Ann E. Power

Amygdala modulation of memory consolidation: Interaction with other brain systems

There is a strong consensus that the amygdala is involved in mediating influences of emotional arousal and stress on learning and memory. There is extensive evidence that the basolateral amygdala (BLA) is a critical locus of integration of neuromodulatory influences regulating the consolidation of several forms of memory. Many drug and stress hormone influences converge in activating the release of norepinephrine (NE) within the BLA. Evidence from studies using in vivo microdialysis and high-performance liquid chromatography indicates that increases in amygdala NE levels assessed following inhibitory avoidance training correlate highly with subsequent retention. Other evidence indicates that NE influences on memory consolidation require muscarinic cholinergic activation within the BLA provided by projections from the nucleus basalis magnocellularis (NB). Evidence from several experiments indicates that activation of the BLA plays an essential role in modulating memory consolidation processes involving other brain regions. These findings provide strong support for the hypothesis that the BLA plays a critical role in regulating the consolidation of lasting memories of significant experiences.

Muscarinic cholinergic influences in memory consolidation

The central cholinergic system and muscarinic cholinergic receptor (mR) activation have long been associated with cognitive function. Although mR activation is no doubt involved in many aspects of cognitive functioning, the extensive evidence that memory is influenced by cholinergic treatments given after training either systemically or intra-cranially clearly indicates that cholinergic activation via mRs is a critical component in modulation of memory consolidation. Furthermore, the evidence indicates that activation of mRs in the basolateral amygdala (BLA) plays an essential role in enabling other neuromodulatory influences on memory consolidation. Memory can also be affected by posttraining activation of mRs in the hippocampus, striatum and cortex. Evidence of increases in hippocampal and cortical acetylcholine (ACh) levels following learning experiences support the view that endogenous ACh release is involved in long-term memory consolidation. Furthermore, the findings indicating that mR drug treatments influence plasticity in the hippocampus and in sensory cortices strongly suggest that mR activation is involved in the storage of information in these brain regions.

Role of the basolateral amygdala in memory consolidation.

Abstract: Memories of emotionally arousing events tend to be more vivid and to persist longer than do memories of neutral or trivial events. Moreover, memories of emotionally influenced information may endure after a single experience. Recent findings strongly suggest that the influence of emotional arousal on memory consolidation is mediated by the release of adrenal stress hormones (epinephrine and glucocorticoids) and neurotransmitters that converge in modulating the noradrenergic system within the amygdala. Considerable evidence also indicates that amygdala activation influences memory by regulating consolidation in other brain regions. The findings suggest further that this memory‐modulatory system may be involved in the formation of traumatic memories and posttraumatic stress disorder in human subjects.

Glucocorticoid enhancement of memory consolidation in the rat is blocked by muscarinic receptor antagonism in the basolateral amygdala

Glucocorticoid‐induced memory enhancement is known to depend on β‐adrenoceptor activation in the basolateral amygdala (BLA). Additionally, inactivation of muscarinic cholinergic receptors in the rat amygdala blocks memory enhancement induced by concurrent β‐adrenergic activation. Together, these findings suggest that glucocorticoid‐induced modulation of memory consolidation requires cholinergic as well as adrenergic activation in the BLA. Two experiments investigated this issue. The first experiment examined whether blockade of muscarinic cholinergic receptors in the BLA with atropine alters the memory‐enhancing effects of the systemically administered glucocorticoid dexamethasone. Dexamethasone (0.3, 1.0 or 3.0 mg/kg, s.c.) administered to rats immediately after inhibitory avoidance training produced dose‐dependent enhancement of 48‐h retention. Concurrent bilateral infusions of the muscarinic cholinergic antagonist atropine (0.5 μg in 0.2 μL per side) into the BLA blocked the memory enhancement. The second experiment investigated whether the BLA is a locus of interaction between glucocorticoid and muscarinic activation. The specific glucocorticoid receptor (GR or type II) agonist RU 28362 (1.0, 3.0 or 10 ng) was infused into the BLA either alone or together with atropine immediately after training. The GR agonist produced dose‐dependent memory enhancement and atropine blocked the memory enhancement. These findings indicate that muscarinic cholinergic activation within the BLA is critical for enabling glucocorticoid enhancement of memory consolidation and that enhancement of memory induced by GR activation in the BLA requires cholinergic activation within the BLA.

Phthalic acid amygdalopetal lesion of the nucleus basalis magnocellularis induces reversible memory deficits in rats.

