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Neuropeptidases, Stress, and Memory—A Promising Perspective

1 Unit of Physiology, University of Jaén, Jaén, Spain;
2 Cardiovascular and Metabolic Syndrome Advisor, Rossemaison, Switzerland

Special Issues: Is the role of the hippocampus in memory one of storage, facilitating cortical association networks, or both?

Stress has been demonstrated to be a key modulator in learning and memory processes, in which the hippocampus plays a central role. A great number of neuropeptides have been reported to modulate learning and memory under stressful conditions. Neuropeptidases are proteolytic enzymes capable of regulating the function of neuropeptides in the central and peripheral nervous system. In this regard, a number of neuropeptidases, i.e. angiotensinases, oxytocinase, or enkephalinases, have received attention. Their involvement in stress and memory processes is a promising perspective, as it is possible to influence their activities through various activators or inhibitors and, consequently, to pharmacologically modulate the functions of the endogenous substrates that are involved. The present review describes the key findings showing the involvement of neuropeptides and neuropeptidases in stress and memory and highlights the role of the hippocampus in these processes.
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Keywords stress; memory; hippocampus; aminopeptidases; angiotensins; oxytocin; vasopressin; enkephalins

Citation: I. Prieto, A.B. Segarra, M. de Gasparo, M. Ramírez-Sánchez. Neuropeptidases, Stress, and Memory—A Promising Perspective. AIMS Neuroscience, 2016, 3(4): 487-501. doi: 10.3934/Neuroscience.2016.4.487


  • 1. Goldstein DS, Kopin IJ (2007) Evolution of concepts of stress. Stress 10: 109-120.    
  • 2. Sterling P (2012) Allostasis: a model of predictive regulation. Physiol Behav 106: 5-15.
  • 3. Davidson RJ, McEwen BS (2012) Social influences on neuroplasticity: stress and interventions to promote well-being. Nat Neurosci 15: 689-695.    
  • 4. Godsil BP, Kiss JP, Spedding M, et al. (2013) The hippocampal-prefrontal pathway: the weak link in psychiatric disorders? Eur Neuropsychopharmacol 23: 1165-1181.    
  • 5. McEwen BS (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87: 873-904.    
  • 6. Ulrich-Lai YM, Herman JP (2009) Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 10: 397-409.    
  • 7. Hernández J, Prieto I, Segarra AB, et al. (2015) Interaction of neuropeptidase activities in cortico-limbic regions after acute restraint stress. Behav Brain Res 287: 42-48.    
  • 8. Segarra AB, Hernández J, Prieto I, et al. (2016) Neuropeptidase activities in plasma after acute restraint stress. Interaction with cortico-limbic areas. Acta Neuropsychiatr 28: 239-243.
  • 9. Sandi C, Pinelo-Nava MT (2007) Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast 2007: 78970.
  • 10. Schwabe L, Joëls M, Roozendaal B, et al. (2012) Stress effects on memory: an update and integration. Neurosci Biobehav Rev 36: 1740-1749.    
  • 11. Richter-Levin G, Akirav I (2000) Amygdala-hippocampus dynamic interaction in relation to memory. Mol Neurobiol 22: 11-20.    
  • 12. Kim JJ, Diamond DM (2002) The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 3: 453-462.
  • 13. Sebastian V, Estil JB, Chen D, et al. (2013) Acute physiological stress promotes clustering of synaptic markers and alters spine morphology in the hippocampus. PLoS One 8: e79077.    
  • 14. Moss RA (2016) A Theory on the Singular Function of the Hippocampus: Facilitating the Binding of New Circuits of Cortical Columns. AIMS Neurosci 3: 264-305.    
  • 15. Toth I, Neumann ID (2013) Animal models of social avoidance and social fear. Cell Tissue Res 354: 107-118.    
  • 16. Campos AC, Fogaça MV, Aguiar DC, et al. (2013) Animal models of anxiety disorders and stress. Rev Bras Psiquiatr 35: S101-111.    
  • 17. Sandi C, Pinelo-Nava MT (2007) Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast 2007: 78970.
