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Involvement of the lateral habenula in fear memory

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Abstract

Increasing evidence points to the engagement of the lateral habenula (LHb) in the selection of appropriate behavioral responses in aversive situations. However, very few data have been gathered with respect to its role in fear memory formation, especially in learning paradigms in which brain areas involved in cognitive processes like the hippocampus (HPC) and the medial prefrontal cortex (mPFC) are required. A paradigm of this sort is trace fear conditioning, in which an aversive event is preceded by a discrete stimulus, generally a tone, but without the close temporal contiguity allowing for their association based on amygdala-dependent information processing. In a first experiment, we analyzed cellular activations (c–Fos expression) induced by trace fear conditioning in subregions of the habenular complex, HPC, mPFC and amygdala using a factorial analysis to unravel functional networks through correlational analysis of data. This analysis suggested that distinct LHb subregions engaged in different aspects of conditioning, e.g. associative processes and onset of fear responses. In a second experiment, we performed chemogenetic LHb inactivation during the conditioning phase of the trace fear conditioning paradigm and subsequently assessed contextual and tone fear memories. Whereas LHb inactivation did not modify rat’s behavior during conditioning, it induced contextual memory deficits and enhanced fear to the tone. These results demonstrate the involvement of the LHb in fear memory. They further suggest that the LHb is engaged in learning about threatening environments through the selection of relevant information predictive of a danger.

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References

  • Agetsuma M, Aizawa H, Aoki T et al (2010) The habenula is crucial for experience-dependent modification of fear responses in zebrafish. Nat Neurosci 13:1354–1356

    CAS  PubMed  Google Scholar 

  • Aizawa H, Kobayashi M, Tanaka S et al (2012) Molecular characterization of the subnuclei in rat habenula. J Comp Neurol 520:4051–4066

    CAS  PubMed  Google Scholar 

  • Aizawa H, Yanagihara S, Kobayashi M et al (2013) The synchronous activity of lateral habenular neurons is essential for regulating hippocampal theta oscillation. J Neurosci 33:8909–8921

    CAS  PubMed  PubMed Central  Google Scholar 

  • Albrechet-Souza L, Carvalho MC, Brandão ML (2013) D(1)-like receptors in the nucleus accumbens shell regulate the expression of contextual fear conditioning and activity of the anterior cingulate cortex in rats. Int J Neuropsychopharmacol 16(5):1045–1057

    CAS  PubMed  Google Scholar 

  • Ali M, Cholvin T, Muller MA et al (2017) Environmental enrichment enhances systems-level consolidation of a spatial memory after lesions of the ventral midline thalamus. Neurobiol Learn Mem 141:108–123

    PubMed  Google Scholar 

  • Amo R, Fredes F, Kinoshita M et al (2014) The habenulo-raphe serotonergic circuit encodes an aversive expectation value essential for adaptive active avoidance of danger. Neuron 84:1034–1048

    CAS  PubMed  Google Scholar 

  • Andres KH, von Düring M, Veh RW (1999) Subnuclear organization of the rat habenular complexes. J Comp Neurol 407(1):130–150

    CAS  PubMed  Google Scholar 

  • Baker PM, Mizumori SJY (2017) Control of behavioral flexibility by the lateral habenula. Pharmacol Biochem Behav 162:62–68

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barrett DW, Gonzalez-Lima F (2018) Prefrontal-limbic functional connectivity during acquisition and extinction of conditioned fear. Neuroscience 376:162–171

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brown PL, Palacorolla H, Brady D, Riegger K, Elmer GI, Shepard PD (2017) Habenula-induced inhibition of midbrain dopamine neurons is diminished by lesions of the rostromedial tegmental nucleus. J Neurosci 37(1):217–225

    CAS  PubMed  PubMed Central  Google Scholar 

  • Calandreau L, Desmedt A, Decorte L, Jaffard R (2005) A different recruitment of the lateral and basolateral amygdala promotes contextual or elemental conditioned association in Pavlovian fear conditioning. Learn Mem Cold Spring Harb N 12:383–388

