Leptin, a peptide mainly secreted in proportion to adipose tissue mass, increases energy expenditure with a parallel increase in breathing. The existence of a leptin-mediated neural circuit linking breathing to metabolism has been speculated, yet the precise central mechanisms were unknown. In my thesis, I show that optogenetic activation of leptin receptor (LepRb)-expressing neurons in the nucleus of the solitary tract (NTS) potently stimulates breathing thereby attesting the existence of a leptin-dependent respiratory motor circuit. I found that these neurons project to the ventrolateral medulla and to the dorsomedial hypothalamus. I discovered that leptin stimulates breathing by activating the sodium leak channel (NALCN) in a subset of LepRb NTS neurons and single-cell patch RNA transcriptomics identified these as glutamatergic neurons that express galanin. In awake, freely moving mice, deletion of NALCN in LepRb neurons produced irregular breathing and increased central apneas. On a high-fat diet, these mice gained weight and increased plasma leptin but, compared to control mice, exhibited a relative depression of tidal volume and minute ventilation. Together, these findings reveal a leptin-dependent, NALCN-mediated mechanism that modulates respiratory drive in proportion to body mass associated changes in metabolism.

Creator

• Do, Jeehaeh

DOI

• https://doi.org/10.21985/n2-ssch-fh81

Subject

• Neurosciences

Language

• en

Alternate Identifier

• etdadmin_upload_763656
• http://dissertations.umi.com/northwestern:15246

Keyword

• NALCN
• obesity
• Nucleus of the Solitary Tract

Date created

• 2020-01-01

Resource type

• Dissertation

Rights statement

• In Copyright