Regulators of thyroid hormone action on adult hippocampal neurogenesis

• Applicant: Dr. Steffen Mayerl
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 386971474

The hippocampal subgranular zone is one of only two areas that continue to generate new neurons in the adult brain. Over the last decade, the importance of this process for normal brain function was unequivocally demonstrated as deficits in hippocampal neurogenesis could clearly be linked to learning and memory impairments in humans and animal models. Adult hippocampal neurogenesis is a highly orchestrated process that involves the proliferation, differentiation, migration, and maturation of neural stem and progenitor cells to form functional granule cell neurons and that is governed by a variety of intrinsic and extrinsic signaling cues. Among the latter, thyroid hormones (THs) have been shown to regulate later stages of the neurogenic program in the adult hippocampus in animal models, and hypothyroidism in humans is associated with learning and memory defects linked to hippocampal neurogenesis. There is, however, only sparse information available about the progenitor stage-specific expression and function of various components of TH signaling. Here, I will elucidate the detailed expression of these components at different stages of the hippocampal neurogenic program in vivo and in vitro, and identify those that respond to changes in circulating TH levels in mouse models of hypo- and hyperthyroidism. Subsequently, I will investigate the in vivo relevance of TH signaling regulators engaged in the process by analyzing hippocampal neurogenesis in appropriate knockout animals, using both immunohistochemical and mRNA profiling techniques. In light of their learning deficits as well as morphological alterations in the hippocampus, mice lacking the TH transporters Mct8 and Oatp1c1 are the ideal starting point for these functional studies. In order to dissect stem cell/progenitor cell-intrinsic functions from global effects I will further generate and analyze mouse mutants that harbor deletions of TH signaling components specifically in the hippocampal lineage. Together, my results will not only provide new insights into the TH-dependent regulation of neural stem cells and progenitor cells in the hippocampus, but also contribute to the search for strategies to improve hippocampal neurogenesis in the aged population.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Charles Ffrench-Constant, Ph.D.