Edwin C. Clayton

Phasic Activation of Monkey Locus Ceruleus Neurons by Simple Decisions in a Forced-Choice Task

The noradrenergic locus ceruleus (LC) system has been implicated in several behavioral functions, most notably, response to salient sensory events. Here, we provide new evidence indicating a role in the execution of responses associated with simple decisions. We examined impulse activity of monkey LC neurons during performance of a forced-choice discrimination task. The timing of LC activity more closely tracked behavioral responses than stimulus presentation. LC neurons were phasically activated preceding behavioral responses for both correct and incorrect identifications but were not activated by stimuli that failed to elicit lever responses nor by nontask-related lever movements. We hypothesize that the LC responds to the outcome of task-related decision processes, facilitating their influence on overt behavior. This role of the LC in regulating the behavioral outcome of decisional processes contrasts with more traditional views of LC responses as primarily related to sensory processes.

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.

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.

Working memory deficits induced by single but not repeated exposures to domoic acid

Single injections of domoic acid, given either intraperitoneally to mice or directly into the hippocampal formation of rats, have been shown to impair learning on the place version of the Morris water maze task and the eight arm radial maze task. The present study was designed to test whether both single and repeated exposures of intraperitoneally administered domoic acid (1.0 or 2.0 mg/kg) impair spatial working memory in mice on a delayed matching-to-sample task. DBA strain mice were given a series of four injections over a 7-day period consisting of either saline or one of two doses of domoic acid. During the 18 days of testing, each subject was given one trial per day consisting of one information run, followed by three test runs. On non-alternation days (days in which the correct response was the same as the preceding day) the saline injected group significantly outperformed the single injection 2.0 mg/kg domoic acid group. This indicates that domoic acid-treated animals were incapable of forming a memory that persisted for 24 h and hence were less able to utilize the prior days experience. However, the repeated exposure groups did not perform as poorly on non-alternation days than the single exposure groups, indicating that domoic acid may affect multiple mechanisms involved in memory consolidation.

Brain Norepinephrine: The locus coeruleus and regulation of behavioral flexibility and attention: clinical implications

It has been proposed that the locus coeruleus (LC) regulates nonspecific arousal and thereby may participate in a wide range of functions. Our work indicates that, while the LC may indeed play an important role in arousal, it has more specific effects on behavior and may regulate cortical mechanisms involved in selective attention and task performance. In one study, we recorded impulse activity of LC neurons in monkeys performing a visual discrimination task. Phasic and tonic firing characteristics of LC neurons varied in close relation to task performance. Phasically, LC neurons were selectively activated by target cues and not by other task events, including behavioral responses. The target-elicited LC responses were limited to periods of good performance, when tonic firing rates were at an intermediate level (∼ 1 to 2 spikes/s). Higher levels of tonic activity were associated with few or no phasic LC responses, and poor task performance. Direct manipulations of LC activity via local microinfusions yielded behavioral results consistent with the above recordings. A computational model was constructed to explore mechanisms that underlie these patterns of LC activity and their relationship to task performance.1 This model revealed that electrotonic coupling among LC neurons can provide a mechanism for regulating the pattern of LC activity between two modes of functioning, which may in turn regulate task performance. In one mode (high electrotonic coupling, resulting in intermediate levels of tonic LC activity and robust phasic responses to task-defined target stimuli), LC responses facilitate the processing of target stimuli while responses to distractors are reduced. In the

Glutamatergic influences on the nucleus paragigantocellularis: contribution to performance in avoidance and spatial memory tasks.

Stimulation of the locus coeruleus (LC) and the subsequent release of norepinephrine contribute to memory consolidation processes. Excitatory input to the LC is derived primarily from neurons in the nucleus paragigantocellularis (PGi). The authors examined the effects of activating the pathway between PGi and the LC on memory. Rats received vehicle or the excitatory amino acid glutamate (25, 50, or 100 nmol/0.5 microl) into PGi after training in an inhibitory avoidance (IA) or delayed matching-to-sample (DMS) task. Rats given the 100-nmol dose had significantly longer retention latencies on a 48-hr IA retention test. Rats treated with the 50- or 100-nmol dose made significantly more correct responses than controls on an 18-hr DMS retention test. Results suggest that encoding and storage of memory for emotional and spatial events may be enhanced by activation of neuronal circuits afferent to the LC.