    Google Scholar 

  • Campbell EJ, Marchant NJ (2018) The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats. Br J Pharmacol 175:994–1003

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chan J, Guan X, Ni Y, Luo L, Yang L, Zhang P, Zhang J, Chen Y (2017) Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats. Behav Brain Res 321:61–68

    CAS  PubMed  Google Scholar 

  • Chastrette N, Pfaff DW, Gibbs RB (1991) Effects of daytime and nighttime stress on Fos-like immunoreactivity in the paraventricular nucleus of the hypothalamus, the habenula, and the posterior paraventricular nucleus of the thalamus. Brain Res 563:339–344

    CAS  PubMed  Google Scholar 

  • Cho J-H, Rendall SD, Gray JM (2017) Brain-wide maps of Fos expression during fear learning and recall. Learn Mem 24:169–181

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chou M-Y, Amo R, Kinoshita M et al (2016) Social conflict resolution regulated by two dorsal habenular subregions in zebrafish. Science 352:87–90

    CAS  PubMed  Google Scholar 

  • Chowdhury N, Quinn JJ, Fanselow MS (2005) Dorsal hippocampus involvement in trace fear conditioning with long, but not short, trace intervals in mice. Behav Neurosci 119:1396–1402

    PubMed  Google Scholar 

  • Congiu M, Trusel M, Pistis M, Mameli M, Lecca S (2019) Opposite responses to aversive stimuli in lateral habenula neurons. Eur J Neurosci 50(6):2921–2930

    PubMed  Google Scholar 

  • Connor DA, Gould TJ (2016) The role of working memory and declarative memory in trace conditioning. Neurobiol Learn Mem 134:193–209

    PubMed  PubMed Central  Google Scholar 

  • Cullinan WE, Herman JP, Battaglia DF et al (1995) Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience 64:477–505

    CAS  PubMed  Google Scholar 

  • Detert JA, Kampa ND, Moyer JR (2008) Differential effects of training intertrial interval on acquisition of trace and long-delay fear conditioning in rats. Behav Neurosci 122:1318–1327

    PubMed  Google Scholar 

  • Duvarci S, Pare D (2014) Amygdala microcircuits controlling learned fear. Neuron 82:966–980

    CAS  PubMed  PubMed Central  Google Scholar 

  • Esclassan F, Coutureau E, Scala GD, Marchand AR (2009) Differential contribution of dorsal and ventral hippocampus to trace and delay fear conditioning. Hippocampus 19:33–44

    PubMed  Google Scholar 

  • Fanselow MS, Dong H-W (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7–19

    CAS  PubMed  PubMed Central  Google Scholar 

  • Geng F, Liu J-Y, Chen X-W et al (2019) ErbB4 receptors in the medial habenula regulate contextual fear memory. Pharmacology 103:68–75

    CAS  PubMed  Google Scholar 

  • Gilmartin MR, Helmstetter FJ (2010) Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex. Learn Mem 17:289–296

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gilmartin MR, Miyawaki H, Helmstetter FJ, Diba K (2013) Prefrontal activity links nonoverlapping events in memory. J Neurosci 33:10910–10914

    CAS  PubMed  PubMed Central  Google Scholar 

  • González-Pardo H, Conejo NM, Lana G, Arias JL (2012) Different brain networks underlying the acquisition and expression of contextual fear conditioning: a metabolic mapping study. Neuroscience 202:234–242

    PubMed  Google Scholar 

  • Goutagny R, Loureiro M, Jackson J et al (2013) Interactions between the lateral habenula and the hippocampus: implication for spatial memory processes. Neuropsychopharmacology 38:2418–2426

    PubMed  PubMed Central  Google Scholar 

  • Guimarais M, Gregório A, Cruz A et al (2011) Time Determines the neural circuit underlying associative fear learning. Front Behav Neurosci 5:89

