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Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

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Abstract

Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine (DA) system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4 (TLR4), an important pattern-recognition receptor in the innate immune system, can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient (TLR4 −/−) and wild-type (WT) mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed, large spaces. We found that TLR4 −/− mice exhibited reduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4 −/− mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approach-avoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4 −/− mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly, the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell (NAcSh) in TLR4 −/− mice than in WT mice. Partially inactivating the NAcSh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4 −/− mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAcSh may contribute to this phenomenon.

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References

  1. Phaf RH, Mohr SE, Rotteveel M, Wicherts JM. Approach, avoidance, and affect: a meta-analysis of approach-avoidance tendencies in manual reaction time tasks. Front Psychol 2014, 5: 378.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 1993, 18: 247–291.

    Article  CAS  PubMed  Google Scholar 

  3. Robinson TE, Berridge KC. The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction 2000, 95 Suppl 2: S91–117.

    PubMed  Google Scholar 

  4. Baker TB, Piper ME, Mccarthy DE, Majeskie MR, Fiore MC. Addiction motivation reformulated: An affective processing model of negative reinforcement. Psychol Rev 2004, 111: 33–51.

    Article  PubMed  Google Scholar 

  5. Volkow ND, Wang GJ, Fowler JS, Tomasi D, Baler R. Food and drug reward: overlapping circuits in human obesity and addiction. Curr Top Behav Neurosci 2012, 11: 1–24.

    Article  CAS  PubMed  Google Scholar 

  6. Pierce K, Courchesne E. Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol Psychiatry 2001, 49: 655–664.

    Article  CAS  PubMed  Google Scholar 

  7. Greco B, Manago F, Tucci V, Kao HT, Valtorta F, Benfenati F. Autism-related behavioral abnormalities in synapsin knockout mice. Behav Brain Res 2013, 251: 65–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Betz C, Mihalic D, Pinto ME, Raffa RB. Could a common biochemical mechanism underlie addictions? J Clin Pharm Ther 2000, 25: 11–20.

    Article  CAS  PubMed  Google Scholar 

  9. Karim R, Chaudhri P. Behavioral Addictions: An Overview. J Psychoactive Drugs 2012, 44: 5–17.

    Article  PubMed  Google Scholar 

  10. Marazziti D, Presta S, Baroni S, Silvestri S, Dell’osso L. Behavioral addictions: a novel challenge for psychopharmacology. CNS Spectr 2014, 19: 486–495.

    Article  PubMed  Google Scholar 

  11. Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, Lathia, JD, et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci USA 2007, 104: 13798–13803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 2011, 34: 269–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Barak B, Feldman N, Okun E. Toll-like receptors as developmental tools that regulate neurogenesis during development: an update. Front Neurosci 2014, 8: 272.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hogg S. A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav 1996, 54: 21–30.

    Article  CAS  PubMed  Google Scholar 

  15. Moraga A, Pradillo JM, Cuartero MI, Hernández-Jiménez M, Oses M, Moro MA, et al. Toll-like receptor 4 modulates cell migration and cortical neurogenesis after focal cerebral ischemia. FASEB J 2014, 28: 4710–4718.

    Article  CAS  PubMed  Google Scholar 

  16. Painsipp E, Koefer MJ, Sinner F, Holzer P. Prolonged depression-like behavior caused by immune challenge: influence of mouse strain and social environment. PLoS One 2011, 6: e20719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pandey GN, Rizavi HS, Ren X, Bhaumik R, Dwivedi Y. Toll-like receptors in the depressed and suicide brain. J Psychiatr Res 2014, 53: 62–68.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Pascual, M, Baliño, P, Alfonso-Loeches, S, Aragón, CM, Guerri, C. Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage. Brain Behav Immun 2011, Suppl 1: S80–91

  19. Jacobsen J, Watkins L, Hutchinson M. Discovery of a Novel Site of Opioid Action at the Innate Immune Pattern-Recognition Receptor TLR4 and its Role in Addiction. Int Rev Neurobiol 2014, 118: 129–163.

