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Noradrenergic System & Alerting Network (Effect of Noradrenaline on…
Noradrenergic System & Alerting Network
Noradrenergic System
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
Effect of Noradrenaline on Attention
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
Target Detection task: spontaneous activity of LC
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
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
Clonidine: alpha2 agonist
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)