    PubMed  PubMed Central  Google Scholar 

  • Heath FC, Jurkus R, Bast T, Pezze MA, Lee JL, Voigt JP, Stevenson CW (2015) Dopamine D1-like receptor signalling in the hippocampus and amygdala modulates the acquisition of contextual fear conditioning. Psychopharmacology 232(14):2619–2629

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heldt SA, Ressler KJ (2006) Lesions of the habenula produce stress- and dopamine-dependent alterations in prepulse inhibition and locomotion. Brain Res 1073–1074:229–239

    PubMed  PubMed Central  Google Scholar 

  • Hennigan K, D’Ardenne K, McClure SM (2015) Distinct midbrain and habenula pathways are involved in processing aversive events in humans. J Neurosci 35:198–208.

  • Hsu Y-WA, Morton G, Guy EG, et al (2016) Dorsal Medial Habenula Regulation of mood-related behaviors and primary reinforcement by tachykinin-expressing habenula neurons. eNeuro 3(3)

  • Ilg A-K, Enkel T, Bartsch D, Bähner F (2018) Behavioral effects of acute systemic low-dose clozapine in wild-type rats: implications for the use of DREADDs in behavioral neuroscience. Front Behav Neurosci 12:173

    PubMed  PubMed Central  Google Scholar 

  • Jacobs NS, Cushman JD, Fanselow MS (2010) The accurate measurement of fear memory in pavlovian conditioning: resolving the baseline issue. J Neurosci Methods 190:235–239

    PubMed  PubMed Central  Google Scholar 

  • Kaouane N, Porte Y, Vallée M et al (2012) Glucocorticoids can induce PTSD-like memory impairments in mice. Science 335:1510–1513

    CAS  PubMed  Google Scholar 

  • Kim T-K, Han P-L (2016) Functional connectivity of basolateral amygdala neurons carrying orexin receptors and melanin-concentrating hormone receptors in regulating sociability and mood-related behaviors. Exp Neurobiol 25:307–317

    PubMed  PubMed Central  Google Scholar 

  • Kim U, Lee T (2012) Topography of descending projections from anterior insular and medial prefrontal regions to the lateral habenula of the epithalamus in the rat. Eur J Neurosci 35:1253–1269

    PubMed  Google Scholar 

  • Lammel S, Lim BK, Ran C et al (2012) Input-specific control of reward and aversion in the ventral tegmental area. Nature 491:212–217

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lecca S, Meye FJ, Trusel M, et al (2017) Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior. eLife 6:e30697

  • Lecourtier L, Defrancesco A, Moghaddam B (2008) Differential tonic influence of lateral habenula on prefrontal cortex and nucleus accumbens dopamine release. Eur J Neurosci 27(7):1755–1762

    PubMed  PubMed Central  Google Scholar 

  • Li H, Pullmann D, Cho JY, Eid M, Jhou TC (2019) Generality and opponency of rostromedial tegmental (RMTg) roles in valence processing. Elife 8. pii: e41542

  • Li H, Pullmann D, Jhou TC (2019) Valence-encoding in the lateral habenula arises from the entopeduncular region. Elife 8. pii: e41223

  • Manvich DF, Webster KA, Foster SL, et al (2018) The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice. Sci Rep 8:3840.z

  • Marchand AR, Luck D, DiScala G (2003) Evaluation of an improved automated analysis of freezing behaviour in rats and its use in trace fear conditioning. J Neurosci Methods 126:145–153

    PubMed  Google Scholar 

  • Maren S, Phan KL, Liberzon I (2013) The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 14:417–428

    CAS  PubMed  PubMed Central  Google Scholar 

  • Marr D (1971) Simple memory: a theory for archicortex. Philos Trans R Soc Lond B Biol Sci 262:23–81

    CAS  PubMed  Google Scholar 

  • Mathis V, Barbelivien A, Majchrzak M, et al (2016) The lateral habenula as a relay of cortical information to process working memory. Cereb Cortex 1–11

