Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses

• Published in: Nature neuroscience Vol. 22; no. 3; pp. 436 - 446
• Main Authors: Besnard, Antoine, Gao, Yuan, TaeWoo Kim, Michael, Twarkowski, Hannah, Reed, Alexander Keith, Langberg, Tomer, Feng, Wendy, Xu, Xiangmin, Saur, Dieter, Zweifel, Larry S., Davison, Ian, Sahay, Amar
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2019; Nature Publishing Group
• Subjects: 14; 14/19; 14/35; 631/378; 631/378/1595; 631/378/1595/2636; 64; 64/60; 9/10; 9/74; Activities of daily living; Adaptation, Psychological - physiology; Analysis; Animal Genetics and Genomics; Animals; Anxiety - physiopathology; Attenuation; Behavior; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain research; CA3 Region, Hippocampal - physiology; Calcium; Calcium imaging; Cancer; Conditioning; Conditioning, Classical; Dentate gyrus; Dentate Gyrus - physiology; Discrimination, Psychological - physiology; Efficiency; Fear; Fear - physiology; Fear conditioning; Footshock; Freezing; Freezing Reaction, Cataleptic; Interneurons; Interneurons - metabolism; Interneurons - physiology; Male; Medical research; Mice; Mobility; Neural Pathways - physiology; Neurobiology; Neuroimaging; Neurons; Neurophysiology; Neurosciences; Optogenetics; Septal Nuclei - metabolism; Septal Nuclei - physiology; Septum; Somatostatin; Somatostatin - metabolism; Stimuli (Psychology); Tonic immobility
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-018-0330-y

Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus–CA3 circuit. Retrograde monosynaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock-responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context-appropriate behavioral fear responses. Besnard et al. uncover functional heterogeneity of somatostatin interneurons (SST-INs) in the dorsolateral septum and reveal a role for a subpopulation of SST-INs as hippocampal relays that govern mobility to calibrate adaptive fear responses.