    Article  PubMed  Google Scholar 

  20. Northcutt AL, Hutchinson MR, Wang X, Baratta MV, Hiranita T, Cochran TA, et al. DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling. Mol Psychiatry 2015, 20: 1525–1537

    Article  CAS  PubMed  Google Scholar 

  21. Enter D, Colzato L, Roelofs K. Dopamine transporter polymorphisms affect social approach–avoidance tendencies. Genes Brain Behav 2012, 11: 671– 676.

    Article  CAS  PubMed  Google Scholar 

  22. Brooks AM, Berns GS. Aversive stimuli and loss in the mesocorticolimbic dopamine system. Trends Cogn Sci 2013, 17: 281–286.

    Article  PubMed  Google Scholar 

  23. Brodkin ES, Hagemann A, Nemetski SM, Silver LM. Social approach–avoidance behavior of inbred mouse strains towards DBA/2 mice. Brain Res 2004, 1002: 151–157.

    Article  CAS  PubMed  Google Scholar 

  24. Franklin K, and Paxinos G. The Mouse Brain in Stereotaxic Coordinates, Third Edition, San Diego: Academic Press, 2008: 45–49.

    Google Scholar 

  25. Hoffman AF, Lupica CR. Direct actions of cannabinoids on synaptic transmission in the nucleus accumbens: a comparison with opioids. J Neurophysiol 2001, 85: 72–83

    CAS  PubMed  Google Scholar 

  26. Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 2010, 28: 367–88

    Article  CAS  PubMed  Google Scholar 

  27. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004, 4: 499–511.

    Article  CAS  PubMed  Google Scholar 

  28. Kaul D, Habbel P, Derkow K, Kruger C, Franzoni E, Wulczyn FG, et al. Expression of Toll-like receptors in the developing brain. PLoS One 2012, 7: e37767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Carty M, Bowie AG. Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol 2011, 81: 825–837.

    Article  CAS  PubMed  Google Scholar 

  30. Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-α. J Neurosci 2005, 25: 3219–3228.

    Article  CAS  PubMed  Google Scholar 

  31. Mandolesi G, Musella A, Gentile A, Grasselli G, Haji N, Sepman H, et al. Interleukin-1β alters glutamate transmission at purkinje cell synapses in a mouse model of multiple sclerosis. J Neurosci 2013, 33: 12105–12121.

    Article  CAS  PubMed  Google Scholar 

  32. Long-Smith CM, Collins L, Toulouse A, Sullivan AM, Nolan YM. Interleukin-1β contributes to dopaminergic neuronal death induced by lipopolysaccharide-stimulated rat glia in vitro. J Neuroimmunol 2010, 226: 20–26.

    Article  CAS  PubMed  Google Scholar 

  33. Hutchinson M, Northcutt A, Hiranita T, Wang X, Lewis S, Thomas J, et al. Opioid activation of toll-like receptor 4 contributes to drug reinforcement. J Neurosci 2012, 32: 11187–11200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hutchinson MR, Watkins LR. Why is neuroimmunopharmacology crucial for the future of addiction research? Neuropharmacology 2014, 76: 218–227.

    Article  CAS  PubMed  Google Scholar 

  35. Okun E, Barak B, Saada-Madar R, Rothman SM, Griffioen KJ, Roberts N, et al. Evidence for a developmental role for TLR4 in learning and memory. PloS One 2012, 7: e47522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Meredith G. The synaptic framework for chemical signaling in nucleus accumbens. Ann NY Acad Sci 1999, 877: 140–156.

    Article  CAS  PubMed  Google Scholar 

  37. Lobo MK, Covington HE, Chaudhury D, Friedman AK, Sun H, Damez-Werno D, et al. Cell type–specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 2010, 330: 385–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bock R, Shin JH, Kaplan AR, Dobi A, Markey E, Kramer PF, et al. Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nat Neurosci 2013, 16: 632–638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hikida T, Yawata S, Yamaguchi T, Danjo T, Sasaoka T, Wang Y, et al. Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors. Proc Natl Acad Sci USA 2013, 110: 342–347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Surmeier DJ, Ding J, Day M, Wang Z, Shen W. D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci 2007, 30: 228–235.

