Skip to main content
    • Aa
    • Aa

Noradrenergic-glucocorticoid modulation of emotional memory encoding in the human hippocampus

  • J. Kukolja (a1) (a2) (a3), D. Klingmüller (a4), W. Maier (a1), G. R. Fink (a2) (a3) and R. Hurlemann (a1)...

Current rodent models emphasize the joint action of the stress mediators noradrenaline (NE) and cortisol (CORT) in conferring a memory advantage of emotional over neutral stimuli.


Using a pharmacological strategy of tackling this stress-related mechanism to enhance human episodic (autobiographical) memory, we measured amygdala-hippocampal responses during encoding of emotional and neutral stimuli with functional magnetic resonance imaging in 51 healthy subjects under four pharmacological conditions in a double-blind parallel group design: (i) placebo; (ii) the NE-reuptake inhibitor reboxetine (4 mg); (iii) hydrocortisone (synthetic CORT) (30 mg); or (iv) both agents in combination.


Differential drug effects were found in the left hippocampus, whereas hydrocortisone alone selectively decreased hippocampal responses to emotional relative to neutral stimuli, reboxetine potentiated hippocampal responses to these stimuli. Importantly, the inhibitory influence of hydrocortisone was reversed by co-administration of reboxetine.


Our results imply that stress levels of CORT alone attenuate hippocampal responses to emotional stimuli, an effect possibly related to a regulatory negative feedback loop. However, when simultaneously elevated to stress levels, NE and CORT act together to synergistically enhance hippocampal activity during encoding of emotional stimuli, a mechanism that may turn maladaptive under circumstances of traumatic stress.

