The Effect of Glucose on Hippocampal-Dependent Contextual Fear Conditioning

Published:November 06, 2013DOI:


      The metabolic challenge of trauma disrupts hippocampal functioning, which is necessary for processing the complex co-occurring elements comprising the traumatic context. Poor contextual memory of trauma may subsequently contribute to intrusive memories and overgeneralization of fear. Glucose consumption following trauma may be a means to protect hippocampal functioning and contextual fear learning. This study experimentally examined the effect of glucose on hippocampal-dependent contextual learning versus cued fear learning in humans.


      Forty-two male participants underwent cued conditioning with an unconditional stimulus (US) (shock) paired with a discrete conditional stimulus (geometric shape) and context conditioning (requiring hippocampal processing) with a US unpredictably paired with a background context (picture of room). Participants were then blindly randomized to consume either a 25 g glucose or sweet-tasting placebo drink and returned for a test phase 24 hours later. Measures included acoustic startle response, US expectancy, blood glucose levels, and arousal ratings.


      The glucose group showed superior retention of hippocampal-dependent contextual learning at test relative to the placebo group, as demonstrated by acoustic startle response and US expectancy ratings. Glucose and placebo groups did not differ on any measure of cued fear learning at test.


      This study provides experimental evidence that in mildly stressed humans postconditioning glucose consumption improves retention of hippocampal-dependent contextual learning but not cued learning. Ultimately, glucose consumption following trauma may be a means of improving learning about the traumatic context, thereby preventing subsequent development of symptoms of posttraumatic stress.

