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HomeNatureFeature-specific threat coding in lateral septum guides defensive action

Feature-specific threat coding in lateral septum guides defensive action

  • Risold, P. Y. & Swanson, L. W. Connections of the rat lateral septal complex. Brain Res. Rev. 24, 115–195 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Besnard, A. & Leroy, F. Top-down regulation of motivated behaviors via lateral septum sub-circuits. Mol. Psychiatry 27, 3119–3128 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Risold, P. Y. & Swanson, L. W. Chemoarchitecture of the rat lateral septal nucleus1Published on the World Wide Web on 2 June 1997.1. Brain Res. Rev. 24, 91–113 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Franklin, T. B., Saab, B. J. & Mansuy, I. M. Neural mechanisms of stress resilience and vulnerability. Neuron 75, 747–761 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Henckens, M. J. A. G., Deussing, J. M. & Chen, A. Region-specific roles of the corticotropin-releasing factor–urocortin system in stress. Nat. Rev. Neurosci. 17, 636–651 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Anthony, T. E. et al. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 156, 522–536 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hashimoto, M. et al. Lateral septum modulates cortical state to tune responsivity to threat stimuli. Cell Rep. 41, 111521 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sheehan, T. P., Chambers, R. A. & Russell, D. S. Regulation of affect by the lateral septum: implications for neuropsychiatry. Brain Res. Rev. 46, 71–117 (2004).

    Article 
    PubMed 

    Google Scholar
     

  • Albert, D. J. & Chew, G. L. The septal forebrain and the inhibitory modulation of attack and defense in the rat. A review. Behav. Neur. Biol. 30, 357–388 (1980).

    Article 
    CAS 

    Google Scholar
     

  • Wirtshafter, H. S. & Wilson, M. A. Lateral septum as a nexus for mood, motivation, and movement. Neurosci. Biobehav. Rev. 126, 544–559 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Dai, B. et al. Experience-dependent dopamine modulation of male aggression. Nature 639, 430–437 (2025).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reyes, N. S. et al. Corticotropin-releasing hormone signaling from prefrontal cortex to lateral septum suppresses interaction with familiar mice. Cell 186, 4152–4171 (2023).

    Article 

    Google Scholar
     

  • Li, L. et al. Social trauma engages lateral septum circuitry to occlude social reward. Nature 613, 696–703 (2023).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, G. et al. Cellular and circuit architecture of the lateral septum for reward processing. Neuron 112, 2783–2798 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Goode, T. D. et al. A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding. Neuron https://doi.org/10.1016/j.neuron.2026.01.025 (2026).

  • Besnard, A. et al. Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses. Nat. Neurosci. 22, 436–446 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brady, J. V. & Nauta, W. J. H. Subcortical mechanisms in emotional behavior: affective changes following septal forebrain lesions in the albino rat. J. Comp. Physiol. Psych. 46, 339–346 (1953).

    Article 
    CAS 

    Google Scholar
     

  • Albert, D. J. & Wong, R. C. Hyperreactivity, muricide, and intraspecific aggression in the rat produced by infusion of local anesthetic into the lateral septum or surrounding areas. J. Comp. Physiol. Psych. 92, 1062–1073 (1978).

    Article 
    CAS 

    Google Scholar
     

  • Ramirez, J. M., Salas, C. & Portavella, M. Offense and defense after lateral septal lesions in Columba Livia. Int. J. Neurosci. 41, 241–250 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Paxinos, G. The septum: neural systems involved in eating, drinking, irritability, muricide, copulation, and activity in rats. J. Comp. Physiol. Psych. 89, 1154–1168 (1975).

    Article 
    CAS 

    Google Scholar
     

  • Reis, D. G., Scopinho, A. A., Guimarães, F. S., Corrêa, F. M. A. & Resstel, L. B. M. Involvement of the lateral septal area in the expression of fear conditioning to context. Learn. Mem. 17, 134–138 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Calandreau, L., Desgranges, B., Jaffard, R. & Desmedt, A. Switching from contextual to tone fear conditioning and vice versa: The key role of the glutamatergic hippocampal-lateral septal neurotransmission. Learn. Mem. 17, 440–443 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Radulovic, J., Rühmann, A., Liepold, T. & Spiess, J. Modulation of learning and anxiety by corticotropin-releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2. J. Neurosci. 19, 5016–5025 (1999).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Henry, B., Vale, W. & Markou, A. The effect of lateral septum corticotropin-releasing factor receptor 2 activation on anxiety is modulated by stress. J. Neurosci. 26, 9142–9152 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Todorovic, C. et al. Differential activation of CRF receptor subtypes removes stress-induced memory deficit and anxiety. Eur. J. Neurosci. 25, 3385–3397 (2007).

