Role of locus coeruleus in attention and behavioral flexibility.

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.

The role of locus coeruleus in the regulation of cognitive performance.

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.

Conditioned responses of monkey locus coeruleus neurons anticipate acquisition of discriminative behavior in a vigilance task.

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.

Locus coeruleus neurons in monkey are selectively activated by attended cues in a vigilance task.

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.

Locus coeruleus activity in monkey: phasic and tonic changes are associated with altered vigilance.

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.

Acute morphine induces oscillatory discharge of noradrenergic locus coeruleus neurons in the waking monkey.

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.

Spontaneous and evoked activities of interpositus nucleus neurons before and after lesion of the cerebellar cortex.

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.

Tonically discharging putamen neurons exhibit set-dependent responses.

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.

Responses of red nucleus neurons to peripheral stimulation in chloralose anesthetized cats.

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.

Simple method of preparation of precise varnish-insulated metal microelectrodes.

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.

Interaction of extracerebellar and cerebellar cortical inputs in dentate neurons of the cat.

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.

The influence of chloralose anesthesia on the activity of red nucleus neurons in cats.

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.

Interaction of peripheral and cerebellar inputs to red nucleus neurons.

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.

Interaction of converging peripheral and cerebellar cortical inputs on interpositus neurons of the cat.

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.