Comprehensive Physiology Wiley Online Library

Neurobiology of Interpreting and Responding to Stressful Events: Paradigmatic Role of the Hippocampus

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Physiological Stress Responses
1.1 What Systems Respond to Stressors?
1.2 Habituation and Sensitization
1.3 Psychosocial Stressors
2 Plasticity and Adaptation in the Central Nervous System: Hippocampus
2.1 Role of the Hippocampus in Behavioral and Neuroendocrine Adaptation
2.2 Plasticity of the Hippocampus
3 Hippocampal Neuronal Morphology is Altered by Hibernation, Chronic Stress, and Aging
3.1 Pharmacological Manipulations of Dendritic Atrophy
3.2 Mechanism of Dendritic Atrophy and Role of Adrenal Steroids
3.3 Hippocampal Neuronal Damage Resulting from Chronic Stress and Aging
3.4 Structural Changes in the Human Hippocampus
3.5 Stress Effects on Cognitive Performance in Rodents and Humans
3.6 Life‐Long Implications of Stressful Experiences
4 The Price of Adaptation: Allostasis and Allostatic Load
4.1 Definitions
4.2 Anticipation and Behavior in Allostatic Load
4.3 Four Types of Allostatic Load
4.4 Individuals versus Groups
4.5 Measurement of Allostatic Load
5 Conclusions
Figure 1. Figure 1.

The brain processes events and interprets them in light of past experiences, early life events, and the current social context. The amygdala is involved in forming and recalling aversive experiences, whereas the hippocampus participates in storing and recalling episodic memory and contextual memories. The net result is the determination of whether a particular event is threatening or nonthreatening. If threatening, there is a choice between a high‐cost or low‐cost response, “cost” referring to the further risk or potential harm to which the response may lead. Aggression and actions such as smoking, drinking, and driving recklessly are high‐cost responses that involve considerable risk; withdrawing from a confrontation is generally considered to be a low‐cost response. If a response is not available or the assessment of the situation leads to uncertainty as to a threat, then a state of vigilance or possibly of helplessness may ensue. Social intelligence is a product of brain function and how astutely an individual evaluates potential threats and the risks involved and how adept the individual is at managing a complex set of social interactions (see Chapter ). Physiological responses of adaptive (allostatic) systems are determined by how threatening or nonthreatening an event is interpreted to be by the brain. PTSD, posttraumatic stress disorder.

Modified from by permission
Figure 2. Figure 2.

Physiological responses to stressful events involve activation of the autonomic nervous system and the hypothalamo‐pituitary‐adrenal axis. Drawn by Dr. Christina McKittrick. ACTH, corticotropin; NE, norepinephrine; GI, gastrointestinal; CRH, corticotropin‐releasing hormone; hc, hippocampus; hyp, hypothalamus.

Figure 3. Figure 3.

Representative dark‐field photomicrographs of immediate‐early gene (IEG) induction after stress in paraventricular nuclei (PVN, mRNAs for both c‐fos and zif/268), locus ceruleus (LC), and midbrain raphe (c‐fos mRNA). Figure shows the lack of a signal in unstressed control brains and the strong signal elicited 1 h after a single restraint stress. Chronic restraint for 14 days, however, causes habituation to acute application of restraint on day 15. Application of a novel stress, namely, shaking, produces a large IEG response in these brain regions (data not shown).

From Watanabe et al. with permission
Figure 4. Figure 4.

Corticosterone (CORT) produces an inverted U‐shaped dose‐response curve for primed‐burst potentiation (PBP), which is related to long‐term potentiation, in CA1 pyramidal neurons of the hippocampus. Each symbol represents data for serum CORT and population spike height for PBP from rats that were intact, adrenalectomized (ADX), or ADX and given subcutaneous CORT pellets.

From Diamond et al. with permission
Figure 5. Figure 5.

Anatomy and plasticity of the hippocampal formation in rats, which resembles that of human hippocampus in basic anatomical organization. Top: Circuit diagram of the hippocampus, showing the three‐cell circuitry. The dentate gyrus receives input from the entorhinal cortex and sends the mossy fiber projection from its granule neurons to the CA3 region, which sends its projection to the CA1 pyramidal neurons. Lower left: The dentate gyrus continues to replace granule neurons in adult life, and this process is inhibited by excitatory input and adrenal steroids, as well as stressful experiences, and increased by an enriched environment, estrogens and serotonin. Lower right: CA3 pyramidal neurons show atrophy of apical dendrites under the combined influence of adrenal steroids and excitatory amino acid (EAA) neurotransmitters acting via N‐methyl‐D‐aspartate (NMDA) receptors. Presynaptic kainate receptors on mossy fiber terminals appear to play an important role in this process, and serotonin acts synergistically with EAAs. Serotonergic input to CA3 affects the more distal portions of the apical dendrites. Repeated stress causes apical dendrites to undergo atrophy by a process that is blocked by interfering with glucocorticoid synthesis, interfering with EAA transmission by dilantin or by NMDA receptor antagonist, administering a benzodiazepine (BZ) to enhance γ‐aminobutyric acid (GABA) inhibitory transmission, or enhancing the reuptake of serotonin using tianeptine, an atypical antidepressant drug.

Figure 6. Figure 6.

