Modulation of memory

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James L. McGaugh and Benno Roozendaal (2008), Scholarpedia, 3(6):3453. doi:10.4249/scholarpedia.3453 revision #89050 [link to/cite this article]
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Curator: Benno Roozendaal

Our memories are not all created equally strong: Some experiences are well remembered and others poorly, if at all. Understanding the neurobiological processes and systems that contribute to such differences in the strength of our memories is the special focus of research on memory modulation. Research on memory modulation was initially stimulated by findings that, in rats, electroconvulsive shock impairs retention of recently learned responses (Duncan, 1949; Gerard, 1949; McGaugh, 1966). Such findings of retrograde amnesia provided compelling evidence that new memory traces perseverate in a fragile state and later become consolidated (Müller & Pilzecker, 1900). Modulation of consolidation is a common feature of animal memory, as it is found in mollusks, fish, birds and bees as well as rodents and primates (McGaugh, 2000).

Such evidence suggested that memory consolidation might also be enhanced by treatments that activate brain functioning. Extensive evidence supports this implication. Many stimulant drugs enhance retention when administered shortly after training (McGaugh & Herz, 1972; McGaugh, 1973; Jarvik & McGaugh, 1978). In studies of memory modulation it is essential to exclude effects of the treatments on attentional, motivational and motor processes. Posttraining administration of drugs provides an effective technique for excluding such performance effects (McGaugh, 1989).


Endogenous Modulation of Memory Consolidation

The susceptibility of memory consolidation to modulating influences occurring after learning enables neurobiological processes activated by emotional arousal to regulate the strength of memory (Gold & McGaugh, 1984; McGaugh & Gold, 1989). Extensive evidence indicates that stress hormones released by the adrenal glands, epinephrine and corticosterone (cortisol in humans) by emotionally arousing experiences play an important role in modulating memory (McGaugh, 1983; McGaugh & Roozendaal, 2002).

Epinephrine: Posttraining injections of the adrenomedullary hormone epinephrine induce dose- and time-dependent enhancement of long-term memory for many different types of training tasks. Epinephrine does not readily cross the blood-brain barrier (Weil-Malherbe et al., 1959). The memory modulation is initiated, at least in part, by activation of peripheral \(\beta\)-adrenoceptors located on vagal afferents that project to the nucleus of the solitary tract (NTS) in the brain stem. The NTS sends noradrenergic projections to forebrain regions both directly and indirectly via the locus coeruleus.

Epinephrine may also influence memory by enhancing glycogenolysis in the liver (Gold, 1995; Messier & White, 1984). Posttraining peripheral administration of glucose produces dose- and time-dependent effects on memory comparable to those produced by epinephrine (Gold, 1986). Glucose may affect memory by directly altering brain functioning as well as by stimulating vagal afferents (Lee et al., 1988).

Glucocorticoids: As with epinephrine, posttraining administration of glucocorticoids produces dose- and time-dependent enhancement of memory. Glucocorticoids are highly lipophilic and, thus, readily enter the brain and bind directly to mineralocorticoid receptors and glucocorticoid receptors. The memory-modulating effects of glucocorticoids appear to involve the selective activation of the low-affinity glucocorticoid receptor. Glucocorticoids act through intracellular and intranuclear receptors and can affect gene transcription by direct binding of receptor homodimers to DNA. However, glucocorticoids may also act more rapidly by interacting with membrane receptors and/or potentiating the efficacy of the norepinephrine-signal cascade via an interaction with G-protein-mediated actions.

Adrenergic-Glucocorticoid Interactions: Catecholamines and glucocorticoids released from the adrenal glands interact in modulating memory. Glucocorticoids alter the sensitivity of epinephrine in influencing memory consolidation and, conversely, adrenergic activation induced by emotional arousal appears to be essential in enabling glucocorticoid modulation of memory consolidation. In rats trained on an object recognition task, prior habituation to the training context reduces the training-induced emotional arousal. Corticosterone administered immediately posttraining to habituated (i.e. non-aroused) rats does not enhance 24 hr retention of object recognition. In contrast, corticosterone enhances retention in rats not given prior habituation (Okuda et al., 2004). Further, in non-habituated rats administration of a \(\beta\)-adrenoceptor antagonist immediately after the object recognition training blocked the corticosterone-induced memory enhancement (Roozendaal et al., 2006).

