Noradrenaline helps us control our attentional focus

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The locus coeruleus, literally the “blue spot,” is a tiny cluster of cells at the base of the brain. As the main source of the neurotransmitter noradrenaline, it helps us control our attentional focus. Synthesizing evidence from animal and human studies, scientists at the Max Planck Institute for Human Development and the University of Southern California have now developed a novel framework describing the way the blue spot regulates our brain’s sensitivity to relevant information in situations requiring attention.

Their findings have been published in an opinion article in the journal Trends in Cognitive Sciences.

Our attention fluctuates. Sometimes, we are distracted and things slip by our awareness, while at other times we can easily focus on what is important. Imagine you are walking home after a day at work; perhaps you are preparing the list of groceries to buy for dinner in your mind—you are in a state of inattentiveness.

However, when a car you did not notice suddenly honks, you are readily able to redirect your attention and respond to this new situation. But how does the brain shift from a state of inattentiveness to one of focused attention?

During states of inattentiveness, our brains are governed by slow, rhythmic fluctuations of neural activity. In particular, neural rhythms at a frequency around 10 Hertz, termed alpha oscillations, are thought to suppress the active processing of sensory inputs during inattentiveness.

Thus, alpha oscillations can be understood as a filter that regulates our brain’s sensitivity for external information.

“While the link between the waxing and waning of alpha oscillations and attention has been established for some time, less is known about what makes these rhythmic firing patterns come and go,” says Markus Werkle-Bergner, Senior Scientist at the Center for Lifespan Psychology at the Max Planck Institute for Human Development and coauthor on the opinion article.

To explore this question, the researchers focused on the blue spot (locus coeruleus), a tiny cell structure that is located in the brainstem, hidden deep under the cortex. This cell cluster is only about 15 millimeters in size, but it is connected to most of the brain via an extensive network of long-ranging nerve fibers.

The blue spot is made up of neurons that are the main source of the neurotransmitter noradrenaline. By regulating neural communication, noradrenaline contributes to the control of stress, memory, and attention.

“Due to its small size and its location deep in the brainstem, it was previously almost impossible to investigate the noradrenergic nucleus non-invasively in living humans. Fortunately, over the past years, animal research has revealed that fluctuations in pupil size are linked to the activity of the blue spot.

Thus, our eyes can be regarded as a window to a brain region that long seemed inaccessible,” says Mara Mather, professor of Gerontology at the University of Southern California and coauthor on the opinion article.

To study whether the blue spot’s noradrenaline could be one factor regulating alpha oscillations, the researchers combined recordings of pupil size and neural oscillations while participants solved a demanding attention task.

As expected, during moments of larger pupil size, indicative of higher noradrenergic activity, alpha oscillations disappeared. Moreover, participants who showed stronger pupil and alpha responses were better at solving the attention task.

These findings, that were published 2020 in an article in the Journal of Neuroscience, suggest that by modulating alpha oscillations, the blue spot can help us focus our attention.

What remained unanswered in this study is how noradrenaline influences alpha oscillations. To approach this question, the authors additionally turned to previous animal research that recorded neural activity directly from neurons in the thalamus, a region in the middle of the brain that functions as a pacemaker of the alpha rhythm.

Importantly, the rhythmic firing of these neurons at rest gives rise to the cortical alpha oscillations seen during states of inattentiveness. However, adding noradrenaline to these neurons abolishes their rhythmicity.

“Assembling the findings across studies, we were able to describe how noradrenaline and the thalamus might interact to control alpha rhythmic activity. We suggest that the blue spot’s noradrenaline regulates our brain’s sensitivity to process relevant information by suppressing alpha generators in the thalamus,” says Martin Dahl, postdoctoral researcher at the Center for Lifespan Psychology, Max Planck Institute for Human Development, and the University of Southern California and first author on the opinion article.

Thus, during situations requiring a sudden shift in attention, a surge of noradrenaline helps us refocus—and quickly dodge the approaching car.

Further long-term studies that assess both the locus coeruleus and thalamus in the same participants may be able to shed new light on the neural mechanisms of attention and its decline in aging and disease.


