Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit.
The extended amygdala has dominated research on the neural circuitry of fear and anxiety, but the septohippocampal axis also plays an important role. The lateral septum (LS) is thought to suppress fear and anxiety through its outputs to the hypothalamus. However, this structure has not yet been dissected using modern tools. The type 2 CRF receptor (Crfr2) marks a subset of LS neurons whose functional connectivity we have investigated using optogenetics. Crfr2(+) cells include GABAergic projection neurons that connect with the anterior hypothalamus. Surprisingly, we find that these LS outputs enhance stress-induced behavioral measures of anxiety. Furthermore, transient activation of Crfr2(+) neurons promotes, while inhibition suppresses, persistent anxious behaviors. LS Crfr2(+) outputs also positively regulate circulating corticosteroid levels. These data identify a subset of LS projection neurons that promote, rather than suppress, stress-induced behavioral and endocrinological dimensions of persistent anxiety states and provide a cellular point of entry to LS circuitry.
Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, M/C 156-29, Pasadena, CA 91125, USA.
Todd E
TE
Anthony
Allen Institute for Brain Science, 551 North 34th Street, Suite 200, Seattle, WA 98103, USA.
Nick
N
Dee
Allen Institute for Brain Science, 551 North 34th Street, Suite 200, Seattle, WA 98103, USA.
Amy
A
Bernard
Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, M/C 156-29, Pasadena, CA 91125, USA.
Walter
W
Lerchner
Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA; Howard Hughes Medical Institute.
Nathaniel
N
Heintz
Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, M/C 156-29, Pasadena, CA 91125, USA; Howard Hughes Medical Institute. Electronic address: wuwei@caltech.edu.
David J
DJ
Anderson
D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D001522:Behavior, Animal; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D020665:Septum of Brain / Q000502:physiology*; D013312:Stress, Physiological
D000305:Adrenal Cortex Hormones; C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone