Adult Hypothalamic Otp Expression is Required for Maintaining Behavioral and Metabolic Homeostasis
2Department of Molecular Cell Biology, Weizmann Institute of Science
3Department of Brain Sciences and Department of Molecular Neuroscience, Weizmann Institute of Science
Aim:
Orthopedia (Otp) is a homeobox gene that has a crucial role in developing neuro-peptidergic hypothalamic neurons. Otp null mutant mice die soon after birth and display progressive neural impairments. Although the expression of Otp is maintained in adult hypothalamic neurons, the role of Otp in the adult is unknown. The experiments described in this work aim to study the cellular identity of Otp neurons and determine the physiological role of hypothalamic Otp in mice.
Methods:
We used immunohistochemistry and reporter mouse lines and analyzed Otp expression in specific neural subpopulations. To elucidate the role of Otp in the adult mice, we characterized a tamoxifen-induced Otp deficient mouse model lacking Otp selectively in forebrain CamKII-positive neurons (cKO). The characterization of the cKO Otp mouse model included a battery of behavioral and physiological tests.
Results:
We demonstrate that Otp is expressed by specific hypothalamic neurons that regulate energy balance and the stress response. Conditional KO of Otp alters the transcriptional response of both HPT and HPA downstream genes. We show that the altered gene expression is not due to neuronal death. We show that adult deletion of Otp leads to impaired adaptation to stressful challenges. A phenotype that was partially explained by the effects on the HPT axis function.
Conclusions:
Adult Otp emerges as a pivotal regulator in the complex interrelated networks which underlie stress response and energy balance. Hypothalamic Otp is potentially a new target in preventing and treating depression and other neuropsychiatric disorders.