    Article 
    PubMed 

    Google Scholar
     

  • Turner, V. S., O’Sullivan, R. O. & Kheirbek, M. A. Linking external stimuli with internal drives: A role for the ventral hippocampus. Curr. Opin. Neurobiol. 76, 102590 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Biane, J. S. et al. Neural dynamics underlying associative learning in the dorsal and ventral hippocampus. Nat. Neurosci. 26, 798–809 (2023).

  • Sternson, S. M. Hypothalamic survival circuits: blueprints for purposive behaviors. Neuron 77, 810–824 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jercog, D. et al. Dynamical prefrontal population coding during defensive behaviours. Nature 595, 690–694 (2021).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Mahn, M. et al. High-efficiency optogenetic silencing with soma-targeted anion-conducting channelrhodopsins. Nat. Commun. 9, 4125 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Heekeren, H. R., Marrett, S. & Ungerleider, L. G. The neural systems that mediate human perceptual decision making. Nat. Rev. Neurosci. 9, 467–479 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Evans, D. A., Stempel, A. V., Vale, R. & Branco, T. Cognitive control of escape behaviour. Trends Cogn. Sci. 23, 334–348 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bentz, D. & Schiller, D. Threat processing: models and mechanisms. Wiley Interdiscip. Rev. Cogn. Sci. 6, 427–439 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Lee, J. & Sabatini, B. L. Striatal indirect pathway mediates exploration via collicular competition. Nature 599, 645–649 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gray, J. A. & McNaughton, N. Comparison between the behavioural effects of septal and hippocampal lesions: A review. Neurosci. Biobehav. Rev. 7, 119–188 (1983).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sibole, W., Miller, J. J. & Mogenson, G. J. Effects of septal stimulation on drinking elicited by electrical stimulation of the lateral hypothalamus. Exp. Neurol. 32, 466–477 (1971).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Azevedo, E. P. et al. A limbic circuit selectively links active escape to food suppression. eLife 9, e58894 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shin, S. et al. Drd3 signaling in the lateral septum mediates early life stress-induced social dysfunction. Neuron 97, 195–208 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rodriguez, L. A. et al. TrkB-dependent regulation of molecular signaling across septal cell types. Transl. Psychiatry 14, 52 (2024).

  • Simon, R. C. et al. Opioid-driven disruption of the septal complex reveals a role for neurotensin-expressing neurons in withdrawal. Neuron 113, 2325–2343.e9 (2025).

  • Reid, C. M. et al. Multimodal classification of neurons in the lateral septum. Preprint at bioRxiv https://doi.org/10.1101/2024.02.15.580381 (2024).

  • Hughes, A. C. et al. A single-vector intersectional AAV strategy for interrogating cellular diversity and brain function. Nat. Neurosci. 27, 1400–1410 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kepecs, A. & Fishell, G. Interneuron cell types are fit to function. Nature 505, 318–326 (2014).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Luo, A. H., Tahsili-Fahadan, P., Wise, R. A., Lupica, C. R. & Aston-Jones, G. Linking context with reward: a functional circuit from hippocampal CA3 to ventral tegmental area. Science 333, 353–357 (2011).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goode, T. et al. 141. Calibration of context-evoked feeding by a genetically defined lateral septum to lateral hypothalamus circuit. Biol. Psychiatry 93, S151 (2023).