The anatomy and pharmacology of noradrenaline and the locus coeruleus

The forebrain noradrenergic input is from a small bilateral collection of neurons called the locus coeruleus (LC), where the cells begin rostrally at the level of the inferior colliculus adjacent to the cerebral aqueduct and end caudally near the lateral wall of the fourth ventricle11; on axial brain slices, the anatomical landmarks are ∼1 mm under the fourth ventricle, ∼3 mm from the midline, and centred ∼14–21 mm above the ponto-medullary junction12 (Fig. 1).

The LC is readily identified at post-mortem by its dark colour owing to the high neuromelanin content; the synthesis of the pigment, neuromelanin, is driven by excess levels of catecholamines in the cytosol and is thus crucially linked to the synthesis and metabolism of noradrenaline.13,14 Other conventional ways to identify noradrenaline producing neurons in the LC is by immunohistochemistry directed at tyrosine hydroxylase (TH), the enzyme that converts L-tyrosine to L-DOPA, or against dopamine beta-hydroxylase, which converts dopamine to noradrenaline.15 

It is widely considered that the two markers are expressed by identical neuronal populations16 representing the noradrenergic neuronal population of LC which constitutes more than 95% of neurons in the LC in controls.17,18 However, a small proportion of large TH-positive neurons, which are more numerous in the rostral than caudal pons, lack pigmentation.15 Within the LC there is heterogeneity in both the population of the residing medium-sized neurons and neuronal numbers across the rostro-caudal gradient.

The majority of medium-sized LC noradrenergic neurons are large multipolar cells (35–45 µm in diameter), with plump cell bodies and short dendrites; in the caudal LC and subcoeruleus, where the density of medium sized neurons is lower, the larger medium sized neurons are interspersed with smaller fusiform noradrenergic neurons (∼15 µm in diameter) with triangular cell bodies and two tufts of long dendrites.19

Along the LC, there is a spatially differentiated neuronal organization such that cells giving rise to hippocampal projections are located in more rostral segments while those that innervate the neocortex, cerebellum and spinal cord are located more caudally; subcortical projections of the LC are more scattered, with a proposed spatial bias towards the caudal portion.14,19 The observation of a rostrocaudal gradient has recently been confirmed in vivo and is important to consider when assessing for neuronal loss secondary to neurodegeneration where selective loss of rostral or caudal groups may be observed.20 We discuss this selective vulnerability later in the review.Figure 1

Neuroanatomical location and projections of the LC. (A) Schematic sagittal view of the brain, illustrating locus coeruleus anatomy, projections, and downstream cognitive dysfunction associated with disturbed LC projections. (B) Coronal and (C) axial views of the locus coeruleus obtained from magnetization transfer weighted sequences at 7 T MRI. Ant = anterior; Post = posterior. Image courtesy of Dr Rong Ye and Dr Claire O’Callaghan.

Neuroanatomical location and projections of the LC. (A) Schematic sagittal view of the brain, illustrating locus coeruleus anatomy, projections, and downstream cognitive dysfunction associated with disturbed LC projections. (B) Coronal and (C) axial views of the locus coeruleus obtained from magnetization transfer weighted sequences at 7 T MRI. Ant = anterior; Post = posterior. Image courtesy of Dr Rong Ye and Dr Claire O’Callaghan.

Neuroanatomical location and projections of the LC. (A) Schematic sagittal view of the brain, illustrating locus coeruleus anatomy, projections, and downstream cognitive dysfunction associated with disturbed LC projections. (B) Coronal and (C) axial views of the locus coeruleus obtained from magnetization transfer weighted sequences at 7 T MRI. Ant = anterior; Post = posterior. Image courtesy of Dr Rong Ye and Dr Claire O’Callaghan.

The LC is now increasingly studied in vivo, through MRI by utilizing the highly paramagnetic neuromelanin content,21–23 where the inferior colliculus and the recess of the fourth ventricle are used as key landmarks for its segmentation.20 Noradrenaline also arises from the subcoeruleus nucleus extending ventrolaterally from the caudal pole of the LC, innervating the brainstem and hypothalamus for neuroendocrine and autonomic regulation,11,24 but these projections are less relevant for higher cognitive functions.

