HORMONES AND MEMORY

Hormones influence many physiological systems involved in regulating adaptation to environmental changes. In addition to their many other influences, hormones serve an adaptive role in regulating the neurobiological processes underlying memory formation and other cognitive processes. Extensive evidence indicates that, in laboratory animals, hormones administered shortly after training influence the retention of recently acquired information. Although many hormones either enhance or impair long-term retention when administered after training, the effects of hormones normally released by mildly stressful stimulation have been studied most extensively. The findings suggest that endogenous hormones released by emotionally arousing training experiences influence long-term memory by modulating memory consolidation processes. In addition to such acute effects, hormones may also have more sustained effects on cognition through neurotrophic and neuroprotective actions.

Epinephrine

The adrenergic catecholamine epinephrine is released into the blood from the adrenal medulla following arousing or stressful stimulation. Systemic injections of epinephrine administered after training produce dose-dependent effects on subsequent retention: Low doses enhance retention, whereas high doses impair retention. As epinephrine passes the blood-brain barrier poorly, epinephrine's effects on memory appear to be initiated by the activation of peripheral adrenoceptors. The finding that drugs that selectively block peripheral β -adrenoceptors (when administered systemically) prevent the memory-enhancing effects of epinephrine supports this conclusion. Epinephrine acts on receptors in the liver to initiate the release of glucose. Evidence that glucose can enhance memory suggests that glycogenolysis may play a role in mediating epinephrine influences on memory. Epinephrine also stimulates the release of the arousal-related neuromodulator norepinephrine in the brain by activating β -adrenoceptors located on vagal afferents terminating on brain-stem noradrenergic cell groups in the nucleus of the solitary tract and locus coeruleus. Noradrenergic projections originating in these nuclei innervate forebrain structures involved in learning and memory. Extensive evidence indicates that the memory-enhancing effects of epinephrine involve the release of norepinephrine and activation of β -adrenoceptors within a specific brain region, the basolateral nucleus of the amygdaloid complex. Microinfusions of β -adrenoceptor antagonists into this brain region block the memory-modulating effects of peripherally administered epinephrine and microinfusions of norepinephrine into this nucleus after training enhance memory. Norepinephrine also enhances memory consolidation when administered to other brain regions, including the nucleus of the solitary tract and the hippocampus.

Glucocorticoids

Glucocorticoids (corticosterone in the rat, cortisol in humans), which is a class of steroid stress hormones released from the adrenal cortex, also influence long-term memory consolidation. Glucocorticoid hormones freely enter the brain and bind to two intracellular types of adrenal steroid receptors, glucocorticoid receptors and mineralocorticoid receptors. The low-affinity glucocorticoid receptors are involved in mediating glucocorticoid effects on memory consolidation. Glucocorticoids act through intracellular and intranuclear receptors and can affect gene transcription by direct binding of receptor homodimers to DNA. Glucocorticoids may also affect memory consolidation through transactivation or protein-protein interactions with other transcription factors or effector systems. Administration of low doses of glucocorticoids enhances memory consolidation and glucocorticoid antagonists impair consolidation. Memory-modulating effects are induced by systemic injections of glucocorticoid receptor agonists and antagonists as well as by infusions administered into several brain regions, including the nucleus of the solitary tract, the basolateral amygdala, or the hippocampus. Glucocorticoid-induced memory-modulating effects require concurrent noradrenergic activation within the amygdala. Glucocorticoid effects on memory consolidation are, thus, conditional, that is, their actions require coactivation of other transmitter systems. Glucocorticoid effects on memory are not restricted to influences on consolidation. Glucocorticoids generally impair short-term memory in experimental animals and human subjects, and, when administered shortly before retention testing, glucocorticoids also impair retrieval of long-term memory for spatial-contextual and declarative information. These effects are temporary and dissipate within several hours after stress exposure or hormone injection. Prolonged exposure to high levels of glucocorticoids due to chronic stress tends to induce prolonged impairment of cognitive functioning.

ACTH and CRH

The peptide hormone adrenocorticotropin (ACTH) is secreted from the anterior pituitary. Early studies investigating the influence of hormones on learning and memory reported that hypophysectomy produced impairment of learning and memory and that the impairment was attenuated by injections of ACTH. Many subsequent experiments using animals with intact pituitary glands found that memory is enhanced by low doses of ACTH and impaired by high doses. Evidence that retention is affected by fragments of the ACTH peptide that do not induce the release of glucocorticoids from the adrenal cortex indicates that ACTH effects on memory are not mediated by glucocorticoids. The corticotropin-releasing hormone (CRH), another peptide hormone released into the blood and brain after arousing or stressful stimulation, enhances memory consolidation when administered shortly after training, an effect that does not require release of glucocorticoids. The involvement of extra-hypothalamic CRH in memory and related cognitive functions has been found in experiments with both animal and human subjects. Local infusions of CRH into the hippocampus, the amygdala, or the bed nucleus of the stria terminalis affect memory consolidation by interacting with noradrenergic mechanisms.

