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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.

We previously reported that noradrenergic neurons in the monkey locus coeruleus (LC) are activated selectively by target stimuli in a target detection task. Here, we varied the discrimination difficulty in this task and recorded impulse activity of LC neurons to analyze LC responses on error trials and in relation to behavioral response times (RTs). In easy and difficult discrimination conditions, LC neurons responded preferentially to target stimuli with phasic activation. These responses consistently preceded behavioral responses regardless of task difficulty. Latencies for LC and behavioral responses increased similarly for difficult compared with easy discrimination trials. LC response latencies were also shorter for fast RT trials compared with slow RT trials regardless of difficulty, indicating a close temporal relationship between LC and behavioral responses. This relationship was confirmed with response-locked histograms of LC activity, which yielded more temporally synchronized LC responses than stimulus-locked histograms. Population histograms of LC activity revealed that nontarget stimuli resulting in false alarm responses produced phasic LC activation (although smaller than for target-hit trials), and nontarget stimuli resulting in correct rejection responses yielded a small inhibition in LC activity. Population analyses also revealed that LC responses included an early, small excitatory component that was not previously detected. This early response was nondiscriminative because it was similar for target and nontarget stimulus trials. These results indicate that LC neurons exhibit early small magnitude responses that are closely linked to sensory stimuli. In addition, these cells show a later, larger magnitude response that is temporally linked to behavioral responses. These and other results lead us to hypothesize that LC responses are driven by decision processes and help facilitate subsequent behavioral responses.

We model spiking neurons in locus coeruleus (LC), a brain nucleus involved in modulating cognitive performance, and compare with recent experimental data. Extracellular recordings from LC of monkeys performing target detection and selective attention tasks show varying responses dependent on stimuli and performance accuracy. From membrane voltage and ion channel equations, we derive a phase oscillator model for LC neurons. Average spiking probabilities of a pool of cells over many trials are then computed via a probability density formulation. These show that: (1) Post-stimulus response is elevated in populations with lower spike rates; (2) Responses decay exponentially due to noise and variable pre-stimulus spike rates; and (3) Shorter stimuli preferentially cause depressed post-activation spiking. These results allow us to propose mechanisms for the different LC responses observed across behavioral and task conditions, and to make explicit the role of baseline firing rates and the duration of task-related inputs in determining LC response., (Copyright 2004 Kluwer Academic Plublishers)

Neurophysiological work in monkeys has shown that changes in tonic and stimulus-induced activity in the noradrenergic brainstem nucleus locus coeruleus (LC) are tightly correlated with fluctuations in behavioral performance in a visual discrimination task. Simulation work suggests transitions between observed modes of LC activity may be mediated by changes in the level of coherent firing among individual LC neurons. We have simplified this simulation by abstracting the LC to a simple, excitable system in two variables modeled after the FitzHugh-Nagumo relaxation oscillator. This abstracted LC simulates population-level dynamics of the nucleus relevant to its influence on behavior. Coherence within the nucleus was simulated as a single parameter which amplified external input to the abstracted LC while attenuating tonic, uncorrelated activity. Simulated results captured LC dynamics and their relationship with behavior observed in monkeys. Behavior was further simulated over a range of potential LC states not, as yet, directly observed. These results suggest a reverse sigmoidal relationship between false alarm rate and coherence, and a more complex, non-monotonic relationship between response time and coherence.

Previous findings have implicated the noradrenergic locus coeruleus (LC) system in functions along the dimension of arousal or attention. It has remained uncertain what role this system has in attention, or what mechanisms may be involved. We review our recent work examining activity of LC neurons in monkeys performing a visual discrimination task that requires focused attention. Results indicate that LC cells exhibit phasic or tonic modes of activity, that closely correspond to good or poor performance on this task, respectively. A computational model was used to simulate these results. This model predicts that alterations in electrotonic coupling among LC cells may produce the different modes of activity and corresponding differences in performance. This model also indicates that the phasic mode of LC activity may promote focused or selective attention, whereas the tonic mode may produce a state of high behavioral flexibility or scanning attentiveness. The implications of these results for clinical disorders such as attention-deficit hyperactivity disorder, stress disorders, and emotional and affective disorders are discussed.

