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The Impact of Repeated Stress on Neuropeptidergic Regulation of Monoamine Systems

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The Impact of Repeated Stress on Neuropeptidergic Regulation of Monoamine Systems The Impact of Repeated Stress on Neuropeptidergic Regulation of Monoamine Systems Julia Cristine Lemos A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2012 Reading Committee: Charles Chavkin, Co-Chair Paul Phillips, Co-Chair David Perkel John Neumaier Program Authorized to Offer Degree: Neurobiology and Behavior University of Washington Abstract The Impact of Repeated Stress on Neuropeptidergic Regulation of Monoamine Systems Julia Cristine Lemos Co-Chairs of Supervisory Committee: Professor Charles Chavkin, Department of Pharmacology Professor Paul Phillips, Department of Psychiatry and Behavioral Science To promote an organism’s evolutionary fitness, neurocircuitry has developed that encodes and responds to stressors. Stress motivates appropriate responding to environmental challenges through a diverse array of mechanisms that integrate cognitive, emotional and motor functions. Neuropeptides are released in an activity- dependent fashion throughout the brain in response to acute stressors and other arousing environmental stimuli and impinge on monoaminergic systems to allow processing of stimuli and produce appropriate behavioral responses. Here I show that corticotropin releasing factor (CRF) causes the release of dynorphin, the endogenous ligand for kappa opioid receptors, in limbic brain regions including the basolateral amygdala (BLA) and dorsal raphe nucleus (DRN) to produce a negative affective state. The DRN is the major serotonergic projection nucleus in the brain. We demonstrate that the dynorphin-KOR system has net inhibitory regulation of serotonergic DRN neuronal excitability. While CRF acting in some limbic regions produces negative affect, when CRF acts specifically in the nucleus accumbens, a subcortical region that is critical for interfacing cognitive, emotional and motor inputs, it promotes appetitive behaviors. I found that intra-nucleus accumbens infusions of CRF produce conditioned place preference and promotes exploration of a novel stimulus. CRF does this by potentiating dopamine release within the nucleus accumbens through co-activation of CRF R1 and R2. Severe or chronic stress produces an affective shift in responses to subsequent stressors from engagement to withdrawal, a hallmark symptom of Major Depressive Disorder. Stressful trauma may lead to this shift by amplifying the negative affective component of stress and ablating the motivation component. Repeated stress leads to several neuroadaptations, many of which target the functionality of stress-related neuropeptides themselves. I discovered that repeated swim stress dysregulates both CRF and dynorphin-KOR regulation of dopamine and serotonin systems respectively. Stress exposure causes a net reduction in KOR-mediated inhibitory regulation of serotonergic neuronal excitability through a p38α MAPK-dependent mechanism. While stress-induced alterations in KOR regulation of serotonin cells was relatively transient, stress-induced ablation of CRF’s ability to potentiate dopamine release was remarkably long-lasting, not recovering for at least 90 days. The behavioral consequence of this long-term dysregulation of CRF-dopamine interactions was a switch in the subjective perception of CRF actions in the nucleus accumbens such that CRF was now experienced as aversive. This dysregulation of CRF signaling in the nucleus accumbens is dependent on stress-induced glucocorticoid activity. The following body of work characterizes how neuropeptides impinge on monoamine systems to produce affect and motivated behaviors in responses to arousing environmental stimuli. Importantly, offers biological substrates that underlie the etiology of stress-induced psychopathologies such as Major Depressive Disorder. i Table of Contents List of Figures .................................................................................................................. iii List of Tables ................................................................................................................... v Chapter 1: Introduction .................................................................................................... 1 Depression and Anxiety Disorders: Etiology and evolution .......................................... 1 Early conceptual framework of Depression .............................................................. 2 Stress-induced Depression ....................................................................................... 4 Models of stress-induced depression ....................................................................... 7 Molecules and systems that underlie stress and depression ..................................... 10 The HPA axis .......................................................................................................... 10 Norepinephrine, Serotonin and Dopamine .............................................................. 12 Stress-related neuropeptides .................................................................................. 23 Chapter 2: CRF receptor activation engages the Dynorphin-KOR system to produce a negative affective state .................................................................................................. 38 Introduction ................................................................................................................ 38 Methods ..................................................................................................................... 40 Results ....................................................................................................................... 42 Discussion .................................................................................................................. 43 Chapter 3: Stress exposure produces a switch from appetitive to aversive signaling by CRF in the nucleus accumbens .................................................................................... 49 Introduction ................................................................................................................ 49 Results and Discussion .............................................................................................. 50 Methods ..................................................................................................................... 61 Chapter 4: Repeated stress dysregulates kappa opioid receptor signaling in the dorsal raphe through a p38 MAPK dependent mechanism ...................................................... 90 Introduction ................................................................................................................ 90 Methods ..................................................................................................................... 92 Results ....................................................................................................................... 98 Discussion ................................................................................................................ 106 Chapter 5: Bi-directional alteration of 5-HT1A autoreceptor function following different stress-exposure paradigms requires activation of the kappa opioid system. ............... 122 ii Introduction .............................................................................................................. 122 Methods ................................................................................................................... 123 Results ..................................................................................................................... 126 Discussion ................................................................................................................ 128 Chapter 6: Dissertation Conclusions ........................................................................... 133 References .................................................................................................................. 145 iii List of Figures Figure 2. 1. CRF-induced KORp-ir in limbic brain regions is blocked by norBNI pre- treatment. ...................................................................................................................... 45 Figure 2.2. CRF-induced KORp-ir is absent in animals lacking the gene for preprodynorphin (Dyn -/-). ............................................................................................. 46 Figure 2.3. CRF-induced KORp-ir can be prevented by blockade of either CRF R1 or CRF R2. ........................................................................................................................ 47 Figure 3.1.Cellular localization of CRF peptide, CRF R1 and CRF R2 in the nucleus accumbens. ................................................................................................................... 67 Figure 3.2. CRF peptide is localized cholinergic interneurons throughout the nucleus accumbens. ................................................................................................................... 68 Figure 3.3. CRF R1 co-localization to TH positive fibers. .............................................. 69 Figure 3.4. CRF R2 antibody validation and localization in the nucleus accumbens of WT littermate and R2 KO mice. ..................................................................................... 70 Figure 3.5. CRF increases dopamine release in the nucleus accumbens through co- activation of CRF R1 and R2. .......................................................................................
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