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        • Kessler R.C.
        • Berglund P.
        • Demler O.
        • Jin R.
        • Merikangas K.R.
        • Walters E.E.
        Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 593-602
        • Hoge C.W.
        • Castro C.A.
        • Messer S.C.
        • McGurk D.
        • Cotting D.I.
        • Koffman R.L.
        Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care.
        N Engl J Med. 2004; 351: 13-22
        • Mahan A.L.
        • Ressler K.J.
        Fear conditioning, synaptic plasticity and the amygdala: Implications for posttraumatic stress disorder.
        Trends Neurosci. 2012; 35: 24-35
        • Yamamoto S.
        • Morinobu S.
        • Fuchikami M.
        • Kurata A.
        • Kozuru T.
        • Yamawaki S.
        Effects of single prolonged stress and D-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD.
        Neuropsychopharmacology. 2008; 33: 2108-2116
        • Choi D.C.
        • Rothbaum B.O.
        • Gerardi M.
        • Ressler K.J.
        Pharmacological enhancement of behavioral therapy: Focus on posttraumatic stress disorder.
        Curr Top Behav Neurosci. 2010; 2: 279-299
        • Brunet A.
        • Orr S.P.
        • Tremblay J.
        • Robertson K.
        • Nader K.
        • Pitman R.K.
        Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder.
        J Psychiatr Res. 2008; 42: 503-506
        • Hoge E.A.
        • Worthington J.J.
        • Nagurney J.T.
        • Chang Y.
        • Kay E.B.
        • Feterowski C.M.
        • et al.
        Effect of acute posttrauma propranolol on PTSD outcome and physiological responses during script-driven imagery.
        CNS Neurosci Ther. 2012; 18: 21-27
        • Chun M.M.
        • Phelps E.A.
        Memory deficits for implicit contextual information in amnesic subjects with hippocampal damage.
        Nat Neurosci. 1999; 2: 844-847
        • Brewin C.R.
        • Dalgleish T.
        • Joseph S.
        A dual representation theory of post-traumatic stress disorder.
        Psychol Rev. 1996; 103: 670-686
        • Brewin C.R.
        • Gregory J.D.
        • Lipton M.
        • Burgess N.
        Intrusive images in psychological disorders: Characteristics, neural mechanisms, and treatment implications.
        Psychol Rev. 2010; 117: 210-222
        • Sapolsky R.M.
        Stress in the Aging Brain, and the Mechanisms of Neuron Death.
        MIT Press, Cambridge, MA1992
        • Jacobs W.J.
        • Nadel L.
        Stress-induced recovery of fears and phobias.
        Psychol Rev. 1985; 92: 512-531
        • Gold P.E.
        Coordination of multiple memory systems.
        Neurobiol Learn Mem. 2004; 82: 230-242
        • Kitayama N.
        • Vaccarino V.
        • Kutner M.
        • Weiss P.
        • Bremner J.D.
        Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: A meta-analysis.
        J Affect Disord. 2005; 88: 79-86
        • Smith M.E.
        Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: A meta-analysis of structural MRI studies.
        Hippocampus. 2005; 15: 798-807
        • Karl A.
        • Schaefer M.
        • Malta L.S.
        • Dörfel D.
        • Rohleder N.
        • Werner A.
        A meta-analysis of structural brain abnormalities in PTSD.
        Neurosci Biobehav Rev. 2006; 30: 1004-1031
        • Acheson D.T.
        • Gresack J.E.
        • Risbrough V.B.
        Hippocampal dysfunction effects on context memory: Possible etiology for posttraumatic stress disorder.
        Neuropharmacology. 2012; 62: 674-685
        • Alvarez R.P.
        • Chen G.
        • Bodurka J.
        • Kaplan R.
        • Grillon C.
        Phasic and sustained fear in humans elicits distinct patterns of brain activity.
        Neuroimage. 2011; 55: 389-400
        • Marschner A.
        • Kalisch R.
        • Vervliet B.
        • Vansteenwegen D.
        • Büchel C.
        Dissociable roles for the hippocampus and the amygdala in human cued versus context fear conditioning.
        J Neurosci. 2008; 28: 9030-9036
        • Armony J.L.
        • Dolan R.J.
        Modulation of auditory neural responses by a visual context in human fear conditioning.
        Neuroreport. 2001; 12: 3407-3411
        • Grillon C.
        Associative learning deficits increase symptoms of anxiety in humans.
        Biol Psychiatry. 2002; 51: 851-858
        • Effting M.
        • Kindt M.
        Contextual control of human fear associations in a renewal paradigm.
        Behav Res Ther. 2007; 45: 2002-2018
        • Neumann D.L.
        • Lipp O.V.
        • Cory S.E.
        Conducting extinction in multiple contexts does not necessarily attenuate the renewal of shock expectancy in a fear-conditioning procedure with humans.
        Behav Res Ther. 2007; 45: 385-394
        • Bouton M.E.
        • Westbrook R.F.
        • Corcoran K.A.
        • Maren S.
        Contextual and temporal modulation of extinction: Behavioral and biological mechanisms.
        Biol Psychiatry. 2006; 60: 352-360
        • Rudy J.W.
        • Huff N.C.
        • Matus-Amat P.
        Understanding contextual fear conditioning: Insights from a two-process model.
        Neurosci Biohehav Rev. 2004; 28: 675-685
        • Maren S.
        • Aharonov G.
        • Fanselow M.S.
        Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats.
        Behav Brain Res. 1997; 88: 261-274
        • Driscoll I.
        • Howard S.R.
        • Prusky G.T.
        • Rudy J.W.
        • Sutherland R.J.
        Seahorse wins all races: Hippocampus participates in both linear and non-linear visual discrimination learning.
        Behav Brain Res. 2005; 164: 29-35
        • Rudy J.W.
        • Barrientos R.M.
        • O’Reilly R.C.
        Hippocampal formation supports conditioning to memory of a context.
        Behav Neurosci. 2002; 116: 530-538
        • Rudy J.W.
        • O’Reilly R.C.
        Contextual fear conditioning, conjunctive representations, pattern completion, and the hippocampus.
        Behav Neurosci. 1999; 113: 867-880
        • Minor T.R.
        • Saade S.
        Poststress glucose mitigates behavioral impairment in rats in the “learned helplessness” model of psychopathology.
        Biol Psychiatry. 1997; 42: 324-334
        • Choi D.W.
        Excitotoxic cell death.
        J Neurobiol. 1992; 23: 1261-1276
        • Clark D.D.
        • Sololoff L.
        Circulation and energy metabolism in the brain.
        in: Siegel G.L. Agranoff B.W. Albers R.W. Molinoff P.B. Brain Neurochemistry. Raven Press, New York1993: 645-680
        • Plumb T.N.
        • Sterlace S.A.
        • Cavanaugh K.A.
        • Minor T.R.
        Stress, brain adenosine signaling, and fatigue-related behavioral processes.
