Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit

• Published in: Cell Vol. 156; no. 3; pp. 522 - 536
• Main Authors: Anthony, Todd E., Dee, Nick, Bernard, Amy, Lerchner, Walter, Heintz, Nathaniel, Anderson, David J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.01.2014
• Subjects: Adrenal Cortex Hormones - metabolism; Amygdala - metabolism; Animals; Anxiety - physiopathology; Behavior, Animal; Female; Hypothalamus - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons - physiology; Receptors, Corticotropin-Releasing Hormone - metabolism; Septum of Brain - physiology; Stress, Physiological
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.12.040

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. [Display omitted] •Crfr2 defines a molecularly distinct subset of predominantly GABAergic LS neurons•Crfr2+ neuronal activation promotes, while inhibition suppresses, persistent anxiety•These anxiogenic effects are exerted in part via projections to medial hypothalamus•LS Crfr2+ outputs positively regulate circulating corticosteroid levels Optogenetic circuit mapping identifies a population of neurons that send long-range projections from the lateral septum to the hypothalamus and enhance stress-induced anxiety behaviors that persist following transient neural activity. The findings provide new insights into the neural substrates of anxiety outside the amygdala and a cellular foothold on a little-explored brain area.