Year: 2012
Type: dissertation
Abstract: Mood disorders, including anxiety or depression, are one of the most prevalent disorders in the modern society. Underlying the etiology of these disorders is, among other factors, a chronic exposure to stress. Stress can be defined as a challenge to the organism’s homeostasis that prepares the organism to a “fight or flight” situation. However, when the stressor is too intense or too prolonged in time, there is a maladaptation of the organism that is associated with a series of morphological and molecular alterations in the central nervous system. Among the brain areas associated with the response of the organism to stressful stimuli, the bed nucleus of the stria terminalis (BNST) is one of the most important for stress-related anxiety. The BNST plays a critical role in the integration and modulation of other limbic inputs; namely from the Infralimbic Cortex (ILCx), Medial and Central Amygdala (CeA) or hippocampus; and in turn it sends projections to the paraventricular nucleus of the hypothalamus, a key region in the activation of the hypothalamic-pituitary-adrenal (HPA) axis that leads to the activation of the hormonal response to stress. Additionally, the BNST has a critical role in activation of stressrelated behaviors and is particularly associated with the development of stress-related anxiety. Previous work from our lab has shown that when rats are presented with a stress-model of anxiety (CUS: chronic unpredictable stress), the BNST of these animals suffers a series of morphological alterations. In the present work we further characterized the alterations induced by CUS in the BNST, particularly at the molecular and electrophysiological level. We have shown that stress induces alterations in several neurotransmitter systems important for the stress response: decrease of the corticotrophin-releasing factor receptor 1 (CRFR1) while increasing the mRNA levels of receptors for glutamate (NR2B), GABA (GABAA receptor) and corticotrophinreleasing factor receptor 2 (CRFR2). At the functional level, we attempted to add new insights to how the neuronal circuit between ILCx and BNST and CeA and BNST was affected by stress exposure. We observed that stress induces a hyperactivation of neurons of the BNST by increasing the excitatory inputs from ILCx while decreasing the inhibitory inputs from CeA. Additionally, we further explored the CeA-BSNT pathway in the development of anxiety behavior by performing excitotoxic lesions in CeA in animals that were later submitted to CUS. CeA is the major extra-hypothalamic source of corticotrophin-releasing factor (CRF), a key player in the stress response and particularly in anxiety-behavior with several authors showing that the activation of CRFR1 is able to induce anxiety-like behavior. For this, we hypothesized that a lesion in CeA would lead to reduced CRF innervation in the BNST and consequently decreased anxietylike behavior. Our observations show that the lesions allowed, indeed, an attenuation of the stress-related anxiety, showing that an intact innervation between CeA and the BNST is essential for a full manifestation of anxiety associated with stress. Together, our findings allowed us to better understand the role of the BNST in the response to stress, showing that stress triggers a hyperactivation of the BNST while altering the mRNA expression of several important receptors. In particular, the decrease of CRFR1 in the BNST can be the result of increased CRF inputs arriving in the BNST from the CeA and that are essential for the manifestation of stress-related anxiety. The observation that a lesion in CeA, and putatively a decrease in CRF input into the BNST, can attenuate the development of anxiety-like behavior supports the essential role of CRF in the expression of stress-induced anxiety.
Author: Ana Paula Ventura Silva
Language: English
Subfield: Behavioral Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2267723473