Corresponding author
*Address for correspondence: J. Kukolja, M.D., Department of Neurology, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany. (Email:
Hide All
Abercrombie HC, Kalin NH, Thurow ME, Rosenkranz MA, Davidson RJ (2003). Cortisol variation in humans affects memory for emotionally laden and neutral information. Behavioral Neuroscience 117, 505516.
Amunts K, Kedo O, Kindler M, Pieperhoff P, Mohlberg H, Shah NJ, Habel U, Schneider F, Zilles K (2005). Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps. Anatomy and Embryology (Berl) 210, 343352.
Brewin CR (2008). What is it that a neurobiological model of PTSD must explain? Progress in Brain Research 167, 217228.
Buchanan TW, Lovallo WR (2001). Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology 26, 307317.
Burgess N, Maguire EA, O'Keefe J (2002). The human hippocampus and spatial and episodic memory. Neuron 35, 625641.
Cahill L, Prins B, Weber M, McGaugh JL (1994). Beta-adrenergic activation and memory for emotional events. Nature 371, 702704.
Chamberlain SR, Muller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ (2006). Neurochemical modulation of response inhibition and probabilistic learning in humans. Science 311, 861863.
Diamond DM, Campbell AM, Park CR, Halonen J, Zoladz PR (2007). The temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, flashbulb and traumatic memories, and the Yerkes-Dodson law. Neural Plasticity 60803, 133.
Dolcos F, LaBar KS, Cabeza R (2004). Interaction between the amygdala and the medial temporal lobe memory system predicts better memory for emotional events. Neuron 42, 855863.
Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K, Zilles K (2005). A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage 25, 13251335.
Goossens L, Kukolja J, Onur OA, Fink GR, Maier W, Griez E, Schruers K, Hurlemann R (2009). Selective processing of social stimuli in the superficial amygdala. Human Brain Mapping 30, 33323338.
Green DM, Swets JA (1966). Signal Detection Theory and Biophysics. Wiley: New York.
Het S, Ramlow G, Wolf OT (2005). A meta-analytic review of the effects of acute cortisol administration on human memory. Psychoneuroendocrinology 30, 771784.
Hurlemann R (2008). Noradrenergic-glucocorticoid mechanisms in emotion-induced amnesia: from adaptation to disease. Psychopharmacology (Berlin) 197, 1323.
Hurlemann R, Hawellek B, Matusch A, Kolsch H, Wollersen H, Madea B, Vogeley K, Maier W, Dolan RJ (2005). Noradrenergic modulation of emotion-induced forgetting and remembering. Journal of Neuroscience 25, 63436349.
Hurlemann R, Matusch A, Hawellek B, Klingmuller D, Kolsch H, Maier W, Dolan RJ (2007). Emotion-induced retrograde amnesia varies as a function of noradrenergic-glucocorticoid activity. Psychopharmacology (Berlin) 194, 261269.
Hurlemann R, Walter H, Rehme AK, Kukolja J, Santoro SC, Schmidt C, Schnell K, Musshoff F, Keysers C, Maier W, Kendrick KM, Onur OA (2010). Human amygdala reactivity is diminished by the beta-noradrenergic antagonist propranolol. Psychological Medicine 40, 18391848.
Joels M, Pu Z, Wiegert O, Oitzl MS, Krugers HJ (2006). Learning under stress: how does it work? Trends in Cognitive Sciences 10, 152158.
Kent JM (2000). SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet 355, 911918.
Kiebel S, Holmes AP (2003). The General Linear Model. In Human Brain Function (ed. Frackowiak R. S. J., Friston K., Frith C. D., Dolan R. J., Price C. J., Ashburner J. and Penny W. D.), pp. 725760. Academic Press: San Diego.
Kukolja J, Schläpfer TE, Keysers C, Klingmüller D, Maier W, Fink GR, Hurlemann R (2008 a). Modeling a negative response bias in the human amygdala by noradrenergic-glucocorticoid interactions. Journal of Neuroscience 28, 1286812876.
Kukolja J, Thiel CM, Wolf OT, Fink GR (2008 b). Increased cortisol levels in cognitively challenging situations are beneficial in young but not older subjects. Psychopharmacology (Berlin) 201, 293304.
LaBar KS, Cabeza R (2006). Cognitive neuroscience of emotional memory. Nature Reviews Neuroscience 7, 5464.
Lang PJ, Bradley MM, Cuthbert BN (2008). International affective picture system (IAPS): affective ratings of pictures and instruction manual. Technical Report A-8. University of Florida: Gainesville, FL.
McGaugh JL, Roozendaal B (2002). Role of adrenal stress hormones in forming lasting memories in the brain. Current Opinion in Neurobiology 12, 205210.
Macmillan NA (1993). Signal detection theory as data analysis method and psychological decision model. In A Handbook for Data Analysis in the Behavioral Sciences: Methodological Issues (ed. Keren G. and Lewis C.), pp. 2157. Erlbaum: Hillsdale, NJ.
