Noradrenergic System & Alerting Network

Noradrenergic System

Effect of Noradrenaline on Attention

Target Detection task: spontaneous activity of LC

originates in brainstem structures: locus cerulean (pons) & medulla

Agonist: Clonidine, Antagonists: Antisychotics, Beta blockers, Tricyclic Antidepressants

Precursor: Dopamine

Two main branches:

dorsal ascending system: projects all over the forebrain, including neocortex & hippocampus
ventral: projects mainly to hypothalamus & limbic system

Functions: arousal, mobilizes brain & body for action, promotes vigilance, enhances retrieval & formation of memory, increases restlessness & anxiety, novelty

least active when you're asleep, most active when you're aroused
increases heart rate, blood pressure, triggers release of glucose from energy stores, increases blood flow to skeletal muscle

Receptors:
Beta Receptor Systems

Beta1: in heart, increases in heart rate, heart muscle contraction, excess can induce arrhythmias
Beta2: in smooth muscle, leads to muscle relaxation

Alpha Receptor Systems

presynaptic alpha2: their activation inhibits NE release
postsynaptic alpha1: on vascular smooth muscle, increase in vasoconstriction & arterial blood pressure -> smooth muscle contraction

Dorsomedial hypothalamic nucleus (DMH) modulates the rhythm of sleep and waking via projections to the LC

SCN- DMH- LC signaling pathway influences the activity of LC

SCN is for temporal organization of sleep-wake cycle
LC as output circuit to provide circadian regulation

hypocretin neurons may transmit circadian information to LC

LC neurons are physically activated by salient stimuli during waking

role in circadian regulation of alertness & performance

NE regulates the states of neurons in thalamus & cerebral cortex

transmission/spike mode: waking, NE release
oscillatory mode: sleep, absence of NE

link between NE cells & alertness -> increased arousal, EEG activity in frontal neocortex, intense theta rhythm in hippocampus

Changes in tonic & stimulus-induced activity in LC are correlated with fluctuations in behavioral performance -> role in regulating different types of cognitive abilities during alertness (target detection task)

global efferent projections from LC to brain areas associated with attentional processing ie. parietal cortex, superior colliculus, pulvinar nucleus

activity is reduced during low arousal (drowsiness, sleep), grooming, consumption, when engaged in automatic activity, inattentive to extrapersonal environmental stimuli

LC neurons phasically responsive to stimuli that disrupt ongoing behavior, also due to stressors eg. painful event, airpuff -> LC neurons are activated by stress-releasing hormone CRH

phasic mode of LC activity -> hightened selective attention -> increased accuracy of responding to task-relevant stimuli

high tonic LC activity -> reduction in selective attention -> increase in responses to task-irrelevant stimuli

LC cells exhibit phasic or tonic modes of activity (correspond to different levels of performance)

phasic: good performance, high visual fixation, may promote focused/selective attention, may be driven by decision processes from ACC, OFC, related to intermediate tonic discharge levels of LC
tonic: poor performance, may produce a state of high flexibility & scanning attentiveness, more frequent false alarms without increases in hits, increased distractability, lower response criterion
--> successful behavior requires capacity for both, selective responding in a stable environment & rapid/adaptive responding in a changing environment

Task:

Each monkey was trained to depress the lever to initiate the task, after which a small fix spot appeared in the center of the monitor
the fix spot was extinguished, & a conditioned stimulus was presented (vertical or horizontal bar)
-> release the lever in response to the target stimulus within 650ms to receive a juice reward

Results: resemble inverted U (performance on Y-axis & tonic LC activity on X-axis)

responses of LC neurons were selective
nearly all 300+ LC neurons were physically activated preferentially by target stimuli (eg.vertical bars)
some LC neurons were weakly inhibited by distractor stimuli
lever release outside of the task or juice delivery elicited no response
reversal of meaning caused LC cells to reverse responsiveness

Latency:

latencies of LC responses to targets were short
latencies of response of LC neurons & lever releases were correlated over trials -> shorter LC responses associated with shorter behavioral responses
-> LC target responses might facilitate behavioral responses to target stimuli

Clinical Implications of LC activity

Stress Disorders ie. PTSD: heightened LC tonic activity or heightened LC responsiveness to conditioned stimuli

drugs that decrease LC discharge rate improve symptoms intensity & frequency of nightmares

Emotion & Affective Disorders: stimuli that cause sympathetic activation also activate LC

chronically hyperactive LC system-> symptoms are manic/depressive, impulsive
chronically decreased LC function -> limited emotionality, flat affect
inappropriate LC hyperresponsiveness to stimuli -> stress & anxiety

ADHD: overly tonic LC mode

Study of Witte & Marrocco: role of NE in arousal & orienting

Clonidine: alpha2 agonist

Fixation training: learning to maintain fixation, to press a bar etc.

Cued covert target detection task:

fixation point & two flanking boxes
at 100, 400, 700ms after the cue's onset, a target was presented in one of the boxes -> respond no later than 850ms
valid, invalid, double/neutral, no cue trials

Drug administration:

alpha2 agonists: Clonidine, Guanfacine
alpha2 antagonists: Idazoxan, Yohimbine
Saline Control: because they were concerned that the injection itself might change the animals' arousal level

Data Analysis:

Response costs: double cue RTs - invalid cue RTs
Response benefits: valid cue RTs - double cue RTs

Results:

significant main effect of cue type: valid faster than invalid, double faster than no cue, valid faster than double
significant main effect of drug: Clonidine enhanced RTs, Guanfacine decreased RTs
significant drug by cue interaction: drugs affected alerting effect (clonidine reduced the size of alerting effect)
drugs didn't affect the orientation of attention: lack of significant change in validity effect

Interpretation: Noradrenaline is involved in maintaining non spatial, sensory readiness to external cues but not in the shifting of the attentional focus

in low doses it acts presynaptically to decrease NE cell firing & release -> areas less excited

broadens attentional focus: impairs performance on tests of sustained attention & increases attention lapses

Supported: Lapses of attention would increase following clonidine challenge. This effect would be reversed either by exposure to noise or by co-administration of Idazoxan

Nr. of lapses greatest in clonidine quiet condition

Role in PTSD:

reduces CNS noradrenergic activity -> treats sleep disturbance & hyperarousal & startle reactions in PTSD (minimal adverse effects)
PTSD patients have elevated urinary NE & NE CSF concentrations
low dose increased REM sleep & decreased NREM (affects alpha2 presynaptically), medium dose did the opposite (acts postsynaptically)

Effect on alertness:

very long RTs, failures to respond -> the effect can be reduced by increasing alertness by exposing the person to a loud noise

Attention Domains

Vigilance (intensity)

Selective, focused attention (selectivity)

Sustained Attention (intensity)

Visuo-spatial attention, Shift of attentional focus (selectivity)

Alertness (intensity)

Divided attention (selectivity)

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