Chronic glucocorticoid treatment for 21d or restraint stress of 21d causes the apical dendrites of CA3 pyramidal neurons to atrophy.

From by permission
Figure 7. Figure 7.

Effect of 1 h immobilization stress on extracellular levels of excitatory amino acids in the hippocampus (A) and medial prefrontal (MPF) cortex (B) of young (3 to 4 months old) and aging (22 to 24 months old) rats. Both young and old rats released glutamate during stress, but during the 2 h poststress period, old rats continued to release glutamate and young rats did not.

From Lowy et al. with permission


Figure 1.

The brain processes events and interprets them in light of past experiences, early life events, and the current social context. The amygdala is involved in forming and recalling aversive experiences, whereas the hippocampus participates in storing and recalling episodic memory and contextual memories. The net result is the determination of whether a particular event is threatening or nonthreatening. If threatening, there is a choice between a high‐cost or low‐cost response, “cost” referring to the further risk or potential harm to which the response may lead. Aggression and actions such as smoking, drinking, and driving recklessly are high‐cost responses that involve considerable risk; withdrawing from a confrontation is generally considered to be a low‐cost response. If a response is not available or the assessment of the situation leads to uncertainty as to a threat, then a state of vigilance or possibly of helplessness may ensue. Social intelligence is a product of brain function and how astutely an individual evaluates potential threats and the risks involved and how adept the individual is at managing a complex set of social interactions (see Chapter ). Physiological responses of adaptive (allostatic) systems are determined by how threatening or nonthreatening an event is interpreted to be by the brain. PTSD, posttraumatic stress disorder.

Modified from by permission


Figure 2.

Physiological responses to stressful events involve activation of the autonomic nervous system and the hypothalamo‐pituitary‐adrenal axis. Drawn by Dr. Christina McKittrick. ACTH, corticotropin; NE, norepinephrine; GI, gastrointestinal; CRH, corticotropin‐releasing hormone; hc, hippocampus; hyp, hypothalamus.



Figure 3.

Representative dark‐field photomicrographs of immediate‐early gene (IEG) induction after stress in paraventricular nuclei (PVN, mRNAs for both c‐fos and zif/268), locus ceruleus (LC), and midbrain raphe (c‐fos mRNA). Figure shows the lack of a signal in unstressed control brains and the strong signal elicited 1 h after a single restraint stress. Chronic restraint for 14 days, however, causes habituation to acute application of restraint on day 15. Application of a novel stress, namely, shaking, produces a large IEG response in these brain regions (data not shown).

From Watanabe et al. with permission


Figure 4.

Corticosterone (CORT) produces an inverted U‐shaped dose‐response curve for primed‐burst potentiation (PBP), which is related to long‐term potentiation, in CA1 pyramidal neurons of the hippocampus. Each symbol represents data for serum CORT and population spike height for PBP from rats that were intact, adrenalectomized (ADX), or ADX and given subcutaneous CORT pellets.

From Diamond et al. with permission


Figure 5.

Anatomy and plasticity of the hippocampal formation in rats, which resembles that of human hippocampus in basic anatomical organization. Top: Circuit diagram of the hippocampus, showing the three‐cell circuitry. The dentate gyrus receives input from the entorhinal cortex and sends the mossy fiber projection from its granule neurons to the CA3 region, which sends its projection to the CA1 pyramidal neurons. Lower left: The dentate gyrus continues to replace granule neurons in adult life, and this process is inhibited by excitatory input and adrenal steroids, as well as stressful experiences, and increased by an enriched environment, estrogens and serotonin. Lower right: CA3 pyramidal neurons show atrophy of apical dendrites under the combined influence of adrenal steroids and excitatory amino acid (EAA) neurotransmitters acting via N‐methyl‐D‐aspartate (NMDA) receptors. Presynaptic kainate receptors on mossy fiber terminals appear to play an important role in this process, and serotonin acts synergistically with EAAs. Serotonergic input to CA3 affects the more distal portions of the apical dendrites. Repeated stress causes apical dendrites to undergo atrophy by a process that is blocked by interfering with glucocorticoid synthesis, interfering with EAA transmission by dilantin or by NMDA receptor antagonist, administering a benzodiazepine (BZ) to enhance γ‐aminobutyric acid (GABA) inhibitory transmission, or enhancing the reuptake of serotonin using tianeptine, an atypical antidepressant drug.



Figure 6.

Chronic glucocorticoid treatment for 21d or restraint stress of 21d causes the apical dendrites of CA3 pyramidal neurons to atrophy.

From by permission


Figure 7.

Effect of 1 h immobilization stress on extracellular levels of excitatory amino acids in the hippocampus (A) and medial prefrontal (MPF) cortex (B) of young (3 to 4 months old) and aging (22 to 24 months old) rats. Both young and old rats released glutamate during stress, but during the 2 h poststress period, old rats continued to release glutamate and young rats did not.

From Lowy et al. with permission
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Bruce S. McEwen. Neurobiology of Interpreting and Responding to Stressful Events: Paradigmatic Role of the Hippocampus. Compr Physiol 2011, Supplement 23: Handbook of Physiology, The Endocrine System, Coping with the Environment: Neural and Endocrine Mechanisms: 155-178. First published in print 2001. doi: 10.1002/cphy.cp070409