Given its extensive projections to both cortical and subcortical areas25 (Fig.1A), the LC is surprisingly small. With variations in preparation and counting techniques, estimates vary in the range 20 000–98 000 neurons in humans,26–31 with the highest estimated neuronal numbers obtained by unbiased stereology.32 Within this collection of neurons lie subgroups that preferentially project to the primary motor cortex and the subregions of the prefrontal cortex33 leading to a non-uniform release of LC-mediated noradrenaline across the cortical mantle.34,35

Three factors contribute to the sophistication of noradrenergic transmission. First, the diversity of noradrenergic receptors (Fig. 2). Second, the distinction between tonic and phasic neurotransmission. Third, the non-linear relationship between innervation and performance (Fig. 3).Figure 2Noradrenaline synthesis pathway, distribution of pre and postsynaptic adrenoreceptors, and available noradrenergic agonist and antagonists used in animal and human studies. Agonists are depicted by a plus symbol and dark green arrows, whilst antagonists are depicted by the letter ‘X’ and orange arrows. Drugs used in human studies and clinical trials are marked with an asterisk. Noradrenaline synthesis pathway: noradrenaline is synthesized from tyrosine, which is initially converted to l-DOPA through the action of tyrosine hydroxylase (TH); l-DOPA is further converted to dopamine by aromatic l-amino acid decarboxylase (AADC), before finally being converted to noradrenaline through the action of dopamine β-monooxygenase (DA-C; also known as dopamine β-hydroxylase). Noradrenaline is recycled through the norepinephrine transporter (NET) and degraded by monoamine oxidase (MOA), to the principal end product vanillylmandelic acid or a conjugated form of 3-methoxy-4-hydroxyphenylglycol (MHPG). Methylphenidate = mixed noradrenaline and dopamine reuptake inhibitor.

Noradrenaline synthesis pathway, distribution of pre and postsynaptic adrenoreceptors, and available noradrenergic agonist and antagonists used in animal and human studies. 

Agonists are depicted by a plus symbol and dark green arrows, whilst antagonists are depicted by the letter ‘X’ and orange arrows. Drugs used in human studies and clinical trials are marked with an asterisk.

Noradrenaline synthesis pathway: noradrenaline is synthesized from tyrosine, which is initially converted to L-DOPA through the action of tyrosine hydroxylase (TH); L-DOPA is further converted to dopamine by aromatic L-amino acid decarboxylase (AADC), before finally being converted to noradrenaline through the action of dopamine β-monooxygenase (DA-C; also known as dopamine β-hydroxylase).

Noradrenaline is recycled through the norepinephrine transporter (NET) and degraded by monoamine oxidase (MOA), to the principal end product vanillylmandelic acid or a conjugated form of 3-methoxy-4-hydroxyphenylglycol (MHPG). Methylphenidate = mixed noradrenaline and dopamine reuptake inhibitor.

Noradrenaline synthesis pathway, distribution of pre and postsynaptic adrenoreceptors, and available noradrenergic agonist and antagonists used in animal and human studies. Agonists are depicted by a plus symbol and dark green arrows, whilst antagonists are depicted by the letter ‘X’ and orange arrows. Drugs used in human studies and clinical trials are marked with an asterisk. Noradrenaline synthesis pathway: noradrenaline is synthesized from tyrosine, which is initially converted to l-DOPA through the action of tyrosine hydroxylase (TH); l-DOPA is further converted to dopamine by aromatic l-amino acid decarboxylase (AADC), before finally being converted to noradrenaline through the action of dopamine β-monooxygenase (DA-C; also known as dopamine β-hydroxylase). Noradrenaline is recycled through the norepinephrine transporter (NET) and degraded by monoamine oxidase (MOA), to the principal end product vanillylmandelic acid or a conjugated form of 3-methoxy-4-hydroxyphenylglycol (MHPG). Methylphenidate = mixed noradrenaline and dopamine reuptake inhibitor.

Figure 3Schematic illustration of the non-linear function of performance versus locus coeruleus activity, analogous to the Yerkes-Dodson model of arousal and comparable to non-linear relationships in dopaminergic and serotonergic systems.