Noradrenergic locus coeruleus (LC) neurons were recorded in monkeys performing a visual discrimination task, and a computational model was developed addressing the role of the LC brain system in cognitive performance. Changes in spontaneous and stimulus-induced patterns of LC activity correlated closely with fluctuations in behavioral performance. The model explains these fluctuations in terms of changes in electrotonic coupling among LC neurons and predicts improved performance during epochs of high coupling and synchronized LC firing. Cross correlations of simultaneously recorded LC neurons confirmed this prediction, indicating that electrotonic coupling in LC may play an important role in attentional modulation and the regulation of goal-directed versus exploratory behaviors.

Impulse activity was recorded extracellularly from noradrenergic neurons in the nucleus locus coeruleus of three cynomolgus monkeys performing a visual discrimination (vigilance) task. For juice reward, the subjects were required to release a lever rapidly in response to an improbable target stimulus (20% of trials) that was randomly intermixed with non-target stimuli presented on a video display. All locus coeruleus neurons examined were phasically and selectively activated by target stimuli in this task. Other task events elicited no consistent response from these neurons (juice reward, lever release, fix spot stimuli, non-target stimuli). With reversal of the task contingency, locus coeruleus neurons ceased responding to the former target stimuli, and began responding instead to the new target (old non-target) stimuli. In addition, the latency of locus coeruleus response to target stimuli increased after reversal (by about 140 ms) in parallel with a similar increase in the latency of the behavioral response. These results indicate that the conditioned locus coeruleus responses reflect stimulus meaning and cognitive processing, and are not driven by physical sensors attributes. Notably, the reversal in locus coeruleus response to stimuli after task reversal occurred rapidly, hundreds of trials before reversal was expressed in behavioral responses. These findings indicate that conditioned responses of locus coeruleus neurons are plastic and easily altered by changes in stimulus meaning, and that the locus coeruleus may play an active role in learning the significance of behaviorally important stimuli.

Impulse activity was recorded extracellularly from noradrenergic neurons in the nucleus locus coeruleus (LC; 47 single-cell and 126 multicell recordings) of four cynomolgus monkeys performing an oddball visual discrimination task. For juice reward, the subjects were required to release a lever rapidly in response to an infrequent (10-20% of trials) target cue (CS+) that was randomly intermixed with nontarget (CS-) stimuli presented on a video display. All LC neurons examined were phasically and selectively activated by target cues in this task. Other task events elicited no consistent response from these neurons (juice reward, lever release, fix-spot stimuli, nontarget stimuli). In one animal, nontarget cues phasically inhibited LC neurons. Phasic LC excitatory responses to target cues in this task occurred at a relatively short latency (mean = 90.7 msec), approximately 200 msec prior to the behavioral response (lever release). In addition, LC response magnitudes varied with behavioral performance, being substantially attenuated during epochs of poor performance (high false alarm rate). There was a positive correlation (r = 0.30, p < 0.0001) between the latency of LC responses and the latency of behavioral responses to same target cues, consistent with the possibility that LC responses may have a role in selective attention by facilitating responses to the CS+ stimulus. Analyses of behavioral response latencies to pairs of stimuli indicated that LC responses may facilitate behavioral responses to subsequent sensory cues, consistent with a role of this system in sustained attention/vigilance. Moreover, responses became reduced in magnitude over time during prolonged task performance (> 90 min), in parallel with a behavioral performance decrement. These results show that LC neurons are activated selectively by attended stimuli that demand a rapid response in this task, and that such LC responses may contribute to conditioned behavioral responses.

Impulse activity of individual neurons in the nucleus locus coeruleus (LC) was recorded from chair-restrained, unanesthetized cynomolgus monkeys. LC activity was closely related to the behavioral state of the animal. In alert waking, LC neurons displayed continuous, moderately irregular activity. In contrast, prolonged pauses in activity accompanied drowsiness. These pauses preceded eye closure and occurred 1-3 s before the onset of slow-wave EEG. At awakening, LC activation preceded by up to 3 s desynchronized EEG and eye opening. LC activity during alertness varied tonically. During behavioral agitation LC activity was higher than during goal-directed task behavior (described below). In addition to these changes in tonic activity, LC neurons were also phasically responsive to certain sensory stimuli. These cells responded selectively to unexpected, meaningful sounds. LC neurons were also recorded during a visual oddball discrimination task in which the monkey was required to selectively release a lever in response to an infrequent visual cue (target cue; CS+) to receive juice reward. LC neurons were selectively activated by CS+ cues in this task; no other task events evoked LC activity. The mean latency of CS+ response was 108 ms (90 ms for multicell recordings), more than 150 ms prior to the behavioral response (lever release). These responses became smaller in later epochs during the session, along with deteriorating task performance. It is proposed that these short-lasting stimulus-evoked LC responses may help optimize behavioral responses and increase vigilance to subsequent sensory stimuli. Together, LC may contribute both to maintaining tonic levels of vigilance and to phasically modulating the current vigilance level in a stimulus-dependent mode.

Neurons were recorded extracellularly from the locus coeruleus (LC) of a waking, chair-restrained cynomolgus monkey before and for 0.5-4 h after intramuscular injections of morphine sulfate (0.3-10 mg/kg). Tonic discharge of each LC neuron tested (n = 11) decreased after morphine injection; this effect appeared to be dose-dependent for the range of 0.3-3.0 mg/kg. Unexpectedly, these same doses of morphine also induced a pronounced burst-pause discharge pattern in all LC neurons recorded. Thus, whereas in the naive animal pauses in discharge longer than 3 s were rare during waking, after morphine injection LC neurons frequently exhibited pauses in impulse activity of 10 s or longer during non-drowsy waking. The bursts in activity following morphine corresponded to orienting behaviors or apparent alertness, whereas pauses were associated with eye closure or slowly drifting gaze. Closer analysis revealed that this burst-pause activity pattern was somewhat regular, with a period of about 15-35 s. This observation was confirmed by autocorrelogram analysis. In view of previous findings in rodent LC, we suggest that acute morphine elicits a dual effect on primate LC neurons: inhibition of discharge by direct effects on opiate receptors located on LC cells, and periodic phasic activation mediated by excitatory afferents to the LC.

Previous microelectrode recordings in the putamen of monkeys have revealed a class of tonically active neurons without apparent behavioral correlates. The present study shows that such neurons have responses to stimuli that trigger movement but that these responses disappear when motor responses to the stimuli are extinguished. The short latency of the responses (less than for other putamen neurons) suggests that they may play a role in linking conditioned stimuli and responses.

Spontaneous and evoked activity of red nucleus neurons is described in chloralose anesthetized cats. It is suggested that some effects, e.g. burst discharges and prolonged inhibitory-excitatory responses, were induced by the use of chloralose.

Spontaneous and evoked activities of nucleus interpositus neurons (IN) of the cerebellum were examined before and after cerebellar paravermal cortex lesions in cats anesthetized with alpha-chloralose. It was found that spontaneous activity increased dramatically following cortical ablation: before the lesion only 4% of cells encountered fired at a rate exceeding 80 impulses/sec., whereas up to 40% discharged at this rate postoperatively. Responses to paw stimulation were also altered: the initial excitation was lengthened from 8.5 to 15.8 msec; narrow; trough causing segmentation in this excitation, which seems to result from Purkinje cell inhibition, was absent; and the succeeding inhibitory period was reduced in duration by 50%. Also after the lesion there was a strong tendency for the neurons to discharge in bursts. It is suggested that changes in cell activity in the IN following cortical lesion unveil neural mechanisms of motor disturbances in lesioned cats.