Other Neuromodulatory Systems: Drugs and hormones affecting many other neuromodulatory and transmitter systems also modulate memory consolidation. Modulation comparable to that induced by stimulant drugs known to act via GABA and catecholamines is also obtained with opiate receptor antagonists and muscarinic cholinergic receptor agonists as well as drugs and hormones affecting several other systems (McGaugh, 1989; McGaugh & Gold, 1989). Opioid peptides and GABA appear to impair memory by decreasing norepinephrine release in the brain (Quirarte et al., 1998; Hatfield et al., 1999). In contrast, cholinergic effects do not appear to be mediated by adrenergic activation. However, muscarinic cholinergic activity is a requirement for norepinephrine-induced memory enhancement. Thus, the memory-modulatory effects of cholinergic activation appear to involve influences downstream from adrenergic activation (Power et al., 2003).

Involvement of the Amygdala in Memory Modulation

Extensive evidence that posttraining electrical stimulation of the amygdala (McGaugh & Gold, 1976) can modulate memory suggested that drug and hormone effects on memory may be mediated by influences involving the amygdala. Considerable evidence supports this implication. Further, such modulation involves noradrenergic activation of the amygdala and efferent projections to other brain regions.

Noradrenergic Influences in the Basolateral Amygdala: Memory consolidation is modulated by noradrenergic agonists and antagonists infused into the amygdala posttraining (Ellis & Kesner, 1981; Gallagher, et al., 1981). The basolateral complex of the amygdala (BLA) is the critical region; the adjacent central nucleus does not appear to play a significant role. Epinephrine effects on memory are mediated by noradrenergic activation within the amygdala, as intra-amygdala infusions of the -adrenoceptor antagonist propranolol block epinephrine modulation of memory consolidation (Liang et al., 1986). Noradrenergic activation of the BLA also mediates the modulatory effects of other hormones and neurotransmitters on memory. Intra-BLA infusions of GABAergic receptor antagonists enhance memory consolidation and GABAergic receptor agonists impair memory (Brioni et al., 1989). Similarly, when infused into the amygdala posttraining opioid peptidergic antagonists enhance memory and opioid peptidergic agonists impair memory. Further, \(\beta\)-adrenoceptor antagonists infused into the amygdala block these effects. Noradrenergic activity within the BLA is also required for mediating the memory-modulatory effect of several other neurotransmitters, including that of dopamine, corticotropin-releasing factor and the opioid-like orphanin FQ/nociceptin (LaLumiere et al., 2004; Roozendaal et al., 2007)

The extensive evidence that adrenoceptor activation within the amygdala modulates memory consolidation suggests that emotionally arousing learning experiences should induce the release of norepinephrine within the amygdala. Findings of studies using in vivo microdialysis and HPLC to measure norepinephrine levels in the amygdala strongly support this implication. Moreover, drugs and hormones that enhance memory potentiate training-induced increases in amygdala norepinephrine levels and drugs that impair memory consolidation decrease norepinephrine levels. Further, inhibitory avoidance training induces a large and sustained increase in norepinephrine release that correlates highly with 24-hr memory (McIntyre et al., 2002).

Glucocorticoid Influences in the Basolateral Amygdala: Glucocorticoids also modulate memory through influences involving the BLA. Disruption of BLA activity blocks the memory-enhancing effects of posttraining systemic injections of glucocorticoids. Furthermore, systemic or intra-BLA infusions of glucocorticoids enhance memory consolidation and such effects require noradrenergic activation within the amygdala (Quirarte et al., 1997). Activation of glucocorticoid receptors in the BLA appears to modulate memory consolidation by potentiating the norepinephrine-signaling cascade through an interaction with G-protein-mediated effects. As with epinephrine, glucocorticoid effects on memory consolidation also involve activation of noradrenergic cell groups in the brain stem that project to the BLA. Posttraining infusions of a glucocorticoid receptor agonist into the NTS enhance memory and intra-BLA infusions of a \(\beta\)-adrenoceptor antagonist block the enhancement (Roozendaal et al., 1999).

