Browsing by Subject "Brain-Derived Neurotrophic Factor"
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Exploring Mechanisms of Depression-Related Behavior and Rapid Antidepressant Action(2011-12-12) Autry, Anita Ellen; Monteggia, LisaMajor Depressive Disorder is a serious mental disorder with a profound disease burden, particularly in the United States. Intriguingly, this disease is almost twice as prevalent in females compared to males. Presently, antidepressant treatment for patients with Major Depressive Disorder requires chronic use and first-line treatment is often ineffective. The neurotrophic hypothesis of depression suggests that a) neurotrophins, in particular brain-derived neurotrophic factor, are necessary for maintaining normal mood states and that b) increases in neurotrophin signaling mediate therapeutic effects of clinical antidepressants. In the laboratory, we have explored aspects of the neurotrophic hypothesis of depression and made progress toward understanding the role of brain-derived neurotrophic factor in depression-related animal models as well as its role in the cellular mechanisms underlying antidepressant efficacy. First, we examined whether loss of brain-derived neurotrophic factor in forebrain neurons impacted susceptibility to chronic stress, an animal model of depression, in a gender-specific manner. Next we examined the contribution of dorsal raphe nucleus brain-derived neurotrophic factor signaling on traditional antidepressant efficacy. Finally, we uncovered a novel role for brain-derived neurotrophic factor in mediating effects of rapid antidepressant efficacy. In the course of my studies, we have found that brain-derived neurotrophic factor expression may be more important for protecting females from negative behavioral effects of chronic stress; that brain-derived neurotrophic factor receptor activation in dorsal raphe is essential for traditional antidepressant efficacy; and finally that brain-derived neurotrophic factor is required for the action of novel rapid antidepressant ketamine.Item Regulation of Brain-Derived Neurotrophic Factor in the Adult Mouse Brain(2005-08-11) Malkovska, Irena; Parada, LuisIn the adult central nervous system (CNS) brain-derived neurotrophic factor (BDNF) has been implicated in neuroprotection and synaptic plasticity among other functions. However, relatively little is known of its regulation. In this thesis, we attempted to learn more about BDNF regulation by means of: an in situ hybridization study of the four distinct untranslated exons in the adult mouse brain; use of transgenic animals to define BDNF promoter regions; and use of comparative genomics to identify evolutionarily conserved regions of BDNF. The in situ hybridization study suggests that the four distinct BDNF promoters are differentially regulated and that neighboring promoters are coregulated. Also it appears that all four promoters function in most of the same nuclei of the adult CNS. Inspite of the large size of the transgenic constructs used in this study specific to exons 1/2 and 3/4 (11.4 kb and 16 kb respectively), they were insufficient to mediate endogenous-like BDNF expression in the adult CNS. However, this study suggests that these regions may drive endogenous-like expression in a subset of nuclei (random chance integration cannot however be ruled out). The bioinformatics study revealed 9 highly conserved elements that are good candidates for cis-regulatory elements of BDNF. In conclusion, the regulation of the BDNF gene appears far more complicated than was previously predicted.Item Role of Tyrosine Receptor Kinase B in the Development and Function of the Central Nervous System(2009-01-14) Li, Yun; Parada, Luis F.Tyrosine Receptor Kinase B (TrkB) was initially identified as the high-affinity receptor for Brain-Derived Neurotrophic Factor (BDNF) in regulating the survival of sympathetic and sensory neurons. In the CNS, however, BDNF-TrkB interaction has been shown to regulate diverse aspects of development, physiology and pathology. In the current studies we focus on the roles of TrkB and its downstream signaling pathways in the progression and amelioration of CNS diseases. Though the nature of the diseases diverges, they share a common molecular regulatory mechanism. First we report that TrkB is required cell-autonomously to regulate the generation of new neurons. Mice lacking TrkB in hippocampal neural progenitor cells had impaired proliferation and neurogenesis, and are behaviorally insensitive to antidepressive treatments. Specific deletion of NF1, an antagonist of Ras, in adult neural progenitor cells enabled rapid proliferative and behavioral responses to sub-chronic antidepressants, and led to spontaneous antidepressive-like behaviors in the long run. Thus, our findings demonstrate impairment of the neural precursor niche as an etiological factor for refractory responses to antidepressive regimen, and the activation of adult neurogenesis as an approach to modulate depression and anxiety-like behaviors. In the second half, we report that ablation of Bdnf from the cortex and the substantia nigra leads to depletion of BDNF protein in the striatum. Mice lacking BDNF-TrkB signaling in the corticostriatal and nigrostriatal circuits displayed severe motor deficits and striatal degeneration reminiscent of the Huntington?disease. In contrast, specific ablation of TrkB from the striatal medium spiny neurons resulted in late-onset neuronal loss and spine degeneration, without causing obvious movement abnormalities. Thus, our results establish an essential role for TrkB in regulating the normal maturation and maintenance of striatal medium spiny neurons.