Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy.

This study investigated whether 21 days of restraint stress (6 hr/day) and the subsequent hippocampal dendritic atrophy would affect fear conditioning, a memory task with hippocampal-dependent and hippocampal-independent components. Restraint-stressed rats were injected daily (21 days) with tianeptine (10 mg/kg; to prevent hippocampal atrophy) or vehicle then tested on fear conditioning (Days 23-25, with 2 tone-shock pairings) and open field (Day 25). Restraint stress enhanced freezing to context (hippocampal-dependent behavior) and tone (hippocampal-independent) and decreased open-field exploration, irrespective of whether tianeptine was given. Results confirmed that stress produced CA3 dendritic atrophy and tianeptine prevented it. Moreover, CA3 dendritic atrophy was not permanent but reversed to control levels by 10 days after the cessation of restraint stress. These data argue that different neural substrates underlie spatial recognition memory and fear conditioning.

[1]  Joseph W. Harding,et al.  Effects of discrete kainic acid-induced hippocampal lesions on spatial and contextual learning and memory in rats , 1996, Brain Research.

[2]  E. Stone,et al.  Brain and adrenal tyrosine hydroxylase activity after chronic footshock stress , 1978, Pharmacology Biochemistry and Behavior.

[3]  J. Csernansky,et al.  Chronic corticosterone treatment impairs spontaneous alternation behavior in rats. , 1994, Behavioral and neural biology.

[4]  C. McKittrick,et al.  Stress and the Brain: A Paradoxical Role for Adrenal Steroids , 1995 .

[5]  J. Juraska,et al.  The dendritic morphology of pyramidal neurons in the rat hippocampal CA3 area. I. Cell types , 1989, Brain Research.

[6]  P. Solomon,et al.  Hippocampus, context, and conditioning. , 1991, Behavioral neuroscience.

[7]  R. Morris,et al.  Place navigation impaired in rats with hippocampal lesions , 1982, Nature.

[8]  M. Silbermann,et al.  The effects of long-term corticosterone administration on hippocampal morphology and cognitive performance of middle-aged rats , 1994, Brain Research.

[9]  V H Denenberg,et al.  OPEN‐FIELD BEHAVIOR IN THE RAT: WHAT DOES IT MEAN? * , 1969, Annals of the New York Academy of Sciences.

[10]  T. Kadar,et al.  Cognitive deficits induced in young rats by long-term corticosterone administration. , 1993, Behavioral and neural biology.

[11]  J. Schulkin,et al.  Effects of corticosterone on CRH mRNA and content in the bed nucleus of the stria terminalis; comparison with the effects in the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus , 1994, Brain Research.

[12]  E. Bullmore,et al.  Society for Neuroscience Abstracts , 1997 .

[13]  O. Bueno,et al.  Rats with dorsal hippocampal lesions do react to new stimuli but not to spatial changes of known stimuli. , 1990, Behavioral and neural biology.

[14]  J. Cassel,et al.  Morphological and behavioural effects of granule cell degeneration induced by intrahippocampal fluid injections in intact and fimbria-fornix lesioned rats , 1994, Behavioural Brain Research.

[15]  R. Sutherland,et al.  Configural association theory: The role of the hippocampal formation in learning, memory, and amnesia , 1989, Psychobiology.

[16]  R. Sapolsky Why Stress Is Bad for Your Brain , 1996, Science.

[17]  J. D. McGaugh,et al.  Glucocorticoid Receptor Agonist and Antagonist Administration into the Basolateral but Not Central Amygdala Modulates Memory Storage , 1997, Neurobiology of Learning and Memory.

[18]  J. R. Royce On the construct validity of open-field measures. , 1977 .

[19]  Y. Watanabe,et al.  Tianeptine attenuates stress-induced morphological changes in the hippocampus. , 1992, European journal of pharmacology.

[20]  W. Paré,et al.  Effect of stress on the behavior and 5-HT system in Sprague-Dawley and Wistar Kyoto rat strains , 1996, Integrative physiological and behavioral science : the official journal of the Pavlovian Society.

