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Basolateral amygdala regulation of adult hippocampal neurogenesis and fear-related activation of newborn neurons

Molecular Psychiatry volume 17, pages 527–536 (2012)Cite this article

Abstract

Impaired regulation of emotional memory is a feature of several affective disorders, including depression, anxiety and post-traumatic stress disorder. Such regulation occurs, in part, by interactions between the hippocampus and the basolateral amygdala (BLA). Recent studies have indicated that within the adult hippocampus, newborn neurons may contribute to support emotional memory, and that regulation of hippocampal neurogenesis is implicated in depressive disorders. How emotional information affects newborn neurons in adults is not clear. Given the role of the BLA in hippocampus-dependent emotional memory, we investigated whether hippocampal neurogenesis was sensitive to emotional stimuli from the BLA. We show that BLA lesions suppress adult neurogenesis, while lesions of the central nucleus of the amygdala do not. Similarly, we show that reducing BLA activity through viral vector-mediated overexpression of an outwardly rectifying potassium channel suppresses neurogenesis. We also show that BLA lesions prevent selective activation of immature newborn neurons in response to a fear-conditioning task. These results demonstrate that BLA activity regulates adult hippocampal neurogenesis and the fear context-specific activation of newborn neurons. Together, these findings denote functional implications for proliferation and recruitment of new neurons into emotional memory circuits.

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References

  1. Richardson MP, Strange BA, Dolan RJ . Encoding of emotional memories depends on amygdala and hippocampus and their interactions. Nat Neurosci 2004; 7: 278–285.

    Article  CAS  Google Scholar 

  2. Tsoory MM, Vouimba RM, Akirav I, Kavushansky A, Avital A, Richter-Levin G . Amygdala modulation of memory-related processes in the hippocampus: potential relevance to PTSD. Prog Brain Res 2008; 167: 35–51.

    Article  CAS  Google Scholar 

  3. Roozendaal B, McEwen BS, Chattarji S . Stress, memory and the amygdala. Nat Rev Neurosci 2009; 10: 423–433.

    Article  CAS  Google Scholar 

  4. McGaugh JL . The amygdala modulates the consolidation of memories of emotionally arousing experiences. Ann Rev Neurosci 2004; 27: 1–28.

    Article  CAS  Google Scholar 

  5. Maren S . Neurotoxic basolateral amygdala lesions impair learning and memory but not the performance of conditional fear in rats. J Neurosci 1999; 19: 8696–8703.

    Article  CAS  Google Scholar 

  6. Maren S, Aharonov G, Fanselow MS . Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: absence of a temporal gradient. Behav Neurosci 1996; 110: 718–726.

    Article  CAS  Google Scholar 

  7. Frey S, Bergado-Rosado J, Seidenbecher T, Pape H-C, Frey JU . Reinforcement of early long-term potentiation (early-LTP) in dentate gyrus by stimulation of the basolateral amgdala: heterosynaptic induction mechansims of late-LTP. J Neurosci 2001; 21: 3697–3703.

    Article  CAS  Google Scholar 

  8. Jas J, Almaguer W, Frey JU, Bergado J . Lesioning the fimbria-fornix impairs basolateral amygdala induced reinforcement of LTP in the dentate gyrus. Brain Res 2000; 861: 186–189.

    Article  CAS  Google Scholar 

  9. Ikegaya Y, Saito H, Abe K . The basomedial and basolateral amygdaloid nuclei contribute to the induction of long-term potentiation in the dentate gyrus in vivo. Eur J Neurosci 1996; 8: 1833–1839.

    Article  CAS  Google Scholar 

  10. Bergado JA, Frey S, Lopez J, Almaguer-Melian W, Frey JU . Cholinergic afferents to the locus coeruleus and noradrenergic afferents to the medial septum mediate LTP-reinforcement in the dentate gyrus by stimulation of the amygdala. Neurobiol Learn Mem 2007; 88: 331–341.

    Article  CAS  Google Scholar 

  11. Paz R, Pelletier JG, Bauer EP, Paré D . Emotional enhancement of memory via amygdala-driven facilitation of rhinal interactions. Nat Neurosci 2006; 9: 1321–1329.

    Article  CAS  Google Scholar 

  12. McIntyre CK, Miyashita T, Setlow B, Marjon KD, Steward O, Guzowski JF et al. Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus. Proc Natl Acad Sci USA 2005; 102: 10718–10723.

    Article  CAS  Google Scholar 

  13. Roozendaal B, Griffith QK, Buranday J, de Quervain DJ-F, McGaugh JL . The hippocampus mediates glucocorticoid-induced impairment of spatial memory retrieval: dependence on the basolateral amygdala. Proc Natl Acad Sci USA 2003; 100: 1328–1333.