  • 18. Gülpinar MA, Yegen BC (2004) The physiology of learning and memory: role of peptides and stress. Curr Protein Pept Sci 5: 457-473.    
  • 19. Bilkei-Gorzo A, Racz I, Michel K, et al. (2008) Control of hormonal stress reactivity by the endogenous opioid system. Psychoneuroendocrinology 33: 425-436.
  • 20. Narita M, Kaneko C, Miyoshi K, et al. (2006) Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala. Neuropsychopharmacology 3:739-750.
  • 21. Neumann ID, Torner L, Wigger A (2000) Brain oxytocin: differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats. Neuroscience 95: 567-575.
  • 22. Neumann ID (2007) Stimuli and consequences of dendritic release of oxytocin within the brain. Bioch Soc Trans 35: 1252-1257.    
  • 23. Wright JW, Yamamoto BJ, Harding JW (2008) Angiotensin receptor subtype mediated physiologies and behaviors: new discoveries and clinical targets. Prog Neurobiol 84: 157-181.    
  • 24. Saavedra JM, Benicky J (2007) Brain and peripheral angiotensin II play a major role in stress. Stress 10: 185-193.    
  • 25. Nomura S, Ito T, Mizutani S (2004) Placental leucine aminopeptidase. Aminopeptidases in biology and disease. Kluwer Academic/Plenum, New York, Hooper NM and Lendeckel U Eds. pp 45-59.
  • 26. Solhonne B, Gros C, Pollard H, et al. (1987) Major localization of aminopeptidase M in rat brain. Neuroscience 22: 225-232.    
  • 27. Thompson MW, Hersh LB (2004) The puromycin-sensitive aminopeptidase. Aminopeptidases in biology and disease. Kluwer Academic/Plenum, New York, Hooper NM and Lendeckel U Eds. pp 1-15.
  • 28. Ramírez-Sánchez M, Prieto I, Wangensteen R, et al. (2013) The renin-angiotensin system: new insight into old therapies. Curr Med Chem 20: 1313-1322.    
  • 29. Prieto I, Villarejo AB, Segarra AB, et al. (2015) Tissue distribution of CysAP activity and its relationship to blood pressure and water balance. Life Sci 134: 173-178.
  • 30. Albiston AL, Mustafa T, McDowall SG, et al. (2003) AT4 receptor is insulin-regulated membrane aminopeptidase: potential mechanisms of memory enhancement. Trends Endocrinol Metab 14: 72-77.    
  • 31. De Bundel D, Smolders I,Vanderheyden P, et al. (2008) Ang II and Ang IV: unraveling the mechanism of action on synaptic plasticity, memory, and epilepsy. CNS Neurosci Ther 14: 315-339.    
  • 32. De Bundel D, Demaegdt H, Lahoutte T, et al. (2010) Involvement of the AT1 receptor subtype in the effects of angiotensin IV and LVV-haemorphin 7 on hippocampal neurotransmitter levels and spatial working memory. J Neurochem 112: 1223-1234.    
  • 33. Drolet G, Dumont EC, Gosselin I, et al. (2001) Role of endogenous opioid system in the regulation of the stress response. Prog Neuropsychopharmacol Biol Psychiatry 25: 729-741.    
  • 34. McCubbin JA (1993) Stress and endogenous opioids: behavioral and circulatory interactions. Biol Psychol 35: 91-122.    
  • 35. Bodnar RJ (2014) Endogenous opiates and behavior: 2013. Peptides 62: 67-136.    
  • 36. Bodnar RJ (2016) Endogenous opiates and behavior: 2014. Peptides 75: 18-70.    
  • 37. Bali A, Randhawa PK, Jaggi AS (2015) Stress and opioids: role of opioids in modulating
  • stress-related behavior and effect of stress on morphine conditioned place preference. Neurosci Biobehav Rev 51: 138-150.
  • 38. Olff M, Frijling JL, Kubzansky LD, et al. (2013) The role of oxytocin in social bonding, stress regulation and mental health: an update on the moderating effects of context and interindividual differences. Psychoneuroendocrinology 38: 1883-1894.    