Vasopressin and Oxytocin

Vasopressin and oxytocin are synthesized in the hypothalamus and are released in the brain and into the cerebrospinal fluid and general circulation (via the posterior pituitary). The possibility that vasopressin may influence learning and memory was suggested by findings that lesions of the posterior pituitary affected the extinction of an avoidance response and that the effect was attenuated by injections of an extract of pituitary tissue containing vasopressin. Subsequent research has provided extensive evidence that memory is enhanced by vasopressin administered immediately after training. Although some evidence suggests that the effects of vasopressin on memory may be mediated, at least in part, by peripheral effects, including alterations in blood pressure, other evidence indicates that central actions of vasopressin influence memory consolidation. Peptide metabolites of vasopressin that do not affect blood pressure have highly potent effects on memory. Additionally, administration of a vasopressin antagonist into the cerebral ventricles blocks the memory-enhancing effect of peripherally administered vasopressin without altering vasopressin effects on blood pressure. Memory is also enhanced by low doses of vasopressin administered directly into a number of brain regions, including the hippocampus. Evidence that lesions of the dorsal adrenergic bundle block the memory-enhancing effect of vasopressin indicates that, as with other hormonal effects of memory, nonadrenergic activation may be required. Although the effects of oxytocin have been less extensively examined, oxytocin may either impair or enhance memory, depending on the experimental training conditions.

Opioid Peptides

Research findings indicating that the opiate drug morphine impairs memory when injected after training suggest that endogenous opioid peptides may play a role in the regulation of memory consolidation. The endogenous opioid peptide β -endorphin is released within the brain and is also released from the anterior pituitary into the blood along with ACTH. Enkephalins are released from the adrenal medulla, together with epinephrine. Experimental findings indicating that effects of these opioid peptides on memory are similar to those of morphine suggest that endogenously released opioid peptides regulate memory consolidation. Studies of the effects of opiate antagonists provide additional support for this view: Opiate antagonists enhance retention when administered after training. As with other hormones, opioid peptide influences on memory involve the amygdala. Injections of opiate agonists and antagonists administered directly into the amygdala after training produce effects on memory highly comparable to those produced by systemic injections. Such effects also involve interactions with the noradrenergic system: β -adrenoceptor antagonists injected into the amygdala block the memory-enhancing effects of the opiate antagonist naloxone. Such findings agree with the evidence that opioid peptides inhibit the release of norepinephrine in the amygdala and other brain regions. Memory can also be influenced by a number of peptide hormones, including substance P, neuropeptide Y, somatostatin, prolactin, and cholecystokinin (CCK) that are not generally thought to be stress related.

Gonadal Hormones

Gonadal hormones generally have more sustained effects on cognitive functioning, but acute effects on memory consolidation have also been reported. For example, testosterone and estradiol, major gonadal steroid hormones, have neurotrophic and neuroprotective actions on the brain. A decline in cognitive function (particularly spatial memory) can be found in postmenopausal women and estrogen-replacement therapy may attenuate the deficits. Estrogens also appear to have a protective effect against the neurodegenerative and memory-impairing effects of excessive glucocorticoids.

Interactions Among Hormonal Systems

There are many interactions among hormones as well as interactions among hormones and transmitter systems in modulating memory consolidation. For example, the effects of epinephrine on memory are influenced by glucocorticoids. The memory-enhancing effects of epinephrine are blocked by metyrapone, a drug that prevents the synthesis and release of glucocorticoids. Furthermore, vasopressin is ineffective in influencing memory consolidation in adrenal demedullated animals. Opioid peptides modulate memory consolidation through influences on central noradrenergic and cholinergic systems. Naloxone effects on memory are blocked by the (-adrenoceptor antagonist propranolol as well as by the muscarinic cholinergic antagonist atropine. Additionally, the muscarinic cholinergic agonist oxytremorine and the acetylcholinesterase inhibitor physostigmine attenuate the memory-impairing effects of β -endorphin. Thus, several hormonal systems known to have important roles in enabling adaptation to stressful conditions also serve a highly adaptive role of influencing memory by interacting with neuromodulatory systems in brain regions involved in regulating memory consolidation.

See also:STRESS AND MEMORY

Bibliography

Bohus, B. (1994). Humoral modulation of learning and memory processes: Physiological significance of brain and peripheral mechanisms. In J. Delacour, ed., The memory system of the brain, pp. 337-364, Singapore: World Scientific.

De Wied, D. (1991). The effects of neurohypophyseal hormones and related peptides on learning and memory processes. In R. C. A. Frederickson, J. L. McGaugh, and D. L. Felten, eds., Peripheral signaling of the brain, pp. 335-350. Toronto: Hogrefe and Huber.

Koob, G. F. (1987). Neuropeptides and memory. In L. L. Iversen and S. H. Snyder, eds., Handbook of psychopharmacology, Vol. 19: Behavioral pharmacology, and update, pp. 531-573. New York: Plenum.

McEwen, B. S. (2000). Stress, sex, and the structural and functional plasticity of the hippocampus. In M. S. Gazzaniga, ed., The new cognitive neurosciences, 2nd edition, pp. 171-198. Cambridge, MA: MIT Press.

McGaugh, J. L., Roozendaal, B., and Cahill, L. (2000). Modulation of memory storage by stress hormones and the amygdaloid complex. In M. S. Gazzaniga, ed., The new cognitive neurosciences, 2nd edition, pp. 1,081-1,098. Cambridge, MA: MIT Press.

Roozendaal, B. (2000). Glucocorticoids and the regulation of memory consolidation. Psychoneuroendocrinology 25, pp. 213-238.

James L.McGaugh

Revised byJames L.McGaugh

andBennoRoozendaal