Onur OA, Walter H, Schlaepfer TE, Rehme AK, Schmidt C, Keysers C, Maier W, Hurlemann R (2009). Noradrenergic enhancement of amygdala responses to fear. Social Cognitive and Affective Neuroscience 4, 119126.
Onur OA, Schlaepfer TE, Kukolja J, Bauer A, Jeung H, Patin A, Otte DM, Shah NJ, Maier W, Kendrick KM, Fink GR, Hurlemann R (2010). The N-methyl-D-aspartate receptor co-agonist D-cycloserine facilitates declarative learning and hippocampal activity in humans. Biological Psychiatry 67, 12051211.
Papps BP, Shajahan PM, Ebmeier KP, O'Carroll RE (2002). The effects of noradrenergic re-uptake inhibition on memory encoding in man. Psychopharmacology (Berlin) 159, 311318.
Penny WD, Holmes AP (2003). Random effects analysis. In Human Brain Function (ed. Frackowiak R. S. J., Friston K. J., Frith C. D., Dolan R. J., Price C. J., Ashburner J. and Penny W. D.), pp. 843850. Academic Press: San Diego.
Phelps EA (2004). Human emotion and memory: interactions of the amygdala and hippocampal complex. Current Opinion in Neurobiology 14, 198202.
Putman P, Hermans EJ, Koppeschaar H, van Schijndel A, van Honk J (2007). A single administration of cortisol acutely reduces preconscious attention for fear in anxious young men. Psychoneuroendocrinology 32, 793802.
Quirarte GL, Roozendaal B, McGaugh JL (1997). Glucocorticoid enhancement of memory storage involves noradrenergic activation in the basolateral amygdala. Proceedings of the National Academy of Sciences USA 94, 1404814053.
Rauch SL, Whalen PJ, Shin LM, McInerney SC, Macklin ML, Lasko NB, Orr SP, Pitman RK (2000). Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biological Psychiatry 47, 769776.
Richardson MP, Strange BA, Dolan RJ (2004). Encoding of emotional memories depends on amygdala and hippocampus and their interactions. Nature Neuroscience 7, 278285.
Roozendaal B, McEwen BS, Chattarji S (2009). Stress, memory and the amygdala. Nature Reviews Neuroscience 10, 423433.
Roozendaal B, Okuda S, van der Zee EA, McGaugh JL (2006). Glucocorticoid enhancement of memory requires arousal-induced noradrenergic activation in the basolateral amygdala. Proceedings of the National Academy of Sciences USA 103, 67416746.
Rosenkranz JA, Venheim ER, Padival M (2010). Chronic stress causes amygdala hyperexcitability in rodents. Biological Psychiatry 67, 11281136.
Scates AC, Doraiswamy PM (2000). Reboxetine: a selective norepinephrine reuptake inhibitor for the treatment of depression. Annals of Pharmacotherapy 34, 13021312.
Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B, Macklin ML, Lasko NB, Cavanagh SR, Krangel TS, Orr SP, Pitman RK, Whalen PJ, Rauch SL (2005). A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Archives of General Psychiatry 62, 273281.
Soravia LM, Heinrichs M, Aerni A, Maroni C, Schelling G, Ehlert U, Roozendaal B, de Quervain DJ (2006). Glucocorticoids reduce phobic fear in humans. Proceedings of the National Academy of Sciences USA 103, 55855590.
Stanislaw H, Todorov N (1999). Calculation of signal detection theory measures. Behavior Research Methods, Instruments and Computers 31, 137149.
Strange BA, Dolan RJ (2004). Beta-adrenergic modulation of emotional memory-evoked human amygdala and hippocampal responses. Proceedings of the National Academy of Sciences USA 101, 1145411458.
van Stegeren AH, Goekoop R, Everaerd W, Scheltens P, Barkhof F, Kuijer JP, Rombouts SA (2005). Noradrenaline mediates amygdala activation in men and women during encoding of emotional material. Neuroimage 24, 898909.
van Stegeren AH, Roozendaal B, Kindt M, Wolf OT, Joels M (2010). Interacting noradrenergic and corticosteroid systems shift human brain activation patterns during encoding. Neurobiology of Learning and Memory 93, 5665.
van Stegeren AH, Wolf OT, Everaerd W, Scheltens P, Barkhof F, Rombouts SA (2007). Endogenous cortisol level interacts with noradrenergic activation in the human amygdala. Neurobiology of Learning and Memory 87, 5766.
Worsley KJ, Marrett S, Neelin P, Vandal AC, Friston KJ, Evans AC (1996). A unified statistical approach for determining significant signals in images of cerebral activation. Human Brain Mapping 4, 5874.
Yamamoto S, Morinobu S, Takei S, Fuchikami M, Matsuki A, Yamawaki S, Liberzon I (2009). Single prolonged stress: toward an animal model of posttraumatic stress disorder. Depression and Anxiety 26, 11101117.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary Materials

Kukolja Supplementary Material
Kukolja Supplementary Data

 Word (37 KB)
37 KB


Full text views

Total number of HTML views: 15
Total number of PDF views: 51 *
Loading metrics...

Abstract views

Total abstract views: 238 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 21st October 2017. This data will be updated every 24 hours.