Schematic illustration of the non-linear function of performance versus locus coeruleus activity, analogous to the Yerkes-Dodson model of arousal and comparable to non-linear relationships in dopaminergic and serotonergic systems.

Schematic illustration of the non-linear function of performance versus locus coeruleus activity, analogous to the Yerkes-Dodson model of arousal and comparable to non-linear relationships in dopaminergic and serotonergic systems.

Noradrenaline exerts an excitatory action through the post-synaptic α1 and β adrenoceptors, and an inhibitory action through mainly presynaptic α2-adrenoreceptors.36 The distribution and affinity of adrenoreceptors is highly variable. For example, α2-adrenoreceptor are common in the prefrontal cortical areas, and noradrenaline has the highest affinity for these,37 and lower affinity for α1- and β-adrenoreceptors.38 

As a consequence moderate levels of noradrenaline engage α2 receptors whilst higher levels (released during stress for example) engage the lower-affinity α1 and β receptors.39 This creates a non-linear relationship between noradrenergic transmission and performance, indicating that response to an excitatory input may be enhanced or suppressed depending on the receptor in action.40

The LC exhibits two broad firing patterns: tonic and phasic (Fig. 3).41 These have distinct properties and signal processing characteristics. For example, during direct physiological recordings in monkeys, in a visuo-motor task with reward and punishment, phasic responses followed salient stimuli but not distractors.41 Phasic responses were diminished or absent in poor performance trials suggesting a role as an attentional filter that selects for the occurrence of task-relevant stimuli.

When not engaged in task performance the LC returns to a tonic firing rate. Within the same visuo-motor task, elevated tonic LC activity reduced the ability to discriminate stimuli from distractors; the monkeys were more distractible and made more errors. These observations are replicated in rats where stimulating LC tonic activity leads to increased decision noise and reduced task participation.42 

The balance between tonic and phasic activity therefore, enables a gating signal function that regulates task engagement or disengagement according to salience and anticipated rewards or punishments, facilitating an adaptive behaviour. This is supported in human studies, where pupillometry has been used as a surrogate for LC activity43,44 such that a large baseline pupil diameter implies LC phasic activity and a smaller one implies tonic LC activity; for example, in an auditory discrimination task, phasic pupillary dilatation correlated with correct responses, whereas tonic pupillary dilatation correlated with periods of low reward value.45 In signal processing terms, dynamic LC activity regulates signal-to-noise ratio both at the level of the LC46 and at target neurons.47

Histological studies of the LC suggest that neuronal number and volume do not change significantly with age30,48; however, there is an increase in the LC neuromelanin content, which may reflect functional changes that contribute to variability in cognitive performance between healthy young and older adults.49,50 Until recently, studying the LC required invasive methods, limited mainly to preclinical models, or relied on indirect inferences based on the pupillometric response which is correlated with the activity of other neural networks besides the LC. However, advances in neuroimaging, by drawing on the paramagnetic features of the neuromelanin rich LC neurons, have aided the direct in vivo study of this structure and its functional connections in humans.

Using MRI enables both in vivo human quantification of LC size and neuromelanin content (Fig. 1B and C), and its functional connectivity, with good reliability.22,51 Better resolution and sensitivity of such sequences is being developed alongside post-mortem validation of the histological changes underlying each MRI contrast.21 Already, MRI has contributed to understanding the role of the LC in human cognition. For example, in a reversal learning task healthy adults (aged 65–84) were asked to make choices from single or double picture trials with reward and loss as feedback; this was then followed by MRI and a memory test of the pictures seen prior to the scanning session.

Those adults with a higher LC signal intensity, performed better at the memory task especially for stimuli associated with negative feedback compared to younger adults (aged 20–31).49 A negative correlation has been proposed, between age and the connectivity between LC and ventral tegmental area, and a more complex non-linear relationship between age and the connectivity of LC to frontotemporal cortex.52 In the next section, we consider how these properties of the noradrenergic system are affected by neurodegenerative disorders.

reference link :https://academic.oup.com/brain/article/144/8/2243/6174120


Original Research: Open access.
Noradrenergic modulation of rhythmic neural activity shapes selective attention” by Martin J. Dahl et al. Trends in Cognitive Sciences

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