The basolateral amygdala (BLA) is extensively implicated in emotional learning and memory. The current study investigated the contribution of cholinergic afferents to the BLA from the nucleus basalis magnocellularis in influencing aversive learning and memory. Sprague-Dawley rats were given permanent unilateral phthalic acid (300 ng) lesions of the nucleus basalis magnocellularis and were chronically implanted with cannulas aimed at the ipsilateral BLA. Lesioned rats showed a pronounced inhibitory avoidance task retention deficit that was attenuated by acute posttraining infusions of the muscarinic cholinergic agonist oxotremorine (4 ng) or the indirect agonist physostigmine (1 microg) into the BLA. Continuous multiple-trial inhibitory avoidance training and testing revealed that lesioned rats have a mild acquisition deficit, requiring approximately 1 additional shock to reach the criterion, and a pronounced consolidation deficit as indicated by a shorter latency to enter the shock compartment on the retention test. Because lesioned rats did not differ from sham-operated controls in performance on a spatial water maze task or in shock sensitivity, it is not likely that the memory impairments produced by the phthalic acid lesions are due to any general sensory or motor deficits. These findings suggest that the dense cholinergic projection from the nucleus basalis magnocellularis to the BLA is involved in both the acquisition and the consolidation of the aversive inhibitory avoidance task.

Slow-wave sleep, acetylcholine, and memory consolidation

There has been a long history of experimentation and conjecture about a potentially critical role in memory consolidation for brain processes unique to sleep (1–3). A role for sleep in memory consolidation is consistent with the fact that new memory traces are not instantly fixed but rather remain susceptible to neuromodulatory influences for several hours after acquisition and require protein synthesis to become stable long-term memories (4). And while it has been clearly demonstrated that sleep deprivation can impair later memory for recently acquired declarative and procedural memory, the precise mechanisms by which sleep may aid or mediate memory storage processes are not known (3, 5). Activation of the cholinergic system has been demonstrated to enhance attention, learning, and memory consolidation and to facilitate plasticity after physiological manipulations and during development (6–8). Acetylcholine levels are high during waking and rapid eye movement (REM; also known as paradoxical) sleep (9). These observations seem consistent with the possibility that REM sleep may play an important role in facilitating synaptic plasticity of recently acquired memory traces. However, the great similarities between the waking and REM sleep states beg the question: What about REM sleep relative to waking is privileged for memory consolidation? Explicitly, REM sleep episodes follow deep slow-wave sleep (SWS) episodes. New findings by Gais and Born (10) presented in this issue of PNAS provide compelling evidence in human subjects that SWS and the accompanying low levels of acetylcholine during SWS may mediate a critical memory consolidation process. These findings support two-stage models …

Cholinergic activation of the basolateral amygdala regulates unlearned freezing behavior in rats

Recent evidence suggests that the basolateral amygdala (BLA) is involved in the expression of freezing behavior in rats. This study investigated the effects of unilateral phthalic acid (PA) lesions of the nucleus basalis magnocellularis (NBM) on fear-motivated behavior in response to a natural predator-stimulus. Such lesions preferentially disrupt the cholinergic projection to the BLA. Rats were placed in a chamber containing either real or fake cat hair, and the amount of time spent freezing and the number of contacts made with the stimulus were measured. Compared with Sham control rats, the PA NBM-lesioned rats displayed significantly less freezing in the presence of the cat hair. Both the Sham and lesioned rats made fewer contacts with the real than the fake cat hair. Pre-testing intra-BLA infusion of the direct muscarinic cholinergic agonist oxotremorine ipsilateral to the PA NBM-lesion attenuated the freezing deficit. The indirect non-specific cholinergic agonist physostigmine increased the time spent freezing in Sham rats, but did not attenuate the freezing deficit in the NBM-lesioned rats. Sham and NBM-lesioned rats given oxotremorine infusions made fewer contacts with either the real or the fake cat hair. The PA NBM-lesion did not affect open field activity. These findings indicate that muscarinic cholinergic activation in the BLA from the NBM influences fear-motivated freezing behavior.

M1 Muscarinic Acetylcholine Receptor Agonism Alters Sleep without Affecting Memory Consolidation

Preclinical studies have implicated cholinergic neurotransmission, specifically M1 muscarinic acetylcholine receptor (mAChR) activation, in sleep-associated memory consolidation. In the present study, we investigated the effects of administering the direct M1 mAChR agonist RS-86 on pre-post sleep memory consolidation. Twenty healthy human participants were tested in a declarative word-list task and a procedural mirror-tracing task. RS-86 significantly reduced rapid eye movement (REM) sleep latency and slow wave sleep (SWS) duration in comparison with placebo. Presleep acquisition and postsleep recall rates were within the expected ranges. However, recall rates in both tasks were almost identical for the RS-86 and placebo conditions. These results indicate that selective M1 mAChR activation in healthy humans has no clinically relevant effect on pre-post sleep consolidation of declarative or procedural memories at a dose that reduces REM sleep latency and SWS duration.