  • 39. Okimoto N, Bosch OJ, Slattery DA, et al. (2012) RGS2 mediates the anxiolytic effect of oxytocin. Brain Res 1453: 26-33.    
  • 40. Neumann ID, Slattery DA (2016) Oxytocin in General Anxiety and Social Fear: A Translational Approach. Biol Psychiatry 79: 213-221.    
  • 41. Light KC, Grewen KM, Amico JA, et al. (2004) Deficits in plasma oxytocin responses and increased negative affect, stress, and blood pressure in mothers with cocaine exposure during pregnancy. Addict Behav 29: 1541-1564.    
  • 42. Linnen AM, Ellenbogen MA, Cardoso C, et al. (2012) Intranasal oxytocin and salivary cortisol concentrations during social rejection in university students. Stress 15: 393-402.    
  • 43. Norman GJ, Cacioppo JT, Morris JS, et al. (2011) Oxytocin increases autonomic cardiac control: moderation by loneliness. Biol Psychol 86: 174-180.    
  • 44. Windle RJ, Kershaw YM, Shanks N, et al. (2004) Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity. J Neurosci 24: 2974-2982.    
  • 45. Domes G, Heinrichs M, Gläscher J, et al. (2007) Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 62: 1187-1190.    
  • 46. Kirsch P, Esslinger C, Chen Q, et al. (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25: 11489-11493.    
  • 47. Viviani D, Charlet A, van den Burg E, et al. (2011) Oxytocin selectively gates fear responses through distinct outputs from the central amygdala. Science 333: 104-107.    
  • 48. Sripada CS, Phan KL, Labuschagne I, et al. (2013) Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex. Int J Neuropsychopharmacol 16: 255-260.    
  • 49. Ferguson JN, Young LJ, Hearn EF, et al. (2000) Social amnesia in mice lacking the oxytocin gene. Nat Genet 25: 284-288.    
  • 50. Wirth MM (2015) Hormones, stress, and cognition: The effects of glucocorticoids and oxytocin on memory. Adapt Human Behav Physiol 1: 177-201.    
  • 51. McDonald JK, Barrett AJ (1986) Mammalian proteases: a glossary and bibliography (Academic Press, London) vol 2.
  • 52. Checler F (1993) Methods in neurotransmitter and neuropeptide research, eds Parvez SH, Naoi M, Nagatsu T, Parvez S (Elsevier, Amsterdam).
  • 53. Ramírez M, Prieto I, Banegas I, et al. (2011) Neuropeptidases. Methods Mol Biol 789: 287-294.    
  • 54. Morales-Mulia M, de Gortari P, Amaya MI, et al. (2012) Activity and expression of enkephalinase and aminopeptidase N in regions of the mesocorticolimbic system are selectively modified by acute ethanol administration. J Mol Neurosci 46: 58-67.    
  • 55. Ramírez M, Prieto I, Alba F, et al. (2008) Role of central and peripheral aminopeptidase activities in the control of blood pressure: a working hypothesis. Heart Fail Rev 13: 339-353.    
  • 56. Reid KJ, McGee-Koch LL, Zee PC (2011) Cognition in circadian rhythm sleep disorders. Prog Brain Res 190: 3-20.    
  • 57. Wright KP, Lowry CA, Lebourgeois MK (2012) Circadian and wakefulness-sleep modulation of cognition in humans. Front Mol Neurosci 5: 50.
  • 58. Ramírez M, Prieto I, Vives F, et al. (2004) Neuropeptides, neuropeptidases and brain asymmetry. Curr Protein Pept Sci 5: 497-506.    
  • 59. Turner AJ (2004) Neprilysin, In Handbook of Proteolytic Enzymes, eds Barrett AJ, Rawlings ND, Woessner JF (Elsevier, London) 419-426.
  • 60. Iwata N, Takaki Y, Fukami S, et al. (2002) Region-specific reduction of A beta-degrading endopeptidase, neprilysin, in mouse hippocampus upon aging. J Neurosci Res 70: 493-500.    
  • 61. Iwata N, Mizukami H, Shirotani K, et al. (2004) Presynaptic localization of neprilysin contributes to efficient clearance of amyloid-beta peptide in mouse brain. J Neurosci 24: 991-998.    