Cholinergic Influences in the Basolateral Amygdala: Cholinergic activation within the BLA also modulates memory consolidation. Posttraining intra-amygdala infusions of muscarinic cholinergic receptor agonists and antagonists enhance and impair, respectively, memory for many kinds of training. Additionally, lesions of the nucleus basalis, the major source of cholinergic innervation of the BLA, impair inhibitory avoidance retention and posttraining intra-BLA infusions of either the cholinergic agonist oxotremorine or the acetylcholinesterase inhibitor physostigmine attenuate this memory impairment (Power & McGaugh, 2002).

Figure 1: summarizes the neuromodulatory interactions within the BLA that are involved in regulating memory consolidation.

Cholinergic activation within the BLA is critical for enabling glucocorticoid as well as dopamine enhancement of memory consolidation. As cholinergic modulation of memory consolidation does not require concurrent noradrenergic activation, such activation in the BLA appears to act downstream from adrenergic activation (Dalmaz et al., 1993).

Amygdala Interactions with Other Brain Systems in Modulating Memory

Comparable memory-modulatory effects of posttraining amygdala treatments have been obtained in experiments using many different kinds of training. And, as different training experiences are known to engage different brain systems, the BLA-induced modulation involves influences on processing occurring in these other brain regions (McGaugh, 2002; 2005).

There is considerable evidence that the caudate nucleus and hippocampus are involved in different kinds of learning. In rats given water-maze training, amphetamine infused posttraining into the caudate nucleus selectively enhances memory of visually cued training whereas infusions administered into the dorsal hippocampus selectively enhance memory of spatial training. In contrast, amphetamine infused into the amygdala posttraining enhances memory for both types of training. Importantly, inactivation of the amygdala prior to retention testing did not block memory of either kind of training (Packard et al., 1994). Thus, the amygdala is not a locus of the enhanced memory for either type of training.

Noradrenergic stimulation of the BLA that enhances memory consolidation also increases dorsal hippocampal levels of activity-regulated cytoskeletal (Arc) protein (McIntyre et al., 2005), an immediate-early gene implicated in hippocampal synaptic plasticity and memory consolidation processes. Additionally, inactivation of the BLA impairs memory consolidation and decreases Arc protein levels in the dorsal hippocampus. Further, intra-BLA infusions of muscimol attenuate the increase in Arc mRNA induced by contextual fear conditioning, a task known to involve the amygdala (Huff et al., 2006). A single footshock of the kind typically used in such training induces a sustained increase in the firing rate of cells in the BLA that may serve to modulate memory processing in efferent brain regions, including the hippocampus as well as other brain regions (Pare et al., 2002; Pelletier & Pare, 2004). Training involving the amygdala induces the expression of several transcriptionally regulated genes implicated in synaptic plasticity in many brain areas, including the hippocampus, caudate nucleus and cortex, as well as the amygdala (Ressler et al., 2002).

Posttraining infusions of drugs into various cortical regions modulate the consolidation of memory for several kinds of training (Izquierdo et al., 1997; Sacchetti et al., 1999; Malin & McGaugh, 2006). Lesions of the BLA prevent the memory enhancement induced by 8-bromo-cAMP infused posttraining into the entorhinal cortex (Roesler et al., 2002). Blocking of \(\beta\)-adrenoceptors in the BLA also prevent the memory-enhancing effects of drugs infused into the insular cortex (Miranda & McGaugh, 2004) and the anterior cingulate cortex (Malin et al., 2006). The BLA also directly interacts with the medial prefrontal cortex in modulating memory consolidation.

The BLA also influences cortical functioning in memory via its projection to the nucleus basalis, which provides cholinergic activation of the cortex. Lesions of cortical nucleus basalis corticopetal cholinergic projections block the memory-modulatory effects of posttraining intra-BLA infusions of norepinephrine (Power et al., 2002).

Figure 2: summarizes the interaction of the BLA with other systems in regulating memory consolidation.

The nucleus basalis-cortical projections are essential for learning-induced cortical plasticity (Miasnikov et al., 2001; 2006; Weinberger, 2003). Stimulation of the BLA activates the cortex, as indicated by EEG desynchronization, and potentiates nucleus basalis influences on cortical activation. Moreover, inactivation of the nucleus basalis blocks the BLA effects on cortical activation (Dringenberg & Vanderwolf, 1996; Dringenberg et al., 2001).

