Cedric L. Williams

Neuromodulatory systems and memory storage: Role of the amygdala

This article reviews findings of research examining the interaction of peripheral adrenergic systems with cholinergic, opioid peptidergic and GABAergic systems in modulating memory storage. It is well established that retention is enhanced by posttraining systemic or intra-amygdala injections of adrenergic agonists, opiate antagonists and GABAergic antagonists. These influences appear to be mediated by activation of NE receptors within the amygdala, as intra-amygdala injections of beta-adrenergic antagonists block the memory-modulating effects of hormones and drugs affecting these systems. Furthermore, these influences also appear to involve, at a subsequent step, activation of a cholinergic system: atropine blocks the memory-enhancing effects of adrenergic agonists and opiate and GABAergic antagonists and oxotremorine attenuate the memory-impairing effects of opiate agonists and GABAergic agonists. These findings suggest that the amygdala integrates the memory-modulating effects of neuromodulatory systems activated by learning experiences.

The effects of peripheral vagal nerve stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala.

Vagal nerve stimulation (VNS) is known to improve cognitive processing, presumably by affecting activity in central nervous system structures that process recently acquired information. It has long been assumed that these effects are related to stimulation-induced increases of norepinephrine (NE) release in limbic brain structures. The present study examined this hypothesis by administering VNS at an intensity and duration that improves memory and then measuring fluctuations in NE output in the basolateral amygdala (BLA) with in vivo microdialysis. In Experiment 1, VNS caused a 98% increase in NE output relative to baseline. In Experiment 2, methyl atropine was given 10 min before VNS to assess whether stimulation-induced increases in amygdala NE are mediated by afferent or efferent vagal branches. Methyl atropine did not alter NE release in the BLA in comparison with saline. The significance of these findings in understanding how peripheral neural activity modulates limbic structures to encode and store new information into memory is discussed.

Interacting brain systems modulate memory consolidation

Emotional arousal influences the consolidation of long-term memory. This review discusses experimental approaches and relevant findings that provide the foundation for current understanding of coordinated interactions between arousal activated peripheral hormones and the brain processes that modulate memory formation. Rewarding or aversive experiences release the stress hormones epinephrine (adrenalin) and glucocorticoids from the adrenal glands into the bloodstream. The effect of these hormones on memory consolidation depends upon binding of norepinephrine to beta-adrenergic receptors in the basolateral complex of the amygdala (BLA). Much evidence indicates that the stress hormones influence release of norepinephrine in the BLA through peripheral actions on the vagus nerve which stimulates, through polysynaptic connections, cells of the locus coeruleus to release norepinephrine. The BLA influences memory storage by actions on synapses, distributed throughout the brain, that are engaged in sensory and cognitive processing at the time of amygdala activation. The implications of the activation of these stress-activated memory processes are discussed in relation to stress-related memory disorders.

Glucocorticoid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: involvement of the basolateral amygdala.

These experiments examined the involvement of glucocorticoid receptors (GRs or type II) located in the A2‐noradrenergic cell group of the rat nucleus of the solitary tract (NTS) in modulating memory storage. Bilateral intra‐NTS infusions (0.5 μL) of the specific GR agonist RU 28362 (11β, 17β‐dihydroxy‐6,21‐dimethyl‐17α‐pregna‐4,6‐trien‐20yn‐3‐one), in doses ranging from 0.01 to 10.0 ng, immediately after inhibitory avoidance training produced a dose‐dependent enhancement of 48 h retention performance. Infusions of 0.1 or 1.0 ng of the agonist enhanced retention, whereas lower or higher doses were ineffective. Post‐training infusions of the GR antagonist RU 38486 [17β‐hydroxy‐11β‐(4‐dimethylaminophenyl)‐17α‐(1‐propynyl)‐oestra‐4,9‐dien‐3‐one, 0.01–10.0 ng] into the NTS did not significantly affect retention performance, but shifted the dose–response effects of post‐training systemic injections of the synthetic glucocorticoid dexamethasone to the right. These results indicate that activation of GRs in the NTS can influence memory formation for inhibitory avoidance training, and suggest that the effects of circulating glucocorticoids on memory are mediated, in part, by an activation of GRs in the NTS. Additionally, pretraining infusions of the β1‐adrenergic antagonist atenolol (0.5 μg in 0.2 μL) into the basolateral nucleus of the amygdala (BLA), a brain structure which receives noradrenergic projections from the NTS and is implicated in memory storage modulation, blocked the memory‐enhancing effects of the GR agonist (1.0 ng) infused into the NTS. These findings provide evidence that memory storage is modulated by glucocorticoid binding to GRs in noradrenergic cell bodies in the NTS and suggest that these modulatory effects are conveyed by ascending projections to the BLA.