  • 62. Li L, Tang BL (2005) Environmental enrichment and neurodegenerative diseases. Biochem Biophys Res Commun 334: 293-297.    
  • 63. Deweerdt S (2011) Prevention: activity is the best medicine. Nature 475: S16-17.    
  • 64. Albiston AL, Fernando R, Ye S, et al. (2004) Alzheimer's, angiotensin IV and an aminopeptidase. Biol Pharm Bull 27: 765-767.    
  • 65. Marvar PJ, Goodman J, Fuchs S, et al. (2014) Angiotensin type 1 receptor inhibition enhances the extinction of fear memory. Biol Psychiatry 75: 864-872.    
  • 66. Hmazzou R, Flahault A, Marc Y, et al. (2016) [OP.6D.03] Mode of action of rb150, an aminopeptidase a inhibitor prodrug as a centrally-acting antihypertensive agent in doca-salt hypertensive rats. J Hypertens 34 Suppl 2: e75.
  • 67. Hernández J, Segarra AB, Ramírez M, et al. (2009) Stress influences brain enkephalinase, oxytocinase and angiotensinase activities: a new hypothesis. Neuropsychobiology 59: 184-189.    
  • 68. Tuppy H, Nesbadva H (1957) The aminopeptidase acitvity of serum in pregnancy and its relationship to the potential for inactivating oxytocin. Monatsh Chem 88: 977-988.    
  • 69. Tsujimoto M, Mizutani S, Adachi H, et al. (1992) Identification of human placental leucine aminopeptidase as oxytocinase. Arch Biochem Biophys 292: 388-392.    
  • 70. Keller SR (2003) The insulin-regulated aminopeptidase: a companion and regulator of GLUT4. Front Biosci 8: s410-420.    
  • 71. Stragier B, De Bundel D, Sarre S, et al. (2008) Involvement of insulin-regulated aminopeptidase in the effects of the renin-angiotensin fragment angiotensin IV: a review. Heart Fail Rev 13: 321-337.    
  • 72. Gard PR (2008) Cognitive-enhancing effects of angiotensin IV. BMC Neurosci 9 Suppl 2: S15.
  • 73. Banegas I, Prieto I, Vives F, et al. (2010) Lateralized response of oxytocinase activity in the medial prefrontal cortex of a unilateral rat model of Parkinson's disease. Behav. Brain Res 213: 328-331.    
  • 74. Ramírez M, Banegas I, Segarra AB, et al. (2012) Bilateral Distribution of Oxytocinase Activity in the Medial Prefrontal Cortex of Spontaneously Hypertensive Rats with Experimental Hemiparkinsonism, Mechanisms in Parkinson's Disease—Models and Treatments, Dr. Juliana Dushanova (Ed.), ISBN: 978-953-307-876-2.
  • 75. Prieto I, Villarejo AB, Segarra AB, et al. (2014) Brain, heart and kidney correlate for the control of blood pressure and water balance: role of angiotensinases. Neuroendocrinology 100: 198-208.    
  • 76. Maroun M, Richter-Levin G (2003) Exposure to acute stress blocks the induction of long-term potentiation of the amygdala-prefrontal cortex pathway in vivo. J Neurosci 23: 4406-4409.
  • 77. Richardson MP, Strange BA, Dolan RJ (2004) Encoding of emotional memories depends on amygdala and hippocampus and their interactions. Nat Neurosci 7: 278-285.    
  • 78. Bass DI, Nizam ZG, Partain KN, et al. (2014) Amygdala-mediated enhancement of memory for specific events depends on the hippocampus. Neurobiol Learn Mem 107: 37-41.    
  • 79. Thayer JF, Lane RD (2009) Claude Bernard and the heart-brain connection: further elaboration of a model of neurovisceral integration. Neurosci Biobehav Rev 33:81-88.    
  • 80. Banegas I, Prieto I, Vives F, et al. (2009) Asymmetrical response of aminopeptidase A and nitric oxide in plasma of normotensive and hypertensive rats with experimental hemiparkinsonism. Neuropharmacology 56:573-579.    


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