Amygdala Activity and Modulation of Human Memory Consolidation

The findings of many human studies of the effects of emotional arousal, stress hormones and amygdala activation on memory are consistent with those of animal studies (Cahill & McGaugh, 1998; 2000; Buchanan & Adolphs, 2004; Dolan, 2000; LaBar & Cabeza, 2006). Cortisol administered to subjects prior to presentations of words or pictures enhances subsequent recall (Buchanan & Lovallo, 2001; Abercrombie et al., 2006; Kuhlmann & Wolf, 2006). Amphetamine administered to human subjects, either before or after they learned lists of words, also enhances long-term memory (Soetens et al., 1993; 1995). Administration of propranolol to subjects prior to their viewing an emotionally arousing slide presentation blocks the memory-enhancing effects of emotional arousal and stress (Cahill et al., 1994; Nielson & Jensen, 1994). Further, epinephrine or cold pressor stress (that stimulates the release of adrenal stress hormones) administered to subjects after they view emotionally arousing pictures enhances the subjects’ memory (Cahill & Alkire, 2003; Cahill et al., 2003).

Amygdala activation is involved in the enhanced memory induced by emotional arousal. Memory for emotionally arousing material is not enhanced in human subjects with selective bilateral lesions of the amygdala (Cahill et al., 1995; Adolphs et al., 1997). Brain imaging studies have provided additional evidence that the influence of emotional arousal on human memory involves amygdala activation (Cahill et al.,1996). Amygdala activity as assessed by PET imaging of subjects as they viewed emotionally arousing films correlates highly with the subjects’ recall of the films assessed in a surprise memory test three weeks later (Cahill et al., 1996). The degree of emotional arousal, and not the valence, appears to be critical in influencing memory. Studies using fMRI have obtained highly similar findings (Canli et al., 2000). Importantly, \(\beta\)-adrenoceptor antagonists (e.g. propranolol) block the increase in amygdala activity and enhanced retention induced by emotional stimuli obtained in fMRI studies (van Stegeren et al., 2005).

Other findings based on an analysis of PET and fMRI scans provide evidence, consistent with that of animal studies, that amygdala activation influences memory processing in other brain regions. Amygdala and hippocampal/parahippocampal regions are activated during emotional arousal (Hamann et al., 1999) and such activation is correlated with subsequent retention (Dolcos et al., 2004). Findings of a “path analysis” study of amygdala activity assessed while subjected viewed emotional films suggest that emotional arousal increases amygdala influences on activity of the ipsilateral parahippocampal gyrus and ventrolateral prefrontal cortex (Kilpatrick & Cahill, 2004).

Involvement of the Amygdala in Modulating Memory Retrieval and Working Memory

Neuromodulatory systems also influence memory retrieval and working memory and the BLA, via its projections to other brain regions, plays an important modulatory role in regulating such effects on these memory functions.

Memory Retrieval: Stress exposure or glucocorticoids administered systemically shortly before retention testing impair memory retrieval. Similarly as described above for memory consolidation, glucocorticoid effects on memory retrieval depend on concurrent activation of noradrenergic mechanisms. A \(\beta\)-adrenoceptor antagonist administered systemically before retention testing blocks the memory retrieval impairment induced by concurrent injections of glucocorticoids (Roozendaal et al., 2004a). Peripheral administration of the opioid peptidergic antagonist naloxone or D2 dopamine receptor antagonists also block the impairing effect of concurrently injected glucocorticoids on memory retrieval (Rashidy-Pour et al., 2004; Pakdel & Rashidy-Pour, 2006).

A glucocorticoid receptor agonist administered into the hippocampus shortly before retention testing also impairs memory retrieval (Roozendaal et al., 2003). Consistent with the findings of experiments of peripherally administered drugs, a \(\beta\)-adrenoceptor antagonist infused into the hippocampus prevents the retrieval-impairing effect of a glucocorticoid receptor agonist administered concurrently (Roozendaal et al., 2004b). Norepinephrine infused into the BLA impairs memory retrieval (Barros et al., 2001). Moreover, the BLA is known to interact with the hippocampus in mediating glucocorticoid effects on memory retrieval. Lesions of the BLA or infusions of a \(\beta\)-adrenoceptor antagonist into the BLA block the impairing effect of a glucocorticoid receptor agonist infused into the hippocampus on memory retrieval (Roozendaal et al., 2003; 2004b).