  • Mathis V, Cosquer B, Avallone M et al (2015) Excitatory transmission to the lateral habenula is critical for encoding and retrieval of spatial memory. Neuropsychopharmacology 40:2843–2851

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mathis V, Cosquer B, Barbelivien A et al (2018) The lateral habenula interacts with the hypothalamo-pituitary adrenal axis response upon stressful cognitive demand in rats. Behav Brain Res 341:63–70

    CAS  PubMed  Google Scholar 

  • Matsumoto M, Hikosaka O (2009) Representation of negative motivational value in the primate lateral habenula. Nat Neurosci 12:77–84

    CAS  PubMed  Google Scholar 

  • Metzger M, Souza R, Lima LB, Bueno D, Gonçalves L, Sego C, Donato J Jr, Shammah-Lagnado SJ (2019) Habenular connections with the dopaminergic and serotonergic system and their role in stress-related psychiatric disorders. Eur J Neurosci. https://doi.org/10.1111/ejn.14647

    Article  PubMed  Google Scholar 

  • Milanovic S, Radulovic J, Laban O et al (1998) Production of the Fos protein after contextual fear conditioning of C57BL/6N mice. Brain Res 784:37–47

    CAS  PubMed  Google Scholar 

  • Misane I, Tovote P, Meyer M et al (2005) Time-dependent involvement of the dorsal hippocampus in trace fear conditioning in mice. Hippocampus 15:418–426

    CAS  PubMed  Google Scholar 

  • Padilla-Coreano N, Do-Monte FH, Quirk GJ (2012) A time-dependent role of midline thalamic nuclei in the retrieval of fear memory. Neuropharmacology 62:457–463

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Elsevier, Academic Press, Amsterdam

    Google Scholar 

  • Penzo MA, Robert V, Tucciarone J et al (2015) The paraventricular thalamus controls a central amygdala fear circuit. Nature 519:455–459

    CAS  PubMed  PubMed Central  Google Scholar 

  • Petzel A, Bernard R, Poller WC, Veh RW (2017) Anterior and posterior parts of the rat ventral tegmental area and the rostromedial tegmental nucleus receive topographically distinct afferents from the lateral habenular complex. J Comp Neurol 525(10):2310–2327

    CAS  PubMed  Google Scholar 

  • Piedra J, Ontiveros M, Miravet S et al (2015) Development of a rapid, robust, and universal picogreen-based method to titer adeno-associated vectors. Hum Gene Ther Methods 26:35–42

    CAS  PubMed  Google Scholar 

  • Radulovic J, Kammermeier J, Spiess J (1998) Relationship between Fos production and classical fear conditioning: effects of novelty, latent inhibition, and unconditioned stimulus preexposure. J Neurosci 18:7452–7461

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rescorla RA (1968) Probability of shock in the presence and absence of CS in fear conditioning. J Comp Physiol Psychol 66:1–5

    CAS  PubMed  Google Scholar 

  • Rescorla RA, Wagner AR (1972) A theory of Pavlovian conditioning: Variations in the effectiveness of reinforcement and nonreinforcement. Class Cond II Curr Res Theory 64–99

  • Root DH, Mejias-Aponte CA, Qi J, Morales M (2014) Role of glutamatergic projections from ventral tegmental area to lateral habenula in aversive conditioning. J Neurosci 34:13906–13910

    PubMed  PubMed Central  Google Scholar 

  • Rudy JW, Barrientos RM, O’Reilly RC (2002) Hippocampal formation supports conditioning to memory of a context. Behav Neurosci 116:530–538

    PubMed  Google Scholar 

  • Runyan JD, Dash PK (2004) Intra-medial prefrontal administration of SCH-23390 attenuates ERK phosphorylation and long-term memory for trace fear conditioning in rats. Neurobiol Learn Mem 82(2):65–70

    CAS  PubMed  Google Scholar 

  • Sánchez-Catalán MJ, Faivre F, Yalcin I, Muller MA, Massotte D, Majchrzak M, Barrot M (2017) Response of the tail of the ventral tegmental area to aversive stimuli. Neuropsychopharmacology 42(3):638–648