        in: Masino S.A. Boison D. Adenosine: A Key Link between Metabolism and Brain Activity. Springer, New York2013
        • Schwabe L.
        • Schächinger H.
        • de Kloet E.R.
        • Oitzl M.S.
        Stress impairs spatial but not early stimulus-response learning.
        Behav Brain Res. 2010; 12: 50-55
        • Shumake J.
        • Edwards E.
        • Gonzalez-Lima F.
        Dissociation of septo-hippocampal metabolism in the congenitally helpless rat.
        Neuroscience. 2002; 114: 373-377
        • Horner H.C.
        • Packan D.R.
        • Sapolsky R.M.
        Glucocorticoids inhibit glucose transport in cultured hippocampal neurons and glia.
        Neuroendocrinology. 1990; 52: 57-64
        • Horner H.C.
        • Munck A.
        • Leinhard G.E.
        Dexamethasone causes translocation of glucose transporters from the plasma membrane to an intracellular site in human fibroblasts.
        J Biol Chem. 1987; 262: 17696-17702
        • Kaouane N.
        • Porte Y.
        • Vallee M.
        • Brayada-Bruno L.
        • Mons N.
        • Calandreu L.
        • et al.
        Glucocorticoids can induce PTSD-like memory impairments in mice.
        Science. 2012; 335: 1510-1513
        • Cahill L.
        • Prins B.
        • Weber M.
        • McGaugh J.
        β-Adrenergic activation and memory for emotional events.
        Nature. 1994; 371: 702-704
        • Kennedy D.O.
        • Scholey A.B.
        Glucose administration, heart rate and cognitive performance: Effects of increasing mental effort.
        Psychopharmacology (Berl). 2000; 149: 63-71
        • Sünram-Lea S.I.
        • Foster J.K.
        • Durlach P.
        • Perez C.
        The effect of retrograde and anterograde glucose administration on memory performance in healthy young adults.
        Behav Brain Res. 2002; 134: 505-516
        • McNay E.C.
        • Gold P.E.
        Food for thought: Fluctuations in brain extracellular glucose provide insight into the mechanisms of memory modulation.
        Behav Cogn Neurosci Rev. 2002; 1: 264-280
        • Flint Jr, R.W.
        • Riccio D.C.
        Post-training glucose administration attenuates forgetting of passive-avoidance conditioning in 18-day-old rats.
        Neurobiol Learn Mem. 1999; 72: 62-67
        • Kopf S.R.
        • Baratti C.M.
        Effects of post-training administration of glucose on retention of a habituation response in mice: Participation of a central cholinergic mechanism.
        Neurobiol Learn Mem. 1996; 65: 253-260
        • Morgan 3rd, C.A.
        • Hazlett G.
        • Southwick S.
        • Rasmusson A.
        • Lieberman H.R.
        Effect of carbohydrate administration on recovery from stress-induced deficits in cognitive function: A double-blind, placebo-controlled study of soldiers exposed to survival school stress.
        Mil Med. 2009; 174: 132-138
        • Kawachi T.
        • Ishii K.
        • Sakamoto S.
        • Matsui M.
        • Mori T.
        • Sasaki M.
        Gender differences in cerebral glucose metabolism: A PET study.
        J Neurol Sci. 2002; 199: 79-83
        • Janghorbani M.
        • Amini M.
        Effects of gender and height on the oral glucose tolerance test: The Isfahan diabetes prevention study.
        Rev Diabet Stud. 2008; 5: 163-170
        • Gailliot M.T.
        • Baumeister R.F.
        • DeWall C.N.
        • Maner J.K.
        • Plant E.A.
        • Tice D.M.
        • et al.
        Self-control relies on glucose as a limited energy source: Willpower is more than a metaphor.
        J Pers Soc Psychol. 2007; 92: 325-336
        • Beck A.T.
        • Ward C.H.
        • Mendelson M.
        • Mock J.
        • Erbaugh J.
        An inventory for measuring depression.
        Arch Gen Psychiatry. 1961; 4: 561-571
        • Carver C.S.
        • White T.L.
        Behavioral inhibition, behavior activation, and affective responses to impending reward and punishment: The BIS/BAS scales.
        J Pers Soc Psychol. 1994; 67: 319-333
        • Fowles D.C.
        Applications of a behavioral theory of motivation to the concepts of anxiety and impulsivity.
        J Res Pers. 1987; 21: 417-435
        • Smith M.A.
        • Riby L.M.
        • van Eekelen J.A.M.
        • Foster J.K.
        Glucose modulation of episodic memory: A comprehensive review of the glucose memory facilitation effect.
        Neurosci Biobehav Rev. 2011; 35: 770-783
        • Durkin T.P.
        • Messier C.
        • de Boer P.
        • Westerink B.H.
        Raised glucose levels enhance scopolamine-induced acetylcholine overflow from the hippocampus: An in vivo microdialysis study in the rat.
        Behav Brain Res. 1992; 49: 181-188
        • Pych J.C.
        • Chang Q.
        • Colon-Rivera C.
        • Gold P.E.
        Acetylcholine release in hippocampus and striatum during testing on a rewarded spontaneous alternation task.
        Neurobiol Learn Mem. 2005; 84: 93-101
        • Pasiakos S.M.
        • Caruso C.M.
        • Kellogg M.D.
        • Kramer F.M.
        • Lieberman H.R.
        Appetite and endocrine regulators of energy balance after 2 days of energy restriction: Insulin, leptin, ghrelin, and DHEA-S.
        Obesity (Silver Spring). 2011; 19: 1124-1130
        • Haracz J.L.
        • Minor T.R.
        • Wilkins J.N.
        • Zommermann E.G.
        Learned helplessness: An experimental model of the DST in rats.
        Biol Psychiatry. 1988; 15: 388-396
        • Swenson R.M.
        • Vogel W.H.
        Plasma catecholamine and corticosterone as well as brain catecholamine changes during coping in rats exposed to stressful footshock.
        Pharmacol Biochem Behav. 1983; 18: 689-693
        • Weiss J.M.
        Psychological factors in stress and disease.
        Sci Am. 1972; 226: 104-113

      Linked Article

      • Contextual Fear Conditioning: Connecting Brain Glucose Sensing and Hippocampal-Dependent Memories
        Biological PsychiatryVol. 75Issue 11
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          Ensembles of spatial-temporal cues determine the context associated with a given episodic memory, and efficient encoding of such cues is critical for producing appropriate behavioral reactions to emotionally charged contexts. Growing evidence suggests that deficiencies in the neural mechanisms regulating contextual memory formation constitute a central component of posttraumatic stress disorder. Because the hippocampus plays a critical role in consolidating contextual spatial-temporal cues, it is plausible to assume that impaired hippocampal function may be causally linked to poor trauma contextual memories and to the etiology of posttraumatic stress disorder.
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