The findings of studies examining stress hormone effects on memory retrieval in humans are consistent with those of animal experiments and indicate that glucocorticoids impair memory retrieval via an interaction with noradrenergic mechanisms. Stress-level cortisol or cortisone administration to human subjects impairs delayed, but not immediate, recall on episodic tasks, and the \(\beta\)-adrenoceptor antagonist propranolol blocks such memory impairment (de Quervain et al., 2007). Recent findings from an H215O-PET study indicate that glucocorticoid effects on memory retrieval in human subjects are also mediated, at least in part, by actions in the hippocampus (de Quervain et al., 2003). Other findings of human imaging studies indicate that the amygdala and hippocampus interact during the retrieval of emotionally arousing information (Smith et al., 2006; Greenberg et al., 2005; Dolcos et al., 2005).

Working Memory: Stress exposure also impairs medial prefrontal cortex-dependent working memory, a dynamic process whereby information is updated continuously. Also, as with stress, glucocorticoid administration impairs working memory in rats (Roozendaal et al., 2004c) and humans (Lupien et al., 1999). Glucocorticoids interact with noradrenergic mechanisms in the medial prefrontal cortex in inducing working memory impairment (Roozendaal et al., 2004c). A \(\beta\)-adrenoceptor antagonist administered either systemically or into the medial prefrontal cortex blocks glucocorticoid effects on working memory. Further, glucocorticoids increase the release of norepinephrine into the medial prefrontal cortex. Excessive levels of norepinephrine in the medial prefrontal cortex also impair working memory, and the effects are mediated by activation of the \(\alpha\)1- and \(\beta\)-adrenoceptor (Arnsten & Jentsch, 1997; Ramos et al., 2005). In contrast, \(\alpha\)2-adrenoceptor activation enhances working memory (Taylor et al., 1999). Dopaminergic D1 receptor agonists influence working memory following an inverted-U shaped dose-response relationship. Too little or too much D1 receptor stimulation appears to impair working memory in mice, rats and monkeys (Zahrt et al., 1997).

Glucocorticoid-induced working memory impairment also depends on interactions of the medial prefrontal cortex with the BLA. The BLA itself does not appear to play a significant role in working memory, but lesions of the BLA block the impairment induced by either systemic administration of corticosterone or infusions of a glucocorticoid receptor agonist into the medial prefrontal cortex (Roozendaal et al., 2004c).


The evidence reviewed above provides extensive evidence that emotional arousal-induced activation of neuromodulatory systems modulates memory consolidation, as well as memory retrieval and working memory, via noradrenergic activation of the BLA and its projections to other brain regions involved in processing memory.


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Internal references

  • Valentino Braitenberg (2007) Brain. Scholarpedia, 2(11):2918.
  • William D. Penny and Karl J. Friston (2007) Functional imaging. Scholarpedia, 2(5):1478.
  • Howard Eichenbaum (2008) Memory. Scholarpedia, 3(3):1747.

Recommended reading

  • Bohus, B. 1994. Humoral modulation of memory processes. Physiological significance of brain and peripheral mechanism. In The Memory System of the Brain, J. Delacour, ed., Advanced Series of Neuroscience. New Jersey: World Scientific, Volume 4, pp. 337-364.
  • Cahill, L. 2000. Modulation of long-term memory in humans by emotional arousal: adrenergic activation and the amygdala. In The Amygdala, J.P. Aggleton, ed., London, Oxford University Press, pp. 631-654.
  • Het, S., Ramlow, G., Wolf, O.T. 2005. A meta-analytic review of the effects of acute cortisol administration on human memory. Psychoneuroendocrinology, 30, 771-784.
  • Lupien, S.J., McEwen, B.S. 1997. The acute effects of corticosteroids on cognition: Integration of animal and human model studies. Brain Research Review, 24, 1-27.
  • McGaugh, J.L. 2003. Memory and Emotion: The Making of Lasting Memories. London: Weidenfeld and Nicolson The Orion House Group Ltd. and New York: Columbia University Press, 162pp.
  • Packard, M.G., Cahill, L. 2001. Affective modulation of multiple memory systems. Current Opinion in Neurobiology, 11, 752-756.
  • Roozendaal, B. 2007. Norepinephrine and long-term memory function. In Brain Norepinephrine: Neurobiology and Therapeutics, G.A.Ordway, M.A.Schwartz & A. Frazer, Eds. Cambridge University Press, pp.236-274.
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