[21]  B. McEwen,et al.  Chronic Psychosocial Stress Causes Apical Dendritic Atrophy of Hippocampal CA3 Pyramidal Neurons in Subordinate Tree Shrews , 1996, The Journal of Neuroscience.

[22]  Robert M. Sapolsky,et al.  Stress, the Aging Brain, and the Mechanisms of Neuron Death , 1992 .

[23]  K. Roth,et al.  Stress, behavioral arousal, and open field activity—A reexamination of emotionality in the rat , 1979, Neuroscience & Biobehavioral Reviews.

[24]  T. Shors,et al.  Stress-induced sensitization and facilitated learning require NMDA receptor activation. , 1995, Neuroreport.

[25]  R. Duman,et al.  Involvement of corticotropin-releasing factor in chronic stress regulation of the brain noradrenergic system. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Joseph E LeDoux,et al.  Corticosterone Potentiation of Conditioned Fear in Rats a , 1994, Annals of the New York Academy of Sciences.

[27]  M. Fanselow,et al.  Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats , 1997, Behavioural Brain Research.

[28]  M. Meaney,et al.  Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[29]  T. Robbins,et al.  Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues , 1991, Neuroscience.

[30]  R. S. Harris,et al.  Vitamins and Hormones , 1948 .

[31]  H. Cameron,et al.  Phenytoin prevents stress‐ and corticosterone‐induced atrophy of CA3 pyramidal neurons , 1992, Hippocampus.

[32]  E. Kandel,et al.  Control of Memory Formation Through Regulated Expression of a CaMKII Transgene , 1996, Science.

[33]  E Save,et al.  Object exploration and reactions to spatial and nonspatial changes in hooded rats following damage to parietal cortex or hippocampal formation. , 1992, Behavioral neuroscience.

[34]  Joseph E LeDoux,et al.  Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. , 1992, Behavioral neuroscience.

[35]  R. Adolphs,et al.  Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans , 1995, Science.

[36]  S. Berent,et al.  Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome , 1992, Biological Psychiatry.

[37]  R. Paylor,et al.  Hippocampal lesions cause learning deficits in inbred mice in the Morris water maze and conditioned-fear task. , 1997, Behavioral neuroscience.

[38]  E. Azmitia,et al.  Brain Corticosteroid Receptors: Studies on the Mechanism, Function, and Neurotoxicity of Corticosteroid Action. Proceedings of a conference. Arlington, Virginia, March 2-5, 1994. , 1995, Annals of the New York Academy of Sciences.

[39]  M. Fanselow,et al.  NMDA processes mediate anterograde amnesia of contextual fear conditioning induced by hippocampal damage: immunization against amnesia by context preexposure. , 1994, Behavioral neuroscience.

[40]  B. McEwen,et al.  Morphological changes in the hippocampal CA3 region induced by non-invasive glucocorticoid administration: a paradox , 1998, Brain Research.

[41]  Paul Leonard Gabbott,et al.  The ‘single’ section Golgi-impregnation procedure: methodological description , 1984, Journal of Neuroscience Methods.

[42]  R N Walsh,et al.  The Open-Field Test: a critical review. , 1976, Psychological bulletin.

[43]  H. Eichenbaum,et al.  The hippocampus--what does it do? , 1992, Behavioral and neural biology.

[44]  G. Winocur,et al.  The hippocampus and conditioning to contextual cues. , 1987, Behavioral neuroscience.

[45]  D. Compton,et al.  Spatial learning following posterior parietal or hippocampal lesions. , 1994, Neuroreport.

[46]  Joseph E LeDoux,et al.  GABAA and GABAB receptors differentially regulate synaptic transmission in the auditory thalamo‐amygdala pathway: An in vivo microiontophoretic study and a model , 1996, Synapse.

[47]  R G Phillips,et al.  Lesions of the fornix but not the entorhinal or perirhinal cortex interfere with contextual fear conditioning , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[48]  Bruce S. McEwen,et al.  Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons , 1992, Brain Research.

[49]  A. Convit,et al.  Cortisol levels during human aging predict hippocampal atrophy and memory deficits , 1998, Nature Neuroscience.

[50]  M. Fanselow,et al.  Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear. , 1993, Behavioral neuroscience.

