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.
© 2014 Elsevier Inc. Under an Elsevier user license. Received: June 10, 2013; Revised: October 15, 2013; Accepted: December 27, 2013; Published: January 30, 2014. Supplemental Information includes Extended Experimental Procedures and seven figures and can be found with this article online at http://dx.doi.org/10.1016/j.cell.2013.12.040. We thank K. Deisseroth for Cre-dependent ChR2 and eNpHR AAV constructs, E. Boyden for Cre-dependent ArchT AAV construct, C. Saper for Cre-dependent hrGFP AAV construct, and L. Lo for HSV129ΔTK-TT; M. Martinez, H-J. Kim, J-S. Chang, and M. McCardle for technical help; M. Zelikowsky for statistics advice; and A. Colon, R. Bayon, R. Sauza, and J. Cochrane for animal care. This work was supported by National Institutes of Heath (NIH) grant 5R01MH070053-10 (D.J.A.), NIH NRSA postdoctoral fellowship grant 1F32HD055198-01 (T.E.A.), and a Beckman Fellowship (T.E.A.). D.J.A. is a Howard Hughes Medical Institute investigator.
Accepted Version - nihms554585.pdf
Supplemental Material - mmc1-supponly.pdf