Anesthetized and immobilized cats were used. The interval between the peripheral (conditioning) and the cortical (testing) stimulation equalled the latency of the response to effective peripheral input. Efferent nuclear neurons were identified by antidromic stimulations from contralateral brainstem nuclei. Various sequences of excitation and inhibition of different duration were induced by peripheral inputs. Initial excitation was observed in efferent neurons in cases of selective reactions to one of the peripheral stimulations. In some neurons both initial excitation and inhibition were observed. Besides selective reactions, in neurons with background activity a convergence of different peripheral inputs was seen. Responses to converging peripheral influences had usually a similar pattern of PSTH, with the shortest latent period to the dominant afferent input. Effects of cerebellar cortical stimulation were observed in nuclear neurons, both efferent and intranuclear. Effects of cortical stimulation were evoked from a limited area of the stimulated cortical surface; convergence and divergence of influences were observed. Peripheral and cortical stimulations induced various patterns of impulse activity of nuclear neurons. Interaction of converging peripheral and cortical inputs on a nuclear neuron was determined by the level of excitation or inhibition evoked by the peripheral stimulus and the phase of the cortical action (inhibition or "disinhibition"). Besides its participation in integrative processes at the nuclear level, the cerebellar cortex determines the duration and frequency of successive onsets of excitatory bursts at the "output" of the cerebellum, thus playing a decisive role in the coding of information to other structures of the brain.

Interaction of afferent influences from pontine nuclei (NRTP, NPL and NPM) and inferior olive (IO) with influences from the cortex of neocerebellum (Crus I and II of hemisphere) was studied in dentate neurons (ND) in anesthetized and immobilized cats. Interaction of converging influences was tested with regard to response latencies. Activation of pontine nuclei (NP) and IO as well as cerebellar cortex affected all varieties of nuclear neurons regardless of their localization within the nucleus and their type (efferent or intranuclear). Stimulation of precerebellar nuclei (NP and IO) evoked in ND neurons an activity similar in firing patterns, displayed as bursts of excitation (S + S) lasting up to 10 ms. Initial excitation with following inhibition (S+-S), or excitation changed into inhibition with "rebound" [S+ - +(2)S] were also observed. Similar patterns of evoked activity were in neighboring nuclear neurons. Stimulation of lateral parts of Crus I and Crus II was most effective for ND. Influences from different parts of stimulated cortex have points of maximal action onto the given nuclear neuron (discrete action); divergence and convergence of influences were also observed. Cerebellar cortex stimulation depressed background impulse activity of ND neuron with gradual return to an initial level (S-S) or through a "rebound" [S- + (2)S]. Interaction of cortical and precerebellar nuclei influences was determined by algebraic summation of excitatory and inhibitory converging actions and the spontaneous activity. The latter persistently decreased in the course of repeated stimulation of the cerebellar cortex. The data show some peculiarities of that interaction and the role of the nuclear activity proper in forming the signals at the "output" of the cerebellum.

In unanesthetized cats peripheral stimulation typically evoked the short-latency excitation followed by short "inhibition". After administration of chloralose a gradual formation of long-lasting excitatory-inhibitory-excitatory response was observed.

In chloralose anesthetized cats responses of red nucleus neurons to cerebellar cortical or peripheral stimulation are described. Interactions between cerebellar (conditioning) and peripheral (test) stimulations were studied at various interstimulus intervals. Peripheral stimulation alone typically evoked a complex response consisting of an early (15 ms latency) burst, a period of depression of activity (inhibition, lasting up to 300 ms) and a late, long-lasting (on an average 300 ms) excitation. Cerebellar cortical stimulation resulted in a similar pattern of response; but it was composed predominantly of only two phases, an initial inhibition followed by a prolonged late discharge. With conditioning- testing intervals in a range of 10-150 ms, depending on the cell, there was a conspicuous depression of the sh0i.t-latency test excitation, followed by a prominent potentiation of this component. An occlusion of the inhibitory or late excitatory responses occurred when conditioning-testing stimuli were applied with an interval shorter than 0.5 s. It is suggested that the early excitation and the subsequent late components are generated in the red nucleus by independent mechanisms. The initial depression of the early test response is explained as an effect of Purkinje cell inhibition, and the later potentiation as a result of temporary blockage of the cerebellar cortex to afferent input.

A new, quick and inexpensive method of precision varnishing of metal microelectrodes is proposed. The circle surface pellicle of dried lacquer produced around the tip promotes microelectrode preparation.