1 mg per gram of body weight), although potentially producing extensive hypothalamic lesions, did not produce demonstrable hyperphagia or obesity, probably due to the anorexia and hypophagia associated with liver and kidney damage,which could counteract the hyperphagia expected to be associated with the extensive hypothalamic lesions produced at dosages over 0.5 milligram per gram of body weight following gold thioglucose administration.

Major depressive disorder (MDD) features symptoms spanning cognitive, affective, behavioral, and physiological domains. While many of the neural circuit disruptions mediating emotional and cognitive disturbances in depression have been described, far fewer studies have explored neurobiological mechanisms underlying its associated motor or physiological impairments. Emotionally motivated behaviors, including responses to stress, are characterized by concomitant somatomotor actions and autonomic changes that require intricate coordination of the motor and autonomic systems. Prior investigations by our group used a pseudorabies virus (PRV)-mediated retrograde tract-tracing approach to identify brain regions with parallel descending premotor and presympathetic efferents that play a role in integrating somatomotor and sympathetic functions. Several nodes of this circuitry, including the hypothalamic paraventricular nucleus (PVN), locus coeruleus (LC), and periaqueductal gray (PAG), are implicated in responses to stressful and emotionally salient stimuli. Based on this observation, it was hypothesized that these parallel descending circuits shape responses to diverse stressors and are altered in clinical depression and comorbid anxiety disorders. To explore this possibility, the experiments in this dissertation used two recombinant PRV strains to trace polysynaptic premotor and presympathetic pathways innervating sympathectomized skeletal muscle and adrenal gland, respectively, in two rat models with heritable differences in emotionality and stress reactivity: the Wistar-Kyoto (WKY) rat and the selectively bred Low Novelty Responder (bLR) rat. During our initial neuroanatomical investigations in the PVN, we observed that both WKY and bLR rats displayed significant decreases in the quantity of PVN neurons with premotor projections to skeletal muscle compared to their respective control strains. Labeling of neurons with presympathetic projections to adrenal gland or dual-labeled polysynaptic projections to both motor and sympathetic targets was not altered in either model. Our subsequent neuroanatomical studies focused on comparing premotor efferent projections from LC and PAG. In LC, fewer premotor efferent projections to skeletal muscle were observed in both models. There were also reductions in the number of premotor efferents in the four subdivisions of the PAG. WKY rats had significantly fewer premotor projections in the dorsomedial (DMPAG), lateral (LPAG), and ventrolateral (VLPAG) subdivisions, while bLR rats had significantly fewer premotor efferents in dorsolateral (DL)PAG. The final experiments in this dissertation sought to determine whether one potential therapeutic intervention, environmental enrichment during late childhood and adolescence, can improve emotional behavior disturbances and reverse premotor circuit alterations in bLR rats. Rearing young bLR rats in conditions with increased environmental complexity partially but incompletely improved aspects of depression- and anxiety-relevant behaviors and their corresponding PVN premotor circuit abnormalities. Cumulatively, these findings highlight somatomotor circuits in several brain structures involved in responses to stress and emotional stimuli that could be implicated in mediating motor-related impairments in clinical depression. / Doctor of Philosophy / Depression is a common and complex illness that features many types of impairing symptoms. Some of these symptoms involve functions regulated by the somatic motor system, which controls movement, and the autonomic nervous system, which regulates many basic bodily functions (for example, heart rate and blood pressure) that occur outside of our conscious control. The ability to coordinate the actions of these two systems is important for many behaviors, including how we respond to emotional or stressful situations. Past experiments in our laboratory used a type of virus (pseudorabies virus, PRV) that travels backwards through neural circuits containing multiple neurons and allows us to label parts of the brain that project to peripheral areas regulated by the somatic motor system (i.e., hindlimb skeletal muscle), the autonomic nervous system (i.e., adrenal gland), or both. These labeling experiments identified neurons in these motor and autonomic circuits in several parts of the brain, including the paraventricular nucleus of the hypothalamus (PVN), locus coeruleus (LC), and periaqueductal gray (PAG). Of note, all of these structures are involved in regulating responses to stressful or emotional situations. This observation led us to hypothesize that motor and autonomic projections from