    Article  CAS  Google Scholar 

  14. Roozendaal B, Nguyen BT, Power AE, McGaugh JL . Basolateral amygdala noradrenergic influence enables enhancement of memory consolidation induced by hippocampal glucocorticoid receptor activation. Proc Natl Acad Sci USA 1999; 96: 11642–11647.

    Article  CAS  Google Scholar 

  15. Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, Monckton JE et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci USA 2006; 103: 17501–17506.

    Article  CAS  Google Scholar 

  16. Hernández-Rabaza V, Llorens-Martín M, Velázquez-Sánchez C, Ferragud A, Arcusa A, Gumus HG et al. Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal. Neurosci 2009; 159: 59–68.

    Article  Google Scholar 

  17. Kitamura T, Saitoh Y, Takashima N, Murayama A, Niibori Y, Ageta H et al. Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell 2009; 139: 814–827.

    Article  CAS  Google Scholar 

  18. Deng W, Saxe MD, Gallina IS, Gage FH . Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J Neurosci 2009; 29: 13532–13542.

    Article  CAS  Google Scholar 

  19. Dupret D, Fabre A, Döbrössy MD, Panatier A, Rodríguez JJ, Lamarque S et al. Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol 2007; 5: 1683–1694.

    Article  CAS  Google Scholar 

  20. Walker TL, White A, Black DM, Wallace RH, Sah P, Bartlett PF . Latent stem and progenitor cells in the hippocampus are activated by neural excitation. J Neurosci 2008; 28: 5240–5247.

    Article  CAS  Google Scholar 

  21. Eriksson PS . Neurogenesis in the adult human hippocampus. Nat Med 1998; 4: 1313–1317.

    Article  CAS  Google Scholar 

  22. Gould E . How widespread is adult neurogenesis in mammals? Nat Rev Neurosci 2007; 8: 481–488.

    Article  CAS  Google Scholar 

  23. Kirby ED, Kaufer D . Stress and adult neurogenesis in the mammalian central nervous system. In: Soreq H, Friedman A and Kaufer D (eds). STRESS: From Molecules To Behavior. Wiley-Blackwell: Weinheim, Germany, 2009, pp 71–91.

    Chapter  Google Scholar 

  24. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH . Functional neurogenesis in the adult hippocampus. Nature 2002; 415: 1030–1034.

    Article  CAS  Google Scholar 

  25. Farioli-Vecchioli S, Saraulli D, Costanzi M, Pacioni S, Cin I, Aceti M et al. The timing of differentiation of adult hippocampal neurons is crucial for spatial memory. PLoS Biol 2008; 6: 2188–2204.

    Article  CAS  Google Scholar 

  26. Revest J-M, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza P-V et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry 2009; 14: 959–967.

    Article  Google Scholar 

  27. Dere E, Pause BM, Pietrowsky R . Emotion and episodic memory in neuropsychiatric disorders. Behav Brain Res 2010; 215: 162–171.

    Article  Google Scholar 

  28. Goosens KA, Maren S . Contextual and auditory fear conditioning are mediated by the lateral, basal, and central amygdaloid nuclei in rats. Learn Mem 2001; 8: 148–155.

    Article  CAS  Google Scholar 

  29. Lee AL, Dumas TC, Tarapore PE, Webster BR, Ho DY, Kaufer D et al. Potassium channel gene therapy can prevent neuron death resulting from necrotic and apoptotic insults. J Neurochem 2003; 86: 1079–1088.

    Article  CAS  Google Scholar 

  30. Kee N, Teixeira CM, Wang AH, Frankland PW . Imaging activation of adult-generated granule cells in spatial memory. Nat Protocol 2007; 2: 3033–3044.

    Article  CAS  Google Scholar 

  31. Paxinos G, Watson C . The Rat Brain in Stereotaxic Coordinates-The New Coronal Set. Elsevier Academic Press: Burlington, MA, 2004.

    Google Scholar 

  32. Ikegaya Y, Saito H, Abe K . Attenuated hippocampal long-term potentiation in basolateral amygdala-lesioned rats. Brain Res 1994; 656: 157–164.

    Article  CAS  Google Scholar 

  33. Mitra R, Ferguson D, Sapolsky RM . SK2 potassium channel overexpression in basolateral amygdala reduces anxiety, stress-induced corticosterone secretion and dendritic arborization. Mol Psychiatry 2009; 14: 847–855.