    PubMed  Google Scholar 

  • Song M, Jo YS, Lee Y-K, Choi J-S (2017) Lesions of the lateral habenula facilitate active avoidance learning and threat extinction. Behav Brain Res 318:12–17

    PubMed  Google Scholar 

  • Stamatakis AM, Stuber GD (2012) Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat Neurosci 15:1105–1107

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stopper CM, Floresco SB (2014) What’s better for me? Fundamental role for lateral habenula in promoting subjective decision biases. Nat Neurosci 17:33–35

    CAS  PubMed  Google Scholar 

  • Stubbendorff C, Hale E, Cassaday HJ, Bast T, Stevenson CW (2019) Dopamine D1-like receptors in the dorsomedial prefrontal cortex regulate contextual fear conditioning. Psychopharmacology 236(6):1771–1782

    CAS  PubMed  PubMed Central  Google Scholar 

  • Trusel M, Nuno-Perez A, Lecca S, Harada H, Lalive AL, Congiu M, Takemoto K, Takahashi T, Ferraguti F, Mameli M (2019) Punishment-predictive cues guide avoidance through potentiation of hypothalamus-to-habenula synapses. Neuron 102(1):120–127

    CAS  PubMed  Google Scholar 

  • Veening JG, Böcker KBE, Verdouw PM et al (2009) Activation of the septohippocampal system differentiates anxiety from fear in startle paradigms. Neuroscience 163:1046–1060

    CAS  PubMed  Google Scholar 

  • Wang D, Li Y, Feng Q, et al (2017) Learning shapes the aversion and reward responses of lateral habenula neurons. eLife 6:e23045

  • Wang Z, Wang L, Yamamoto R et al (2013) Role of the lateral habenula in shaping context-dependent locomotor activity during cognitive tasks. NeuroReport 24:276–280

    PubMed  Google Scholar 

  • Wirtshafter D, Asin KE, Pitzer MR (1994) Dopamine agonists and stress produce different patterns of Fos-like immunoreactivity in the lateral habenula. Brain Res 633:21–26

    CAS  PubMed  Google Scholar 

  • Yamaguchi T, Danjo T, Pastan I et al (2013) Distinct roles of segregated transmission of the septo-habenular pathway in anxiety and fear. Neuron 78:537–544

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zahm DS, Root DH (2017) Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving. Pharmacol Biochem Behav 162:3–21

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Tan L, Ren Y et al (2016) Presynaptic excitation via GABAB receptors in habenula cholinergic neurons regulates fear memory expression. Cell 166:716–728

    CAS  PubMed  Google Scholar 

  • Zhou W, Jin Y, Meng Q et al (2019) A neural circuit for comorbid depressive symptoms in chronic pain. Nat Neurosci 22:1649–1658

    CAS  PubMed  Google Scholar 

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  1. Victor Mathis

    Present address: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, NY, 10029–6574, USA

  2. Laura Durieux, Victor Mathis, Sylvain Hugel, Monique Majchrzak and Lucas Lecourtier equally contributed to this study.

Authors and Affiliations

  1. Université de Strasbourg, Centre National de La Recherche Scientifique, Laboratoire de Neurosciences Cognitives Et Adaptatives (LNCA), UMR 7364, 12 rue Goethe, 67000, Strasbourg, France

    Laura Durieux, Victor Mathis, Karine Herbeaux, Marc–Antoine Muller, Alexandra Barbelivien, Chantal Mathis, Monique Majchrzak & Lucas Lecourtier

  2. Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR 3212, CNRS, 8 Allée du Général Rouvillois, 67000, Strasbourg, France

    Rémy Schlichter & Sylvain Hugel

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  1. Laura Durieux
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Durieux, L., Mathis, V., Herbeaux, K. et al. Involvement of the lateral habenula in fear memory. Brain Struct Funct 225, 2029–2044 (2020). https://doi.org/10.1007/s00429-020-02107-5

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