these areas of the brain are important for regulating how we respond to stress and might be altered in individuals suffering from depression. To test this idea, we labeled motor- and autonomic-projections with PRV in two separate rat models with a genetic disposition for emotional behaviors that resemble symptoms of clinical depression or anxiety. When we analyzed the PVN, LC, and PAG of rats with depression-relevant behaviors, we discovered that each of these brain areas contained fewer labeled neurons with motor projections to skeletal muscle. Based on these findings, we were interested in exploring whether enriching or stimulating experiences during early life had the potential to reverse deficits in the PVN motor projections and improve emotional behavior in one of our rat models for depression. Although enrichment partially improved behavioral and circuit-level outcomes, it was not fully effective. Taken together, our experimental findings highlight disruptions of motor projecting circuits in several brain structures implicated in mediating responses to stressful or emotional stimuli in two rat models relevant to depression and anxiety disorders. These motor circuit disruptions could be implicated in mediating motor-related symptoms observed in clinically depressed patients.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed to pregnant women suffering with depression, although the long-term impact of these medications on exposed offspring are poorly understood. Perinatal SSRI exposure alters human offspring's neurodevelopment and increases risk for psychiatric illness in later life. Rodent studies suggest that perinatal SSRI-induced behavioral abnormalities are driven by changes in the serotonin system as well as epigenetic and transcriptomic changes in the developing hippocampus. Studies in humans and experimental animal models shows that perinatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants can lead to abnormal emotional behaviors in adulthood, with a majority of the studies focusing on male offspring behavior. In this dissertation, we assessed whether SSRI-induced neurobiological and behavior changes occur in both sexes and whether these changes emerge in the juvenile period. In addition, we observed gene expression changes in the hippocampus related to metabolism and synaptogenesis. Given that, we hypothesized that the behavioral impacts following SSRI exposure may be driven, in part, by these processes. Juvenile offspring exposed to SSRIs in early life, regardless of sex, displayed increased anxiety-like behavior and altered social play. In adulthood, perinatal SSRI-exposed male and female offspring displayed increased passive coping in the Forced Swim Test but showed no differences in anxiety-like behavior. In addition to emotional behaviors, dams with a history of early-life SSRI exposure exhibited decreased maternal care, including diminished arched-back nursing, reduced licking and grooming of pups, and increased behavioral inconsistency. Alongside these behavioral changes, during infancy, we observed increased metabolic activity in the dentate gyrus of the hippocampus and decreased activity in the basolateral amygdala. During adulthood, the CA and dentate gyrus of the hippocampus in both sexes and the paraventricular nucleus of the hypothalamus in female offspring were more metabolically active in exposed offspring. We also observed differences in inter-correlations of limbic region COX activity in perinatal SSRI exposed and control offspring. Finally, a major gene altered by perinatal SSRI exposure is the G-protein coupled receptor Brain Angiogenesis Inhibitor 3 (BAI3). As a G-protein coupled receptor (GPCR), it is an interesting potential therapeutic target, since most recently approved drugs in the central nervous system act on GPCRs. Data present here show that perinatal exposure to the SSRI citalopram increases mRNA expression of Bai3 and related molecules (including its C1ql ligands) in the early postnatal dentate gyrus of male and female offspring. Transient Bai3 mRNA knockdown in perinatal SSRI-exposed dentate gyrus lessened behavioral consequences of perinatal SSRI exposure, leading to increased active stress coping. To determine translational implications of this work, we examined expression of BAI3 and related molecules in hippocampus and prefrontal cortex from patients that suffered with depression or schizophrenia relative to healthy control subjects. We found sex- and region-specific changes in mRNA expression of BAI3 and its ligands C1QL2 and C1QL3 in men and women with a history of psychiatric disorders compared to healthy controls. Together, these results suggest that abnormal BAI3 signaling may contribute to molecular mechanisms and metabolic changes that drive adverse effects of perinatal SSRI exposure and show evidence for alterations of BAI3 signaling in the hippocampus of patients that suffer depression and schizophrenia. Therefore, these data suggest that investigate the Bai3 network may be an exciting route as a potential therapeutic target for depression. / Doctor of Philosophy / Environmental factors during development play an important role in shaping the growth, structure, and function of the brain and as well behavior of an organism. Some of these factors that alter development which can negatively impact behavior include early life exposure to stress, toxins, or drugs. In this dissertation, we will discuss the impact of early life exposure to antidepressants. Many people take selective serotonin reuptake inhibitor (SSRI) antidepressants as a way to treat their depression during pregnancy. It is important to note that is it essential to treat depression during pregnancy, since depression can drastically impact the behavior of the offspring. However, while considering this, it is also critical to understand how exposure to SSRI antidepressants influences behavior of the offspring. SSRI antidepressants work by increasing the neurotransmitter serotonin in the brain and body. Previous work has demonstrated that early life exposure to SSRIs can alter the way the serotonin system develops in the brain and also increases the chance of children to develop emotional disorders (e.g., depression and anxiety). The same is true in rodents, a model organism in research, since we see an increase in depression-related behavior in our rats that are exposed to SSRI antidepressants in early life. Data shown in this dissertation support this claim, as we see altered behavior not only in adult but juvenile male and female rodent offspring. In adults, we found increased depression-related behavior and social deficits (e.g., maternal care). In the juvenile offspring, we saw alterations of social play behaviors and increase in anxiety-related behavior. Given this observation, we were interested in determining what occurs in the brain that alters these emotional and social behavior. To do this, we observed gene changes in the brain following early life SSRI exposure. We found changes in genes related to metabolic activity and communication between neurons (i.e., synaptogenesis). As a follow up to this study, we next wanted to characterize the metabolic and morphological (i.e., structural) changes that as a result of early life SSRI exposure. We found increased activity in several regions of the brain associated with emotion, including the hippocampus, amygdala, and hypothalamus. In addition, we did not find any morphological changes in the hippocampus, although ongoing studies will continue to analyze other brain regions. Lastly, when considering specific pathways whereby early life SSRI exposure can alter emotional and social behavior, we are interested in identifying potential therapeutic targets. One set of proteins (G-coupled protein receptors; GPCRs) are interesting targets to investigate, since most FDA approved medications in the central nervous system target these GPCRs. Interestingly, one GPCR stood out in our gene studies: Bai3. In this dissertation, we present data to show that the Bai3 network is altered in rodents exposed to SSRIs in early life. In addition, we show that manipulating Bai3 in early life can help to improve depression-related behavior. Lastly, to understand if Bai3 could play a role in depression, we assessed human postmortem samples to see if Bai3 alterations occur in the depressed human condition. In this study, we found increased Bai3 levels in human male sample relative to healthy patients. Overall, the work presented here shows that early life SSRI exposure negatively impacts emotional and social behaviors in rodents. Coinciding with these behavior changes, we find differences in gene expression and metabolic activity, thus providing us with a potential mechanism whereby early life SSRI exposure influences behavior. It is possible that by manipulating these aspects of brain function represent fruitful options for therapeutic targets for depression and other mood disorders.

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The hippocampus is known to play a critical role in episodic memory function. Understanding the relation between electrophysiological activity in a rat hippocampus and rat behavior may be helpful in studying pathological diseases that corrupt electrical signaling in the hippocampus, such as Parkinson’s and Alzheimer’s. Additionally, having a method to interpret rat behaviors from neural activity may help in understanding the dynamics of rat neural activity that are associated with certain identified behaviors. In this thesis, neural networks are used as a black-box model to map electrophysiological data, representative of an ensemble of neurons in the hippocampus, to a T-maze, wheel running or open exploration behavior. The velocity and spatial coordinates of the identified behavior are then predicted using the same neurological input data that was used for behavior identification. Results show that a nonlinear autoregressive process with exogenous inputs (NARX) neural network can partially identify between different behaviors and can generally determine the velocity and spatial position attributes of the identified behavior inside and outside of the trained interval