Norepinephrine release in the amygdala after systemic injection of epinephrine or escapable footshock: contribution of the nucleus of the solitary tract.

Several findings based largely on lesions and drug manipulations within the amygdala suggest that norepinephrine (NE) systems in the amygdala contribute to enhancement of memory processes by epinephrine (EPI). However, no studies to date have directly measured changes in the release of NE in the amygdala after EPI injection. In Experiment 1, in vivo microdialysis was used to assess amygdala NE release after systemic injection of saline, EPI (0.1 or 0.3 mg/kg), and administration of an escapable footshock (0.8 mA, 1 s). Both doses of EPI produced a significant elevation in NE release that persisted for up to 60 min. In Experiment 2, the local anesthetic lidocaine (2%) was infused (0.5 microl) into the nucleus of the solitary tract (NTS) immediately before injection of 0.3 mg/kg EPI. The EPI-induced elevation in amygdala NE release observed in Experiment I was attenuated by inactivation of the NTS. These findings indicate that systemic injection of EPI increases release of NE in the amygdala and suggest that the effects are mediated in part by activation of brainstem neurons in the NTS that project to the amygdala.

Reversible lesions of the nucleus of the solitary tract attenuate the memory-modulating effects of posttraining epinephrine.

Rats implanted with cannula tips placed above the nucleus of the solitary tract (NTS) were trained to obtain food pellets placed in 2 arms of a Y maze and then given a footshock in 1 arm of the maze. The rats then received bilateral injections of lidocaine or buffer into the NTS and peripheral injections of saline or epinephrine (0.01 or 0.05 mg/kg ip). Two tests were given 24 and 48 hr after training to assess retention in the presence and absence of contextual cues (the stainless steel floor) associated with the footshock training trial. Epinephrine (0.05 mg/kg) produced a significant enhancement in retention, which was attenuated by injections of lidocaine into the NTS. These findings indicate that the NTS is involved in mediating the memory-modulating effects of peripheral epinephrine and that such effects are initiated at least in part by activation of vagal afferents projecting to the NTS.

Adrenergic activation of the nucleus tractus solitarius potentiates amygdala norepinephrine release and enhances retention performance in emotionally arousing and spatial memory tasks

It is well documented that noradrenergic systems in the amygdala modulate memory formation, however, less research has examined how sources of limbic norepinephrine contribute to this process. The amygdala receives a dense supply of norepinephrine from neurons in the nucleus of the solitary tract (NTS). The present experiments examined whether adrenergic activation of these NTS neurons affects memory in learning tasks that are sensitive to amygdala norepinephrine release. Separate groups of male Sprague-Dawley rats were trained in either an emotionally arousing or spatial memory task. They then received vehicle or the adrenergic agonist epinephrine (50, 125, or 250 ng/0.5 microl) into the NTS. Rats given the 125 ng dose had significantly longer retention latencies on a 48 h inhibitory avoidance retention test and made a significantly higher percentage of correct responses on an 18 h delayed radial maze retention test. A third experiment using in vivo microdialysis and high performance liquid chromatography (HPLC) demonstrated that intra-NTS infusion of a memory-enhancing dose of epinephrine potentiated amygdala norepinephrine release. Collectively, these results suggest that stimulation of the NTS contributes to memory processing by influencing noradrenergic systems in the amygdala.

