The dorsal raphe nucleus (DR) is critical to serotonin (5-HT) neurotransmission, as it contains the brain's major source of ascending 5-HT innervation. Corticotropin-releasing factor (CRF) is among the many modulators of 5-HT transmission in the DR, but its effects on this system are still not completely clear. We hypothesize that chronic and acute stressors each have unique means of affecting 5-HT neurotransmission in the brain - including physiological effects in the DR. We propose that, in a state of dysregulated 5-HT neurotransmission where circuits are more sensitive to stress effects, changes elicited by stressors will be more profound and may lead to long-lasting dysregulation of 5-HT neurotransmission. Using a genetic model of elevated stress sensitivity and a multi-level experimental approach, we will assess effects of these stresses on DR physiology and 5-HT neurotransmission. Analysis will utilize stress-sensitive transgenic mice deficient in the CRF type 2 receptor (CRFR2). DR tissue from normal and stress-sensitive animals exposed to acute and chronic stress will be analyzed using in situ techniques to elucidate how stress and the CRF system are involved in genetic regulation. As prolonged alteration in 5-HT signaling can change DR target nuclei in the brain, 5-HT receptor analysis and 5-HT levels will be analyzed at these sites using receptor autoradiography and tissue content for 5-HT levels. Additionally, In situ and autoradiographic techniques will determine how raphe input regions are altered in the stress-sensitive animal model, and how stress exposure influences CRF and glucocorticoid expression in these nuclei. Whole cell electrophysiology will analyze cellular characteristics of 5-HT and non 5-HT cells in the DR, as well as how CRF can induce pre and postsynaptic alterations in these cells. The above techniques will be combined with several behavioral testing paradigms, which will allow a direct test of how observed changes in the CRF/5-HT interaction may manifest at the level of the whole organism. Behavioral responses to stress tests will then be assessed under chronic and acute administration of serotonin reuptake inhibitors, which will serve to enhance 5-HT in terminal regions of the DR.
While experiencing stress is an everyday aspect of life, periods of chronic stress and traumatic life experiences, can provoke severe mood disorders. Corticotropin-releasing factor (CRF) is a stress neurotransmitter that has been implicated in many of these cases, and is thought to enhance mood disorder induction. This body of work will analyze how this protein is important to normal brain function, and how natural genetic variation can alter its function and change the risk of developing mood disorders. ? ? ?
| McEuen, Jonathan G; Semsar, Katharine A; Lim, Maria A et al. (2009) Influence of sex and corticotropin-releasing factor pathways as determinants in serotonin sensitivity. Endocrinology 150:3709-16 |
| McEuen, Jonathan G; Beck, Sheryl G; Bale, Tracy L (2008) Failure to mount adaptive responses to stress results in dysregulation and cell death in the midbrain raphe. J Neurosci 28:8169-77 |