[51]  T. Tabira,et al.  Stress induces neuronal death in the hippocampus of castrated rats , 1992, Neuroscience Letters.

[52]  C. McKittrick,et al.  Effects of chronic social stress on tyrosine hydroxylase mRNA and protein levels. , 1995, Brain research. Molecular brain research.

[53]  R. J. McDonald,et al.  Hippocampus, amygdala, and memory deficits in rats , 1990, Behavioural Brain Research.

[54]  B. McEwen,et al.  Effects of chronic corticosterone ingestion on spatial memory performance and hippocampal serotonergic function , 1993, Brain Research.

[55]  Joseph E LeDoux,et al.  Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning. , 1994, Learning & memory.

[56]  James L. McGaugh,et al.  Amygdaloid Nuclei Lesions Differentially Affect Glucocorticoid-Induced Memory Enhancement in an Inhibitory Avoidance Task , 1996, Neurobiology of Learning and Memory.

[57]  N. Kalin,et al.  Restraint stress increases corticotropin-releasing hormone mRNA content in the amygdala and paraventricular nucleus , 1994, Brain Research.

[58]  Michael S. Fanselow,et al.  Electrolytic Lesions of the Fimbria/Fornix, Dorsal Hippocampus, or Entorhinal Cortex Produce Anterograde Deficits in Contextual Fear Conditioning in Rats , 1997, Neurobiology of Learning and Memory.

[59]  L. Nadel,et al.  The Hippocampus as a Cognitive Map , 1978 .

[60]  R. C. Honey,et al.  Dissociable effects of selective lesions to hippocampal subsystems on exploratory behavior, contextual learning, and spatial learning. , 1997, Behavioral neuroscience.

[61]  C Weiss,et al.  Stress-induced facilitation of classical conditioning. , 1992, Science.

[62]  B. McEwen,et al.  Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment. , 1996, Behavioral neuroscience.

[63]  E. R. Kloet,et al.  Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. , 1985, Endocrinology.

[64]  J. A. Heyden,et al.  Characterization of stress-induced long-term behavioural changes in rats: Evidence in favor of anxiety , 1992, Physiology & Behavior.

[65]  Alcino J. Silva,et al.  The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. , 1998, Behavioral neuroscience.

[66]  M. Fanselow,et al.  Modality-specific retrograde amnesia of fear. , 1992, Science.

[67]  Bruce S. McEwen,et al.  Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons , 1990, Brain Research.

[68]  Michael Davis,et al.  Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala , 1990, Nature.

[69]  Jonathan C. Gewirtz,et al.  Second-order fear conditioning prevented by blocking NMDA receptors in amygdala , 1997, Nature.

[70]  B. McEwen,et al.  Selective Retention of Corticosterone by Limbic Structures in Rat Brain , 1968, Nature.

[71]  C. Sandi,et al.  Correlational relationship between shock intensity and corticosterone secretion on the establishment and subsequent expression of contextual fear conditioning. , 1998, Behavioral neuroscience.

[72]  G. Hall,et al.  Contextual control of conditioned responding in rats with dorsal hippocampal lesions. , 1996, Behavioral neuroscience.

[73]  Sunanda,et al.  Effect of chronic restraint stress on dendritic spines and excrescences of hippocampal CA3 pyramidal neurons—a quantitative study , 1995, Brain Research.

[74]  J. D. McGaugh,et al.  Amygdala modulation of hippocampal-dependent and caudate nucleus-dependent memory processes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[75]  D C Blanchard,et al.  Crouching as an index of fear. , 1969, Journal of comparative and physiological psychology.

[76]  H. Thoenen Induction of Tyrosine Hydroxylase in Peripheral and Central Adrenergic Neurones by Cold-exposure of Rats , 1970, Nature.

[77]  Bruce S. McEwen,et al.  Repeated stress causes reversible impairments of spatial memory performance , 1994, Brain Research.

[78]  A. S. Clark,et al.  Anabolic-androgenic steroid and adrenal steroid effects on hippocampal plasticity , 1995, Brain Research.

[79]  R. Sapolsky,et al.  Hippocampal damage associated with prolonged and fatal stress in primates , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[80]  M. Fanselow,et al.  N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats , 1996 .