    Article  CAS  Google Scholar 

  34. Tashiro A, Makino H, Gage FH . Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J Neurosci 2007; 27: 3252–3259.

    Article  CAS  Google Scholar 

  35. Kee N, Teixeira CM, Wang AH, Frankland PW . Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 2007; 10: 355–362.

    Article  CAS  Google Scholar 

  36. Stone SS, Teixeira CM, Zaslavsky K, Wheeler AL, Martinez-Canabal A, Wang AH et al. Functional convergence of developmentally and adult-generated granule cells in dentate gyrus circuits supporting hippocampus-dependent memory. Hippocampus 2010; e-pub ahead of print 7 September 2010; doi:10.1002/hipo.20845.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  38. Gao C, Gill MB, Tronson NC, Guedea AL, Guzmán YF, Huh KH et al. Hippocampal NMDA receptor subunits differentially regulate fear memory formation and neuronal signal propagation. Hippocampus 2010; 20: 1072–1082.

    Article  CAS  Google Scholar 

  39. LeDoux JE . Emotion circuits in the brain. Ann Rev Neurosci 2000; 23: 155–184.

    Article  CAS  Google Scholar 

  40. Meir A, Ginsburg S, Butkevich A, Kachalsky SG, Kaiserman I, Ahdut R et al. Ion channels in presynaptic nerve terminals and control of transmitter release. Physiol Rev 1999; 79: 1019–1088.

    Article  CAS  Google Scholar 

  41. Wenzel HJ, Vacher H, Clark E, Trimmer JS, Lee AL, Sapolsky RM et al. Structural consequences of Kcna1 gene deletion and transfer in the mouse hippocampus. Epilepsia 2007; 48: 2023–2046.

    Article  CAS  Google Scholar 

  42. Pikkarainen M, Ronkko S, Savander V, Insausti R, Pitkanen A . Projections from the lateral, basal and accessory basal nuclei of the amygdala to the hipoocampal formation in the rat. J Comp Neurol 1999; 403: 229–260.

    Article  CAS  Google Scholar 

  43. Wheal HV, Millera JJ . Pharmacological identification of acetylcholine and glutamate excitatory systems in the dentate gyrus of the rat. Brain Res 1980; 182: 145–155.

    Article  CAS  Google Scholar 

  44. Itou Y, Nochi R, Kuribayashi H, Saito Y, Hisatsune T . Cholinergic activation of hippocampal neural stem cells in aged dentate gyrus. Hippocampus 2010; 21: 446–459.

    Article  Google Scholar 

  45. Ge S, Sailor KA, Ming G-l, Song H . Synaptic integration and plasticity of new neurons in the adult hippocampus. J Physiol 2008; 586: 3759–3765.

    Article  CAS  Google Scholar 

  46. Joo J-Y, Kim B-W, Lee J-S, Park J-Y, Kim S, Yun Y-J et al. Activation of NMDA receptors increases proliferation and differentiation of hippocampal neural progenitor cells. J Cell Sci 2007; 120: 1358–1370.

    Article  CAS  Google Scholar 

  47. Bruel-Jungerman E, Davis S, Rampon C, Laroche S . Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J Neurosci 2006; 26: 5888–5893.

    Article  CAS  Google Scholar 

  48. Chun SK, Sun W, Park JJ, Jung MW . Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus. Neurobiol Learn Mem 2006; 86: 322–329.

    Article  Google Scholar 

  49. Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E . Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 2002; 12: 578–584.

    Article  Google Scholar 

  50. Snyder JS, Choe JS, Clifford MA, Jeurling SI, Hurley P, Brown A et al. Adult-born hippocampal neurons are more numerous, faster maturing, and more involved in behavior in rats than in mice. J Neurosci 2009; 29: 14484–14495.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Chloe LaLonde, Abhiram Gande, Anna Geraghty and Brandon Thai for technical assistance. EDK was supported by a California Institute for Regenerative Medicine pre-doctoral fellowship and a National Defense Science and Engineering Graduate Research fellowship from the Department of Defense. KG was supported by a NARSAD Young Investigator Award and the NIH (R01MH849662). DK was supported by a NARSAD Young Investigator Award and the NIMH BRAINS award (R01MH087495).

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Authors and Affiliations

  1. Helen Wills Neuroscience Institute, University of California-Berkeley, Berkeley, CA, USA

    E D Kirby & D Kaufer

  2. Department of Integrative Biology, University of California-Berkeley, Berkeley, CA, USA

    A R Friedman, C Ying, W G Sun & D Kaufer

  3. Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, CA, USA

    D Covarrubias

  4. McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    K A Goosens

  5. Department of Biological Sciences, Neurology and Neurological Sciences, Stanford, CA, USA

    R M Sapolsky

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  1. E D Kirby
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Correspondence to D Kaufer.

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Kirby, E., Friedman, A., Covarrubias, D. et al. Basolateral amygdala regulation of adult hippocampal neurogenesis and fear-related activation of newborn neurons. Mol Psychiatry 17, 527–536 (2012). https://doi.org/10.1038/mp.2011.71

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