    Article  CAS  PubMed  Google Scholar 

  41. Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 2011, 12: 623–637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pothuizen HH, Jongen-Rêlo AL, Feldon J. The effects of temporary inactivation of the core and the shell subregions of the nucleus accumbens on prepulse inhibition of the acoustic startle reflex and activity in rats. Neuropsychopharmacology 2005, 30: 683–696.

    CAS  PubMed  Google Scholar 

  43. Ghods-Sharifi S, Floresco SB. Differential effects on effort discounting induced by inactivations of the nucleus accumbens core or shell. Behav Neurosci 2010, 124: 179–191

    Article  PubMed  Google Scholar 

  44. Johansson K, Hansen S. Novelty seeking and harm avoidance in relation to alcohol drinking in intact rats and following axon-sparing lesions to the amygdala and ventral striatum. Alcohol 2002, 37:147–156.

    Article  Google Scholar 

  45. Hikida T, Kimura K, Wada N, Funabiki K, Nakanishi S. Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior. Neuron 2010, 66: 896–907

    Article  CAS  PubMed  Google Scholar 

  46. Brog JS, Salyapongse A, Deutch AY, Zahm DS. The patterns of afferent innervation of the core and shell in the “Accumbens” part of the rat ventral striatum: Immunohistochemical detection of retrogradely transported fluoro-gold. J Comp Neurol 1993, 338: 255–278.

    Article  CAS  PubMed  Google Scholar 

  47. Reynolds SM, Zahm DS. Specificity in the projections of prefrontal and insular cortex to ventral striatopallidum and the extended amygdala. J Neurosci 2005, 25: 11757–11767.

    Article  CAS  PubMed  Google Scholar 

  48. Reynolds SM, Berridge KC. Emotional environments retune the valence of appetitive versus fearful functions in nucleus accumbens. Nat Neurosci 2008, 11: 423–425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ahmari SE, Spellman T, Douglass NL, Kheirbek MA, Simpson HB, Deisseroth K, et al. Repeated cortico-striatal stimulation generates persistent OCD-like behavior. Science 2013, 340: 1234–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Seif T, Chang S-J, Simms JA, Gibb SL, Dadgar J, Chen BT, et al. Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake. Nat Neurosci 2013, 16: 1094–1100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bardo MT, Donohew RL, Harrington NG. Psychobiology of novelty seeking and drug seeking behavior. Behav Brain Res 1996, 77: 23–43.

    Article  CAS  PubMed  Google Scholar 

  52. Belin D, Berson N, Balado E, Piazza PV, Deroche-Gamonet V. High-novelty-preference rats are predisposed to compulsive cocaine self-administration. Neuropsychopharmacology 2011, 36: 569–579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Daffner KR, Rentz DM, Scinto LFM, Faust R, Budson AE, Holcomb PJ. Pathophysiology underlying diminished attention to novel events in patients with early AD. Neurology 2001, 56: 1377–1383.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Basic Research Development Program (973 Program) of China (2013CB530902), the National Natural Science Foundation of China (91132712, 81571125, 81221003 and 81300979), the Natural Science Foundation of Zhejiang Province, China (LR12C09001 and Q13C090002), and the Fundamental Research Funds for the Central Universities of China (2014FZA7008). Chunlu Li was partly supported by a Chinese Postdoctoral Science Foundation grant (2015M570501).

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    Authors and Affiliations

    1. Department of Neurobiology and the Collaborative Innovation Center for Brain Science, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310058, China

      Chunlu Li, Jingjing Cheng, Yi Shen & Yu-Dong Zhou

    2. Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

      Yixiu Yan & Junlu Wang

    3. Department of Biological Science, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China

      Gang Xiao

    4. Department of Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China

      Jueqing Gu, Luqi Zhang & Siyu Yuan

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    1. Chunlu Li
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    Chunlu Li and Yixiu Yan have contributed equally to this work.

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    Li, C., Yan, Y., Cheng, J. et al. Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict. Neurosci. Bull. 32, 127–136 (2016). https://doi.org/10.1007/s12264-016-0015-z

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