    Article 

    Google Scholar
     

  • Tingley, D. & Buzsáki, G. Transformation of a spatial map across the hippocampal-lateral septal circuit. Neuron 98, 1229–1242 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tingley, D. & Buzsáki, G. Routing of hippocampal ripples to subcortical structures via the lateral septum. Neuron 105, 138–149 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mogg, K. & Bradley, B. P. Anxiety and threat-related attention: cognitive-motivational framework and treatment. Trends Cogn. Sci. 22, 225–240 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Sussman, T. J., Jin, J. & Mohanty, A. Top-down and bottom-up factors in threat-related perception and attention in anxiety. Biol. Psychol. 121, 160–172 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Bishop, S. J. Neural mechanisms underlying selective attention to threat. Ann. N. Y. Acad. Sci. 1129, 141–152 (2008).

    Article 
    ADS 
    PubMed 

    Google Scholar
     

  • Rauss, K. & Pourtois, G. What is bottom-up and what is top-down in predictive coding? Front. Psychol. 4, 276 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reardon, T. R. et al. Rabies virus CVS-N2cΔG strain enhances retrograde synaptic transfer and neuronal viability. Neuron 89, 711–724 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sumser, A., Joesch, M., Jonas, P. & Ben-Simon, Y. Fast, high-throughput production of improved rabies viral vectors for specific, efficient and versatile transsynaptic retrograde labeling. eLife 11, e79848 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, X. et al. Genetically identified amygdala–striatal circuits for valence-specific behaviors. Nat. Neurosci. 24, 1586–1600 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, J. et al. Divergent projections of the paraventricular nucleus of the thalamus mediate the selection of passive and active defensive behaviors. Nat. Neurosci. 24, 1429–1440 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xiao, X. et al. A genetically defined compartmentalized striatal direct pathway for negative reinforcement. Cell 183, 211–227 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • LeDuke, D. O., Borio, M., Miranda, R. & Tye, K. M. Anxiety and depression: A top-down, bottom-up model of circuit function. Ann. N. Y. Acad. Sci. 1525, 70–87 (2023).

  • Wong, L. C. et al. Effective modulation of male aggression through lateral septum to medial hypothalamus projection. Curr. Biol. 26, 593–604 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leroy, F. et al. A circuit from hippocampal CA2 to lateral septum disinhibits social aggression. Nature 564, 213–218 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Prescott, S. L., Umans, B. D., Williams, E. K., Brust, R. D. & Liberles, S. D. An airway protection program revealed by sweeping genetic control of vagal afferents. Cell 181, 574–589 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Matho, K. S. et al. Genetic dissection of the glutamatergic neuron system in cerebral cortex. Nature 598, 182–187 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rossi, J. et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 13, 195–204 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Williams, E. K. et al. Sensory neurons that detect stretch and nutrients in the digestive system. Cell 166, 209–221 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pan, W. et al. Essential role for hypothalamic calcitonin receptor-expressing neurons in the control of food intake by leptin. Endocrinology 159, 1860–1872 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rousso, D. L. et al. Two pairs of ON and OFF retinal ganglion cells are defined by intersectional patterns of transcription factor expression. Cell Rep. 15, 1930–1944 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Trusel, M. et al. Punishment-predictive cues guide avoidance through potentiation of hypothalamus-to-habenula synapses. Neuron 102, 120–127 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Weinreb, C. et al. Keypoint-MoSeq: parsing behavior by linking point tracking to pose dynamics. Nat. Methods 21, 1329–1339 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Arch, V. S. & Narins, P. M. ‘Silent’ signals: selective forces acting on ultrasonic communication systems in terrestrial vertebrates. Animal Behaviour 76, 1423–1428 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kennedy, A. et al. Stimulus-specific hypothalamic encoding of a persistent defensive state. Nature 586, 730–734 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hersman, S., Allen, D., Hashimoto, M., Brito, S. I. & Anthony, T. E. Stimulus salience determines defensive behaviors elicited by aversively conditioned serial compound auditory stimuli. eLife 9, e53803 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dinç, F. et al. Fast, scalable, and statistically robust cell extraction from large-scale neural calcium imaging datasets. Preprint at bioRxiv https://doi.org/10.1101/2021.03.24.436279 (2024).

  • Pachitariu, M. et al. Suite2p: beyond 10,000 neurons with standard two-photon microscopy. Preprint at bioRxiv https://doi.org/10.1101/061507 (2017).

  • Burgess, C. R. et al. Hunger-dependent enhancement of food cue responses in mouse postrhinal cortex and lateral amygdala. Neuron 91, 1154–1169 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

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