Peripheral arousal-related hormones modulate norepinephrine release in the hippocampus via influences on brainstem nuclei

The peripheral hormone epinephrine (EPI) is known to modulate memory for arousing experiences. The mnemonic effects of EPI are attributed almost exclusively to actions on amygdala noradrenergic (NE) systems. EPI also increases neuronal activity in the locus coeruleus (LC), the primary source of NE to other limbic structures that process memory such as the hippocampus (HIPP). The actions of EPI on the LC suggest that its mnemonic properties may also be mediated by influencing NE output in the HIPP. To test this hypothesis, dialysate levels of NE were collected from the HIPP of male rats given an i.p. injection of saline that was followed 100 min later by i.p. EPI (0.3 mg/kg). NE levels sampled 20 min after EPI injection were significantly larger than baseline and continued to show significant peaks for 60 min. Experiment 2 examined whether peripheral signals initiated by EPI influence the HIPP via the nucleus of the solitary tract (NTS) by inactivating this nucleus with lidocaine prior to EPI injection. EPI injection did not increase NE levels sampled from the HIPP of rats given lidocaine into the NTS. EPI injection did produce significant elevations in HIPP NE levels in animals given a control solution into the NTS prior to the EPI injection. These findings indicate that the mnemonic effects of EPI reported in a wide range of learning conditions may not be mediated solely by NE release in the amygdala, but may also involve coactivation of the HIPP NE system.

Enhancement of memory processing in an inhibitory avoidance and radial maze task by post-training infusion of bombesin into the nucleus tractus solitarius

Bombesin is a peptide known to modulate memory storage when given either systemically or intraventricularly immediately after training. Two experiments were conducted to determine whether the nucleus of the solitary tract (NTS) mediates the effects of bombesin on memory. In the first experiment male Sprague-Dawley rats were trained in an inhibitory avoidance task (0.35 mA, 0.5 s footshock) and bombesin or vehicle was infused unilaterally into the NTS through implanted cannulae immediately after training. Retention was assessed either 2 or 7 days later. Doses of 25 or 50 ng of bombesin significantly enhanced retention on the 2 day test (P < 0.05 and 0.01 compared with vehicle controls, respectively). There were no differences between the drug and control groups on the 7 day retention test. In the second experiment, bombesin (25, 50, or 250 ng) or vehicle was infused unilaterally into the NTS immediately after the animals were trained in a win-shift radial arm maze task. On retention tests given 18 h later, groups that received 25 ng or 50 ng of bombesin made a significantly greater percentage of correct choices on the retention test than did the vehicle-treated controls (P < 0.02 and P < 0.05, respectively). The findings indicating that bombesin influences retention by activating the NTS is consistent with recent evidence suggesting that the NTS is involved in regulating memory storage.

Reversible inactivation of the nucleus of the solitary tract impairs retention performance in an inhibitory avoidance task

Several peripherally acting hormones and drugs are known to modulate memory storage processes, yet the mechanisms which permit these agents to influence memory is not well understood since they do not freely enter the brain. The nucleus of the solitary tract (NTS) is one brainstem structure which receives important neural input from the periphery. Therefore, the objective of this experiment was to determine whether the NTS is involved in modulating processes contributing to memory formation. Male Sprague-Dawley rats were trained in a one-trial inhibitory avoidance task (0.35 mA, 0.5 s footshock). Immediately or 2 h after training microinjections of 2% lidocaine hydrochloride (20 mg/kg) or a phosphate buffer solution were administered bilaterally into the NTS. Two other groups received microinjections of lidocaine into the fourth ventricle or cerebellum. On retention tests given 48 h after training the latency to reenter the dark compartment of the apparatus was recorded. The retention latencies of rats receiving bilateral microinjections of 0.5 microliter of lidocaine hydrochloride into the NTS were significantly shorter than those of animals given injections of a buffer solution (0.5 microliter), delayed injections of buffer or lidocaine, or control injections of lidocaine into the cerebellum or fourth ventricle. These findings suggest that memory storage processes are impaired by reversible inactivation of the NTS after training. The implications of these findings in terms of a possible role of the NTS in modulating brain processes involved in memory storage are discussed.