Thyroid Hormone-dependent Regulation of Adult Hippocampal Neurogenesis

• Applicant: Dr. Steffen Mayerl
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 548527247

Adult hippocampal neurogenesis represents a key process in hippocampus-dependent learning and memory. In this highly orchestrated programme, stem and progenitor cells in the hippocampal subgranular zone proliferate, differentiate, migrate and mature to generate new granule cell neurons that are functionally integrated into the existing granule cell network. Among various extrinsic and intrinsic factors influencing this process, adult hippocampal neurogenesis is highly dependent on proper thyroid hormone (TH) supply. Adult-onset hypothyroidism in animal models has been demonstrated to result in impaired adult hippocampal neurogenesis and hippocampal functions. Similarly, adult-onset hypothyroidism in patients is associated with learning and memory defects which may be explained by a compromised adult hippocampal neurogenic programme. TH signalling requires the transporter-mediated transmembrane passage of TH into target cells, where thyroid hormone can bind and activate its nuclear receptors. In my previous studies, I could unravel a strongly impeded adult hippocampal neurogenesis in mice with a global deletion of the TH transporters Mct8 and Oatp1c1. Furthermore, I could demonstrate the presence of Mct8 and Oatp1c1 as well as of the TH receptor TRα1 within the neurogenic cell lineage as well as in the stem cell niche. Yet, how exactly perturbations in the cell-specific TH signalling directly and indirectly affect neurogenic lineage progression remains open. Here, we strive to elucidate the lineage-autonomous versus non-lineage-autonomous functions of TH in regulating adult hippocampal neurogenesis. To that end, we will employ cell-specific mouse mutants expressing a dominant negative form of TRα1 in the adult hippocampal neurogenic lineage or harbouring a deletion of Mct8/Oatp1c1 within the lineage, in astrocytes or in endothelial cells only. Behaviour analyses, lineage tracing and high-resolution confocal microscopy will shed new light on the cell type-specific impact of TH signalling components on lineage progression and hippocampal function in vivo. Moreover, RNA sequencing studies will provide ground knowledge as to the fundamental mechanistic bases. Altogether, our anticipated studies will strongly advance our understanding as to how TH governs the adult hippocampal neurogenic program and may ultimately enable us to harness TH’s regulatory power to stimulate the neurogenic program in learning and memory disorders.

• DFG Programme: Research Grants