Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation.
TL;DR: The locus coeruleus is the major noradrenergic nucleus of the brain, giving rise to fibres innervating extensive areas throughout the neuraxis, resulting in complex patterns of neuronal activity throughout the brain.
Abstract: The locus coeruleus (LC) is the major noradrenergic nucleus of the brain, giving rise to fibres innervating extensive areas throughout the neuraxis. Recent advances in neuroscience have resulted in the unravelling of the neuronal circuits controlling a number of physiological functions in which the LC plays a central role. Two such functions are the regulation of arousal and autonomic activity, which are inseparably linked largely via the involvement of the LC. The LC is a major wakefulness-promoting nucleus, resulting from dense excitatory projections to the majority of the cerebral cortex, cholinergic neurones of the basal forebrain, cortically-projecting neurones of the thalamus, serotoninergic neurones of the dorsal raphe and cholinergic neurones of the pedunculopontine and laterodorsal tegmental nucleus, and substantial inhibitory projections to sleep-promoting GABAergic neurones of the basal forebrain and ventrolateral preoptic area. Activation of the LC thus results in the enhancement of alertness through the innervation of these varied nuclei. The importance of the LC in controlling autonomic function results from both direct projections to the spinal cord and projections to autonomic nuclei including the dorsal motor nucleus of the vagus, the nucleus ambiguus, the rostroventrolateral medulla, the Edinger-Westphal nucleus, the caudal raphe, the salivatory nuclei, the paraventricular nucleus, and the amygdala. LC activation produces an increase in sympathetic activity and a decrease in parasympathetic activity via these projections. Alterations in LC activity therefore result in complex patterns of neuronal activity throughout the brain, observed as changes in measures of arousal and autonomic function.
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TL;DR: A tight correlation between the activity of the locus coeruleus (i.e., the "hub" of the noradrenergic system) and pupillary dilation and neurophysiological findings provide new important insights to the meaning of pupillary responses for mental activity.
Abstract: The measurement of pupil diameter in psychology (in short, "pupillometry") has just celebrated 50 years. The method established itself after the appearance of three seminal studies (Hess & Polt, 1960, 1964; Kahneman & Beatty, 1966). Since then, the method has continued to play a significant role within the field, and pupillary responses have been successfully used to provide an estimate of the "intensity" of mental activity and of changes in mental states, particularly changes in the allocation of attention and the consolidation of perception. Remarkably, pupillary responses provide a continuous measure regardless of whether the participant is aware of such changes. More recently, research in neuroscience has revealed a tight correlation between the activity of the locus coeruleus (i.e., the "hub" of the noradrenergic system) and pupillary dilation. As we discuss in this short review, these neurophysiological findings provide new important insights to the meaning of pupillary responses for mental activity. Finally, given that pupillary responses can be easily measured in a noninvasive manner, occur from birth, and can occur in the absence of voluntary, conscious processes, they constitute a very promising tool for the study of preverbal (e.g., infants) or nonverbal participants (e.g., animals, neurological patients).
733 citations
Cites background from "Functional neuroanatomy of the nora..."
...The LC might be a key node within the neural circuitry that also controls the muscles of the iris (Samuels & Szabadi, 2008), so that activity within this system gets reflected in the dilation of the eye’s pupil....
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TL;DR: It is shown that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner.
Abstract: Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression. Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner. Repeated social defeat also significantly increased the number of CD11b+/CD45high/Ly6Chigh macrophages that trafficked to the brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes [glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)]. The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist. Microglia isolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharide compared with microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1-deficient mice, but did not promote anxiety-like behavior or microglia activation in the absence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergic and IL-1 receptors.
545 citations
Cites background from "Functional neuroanatomy of the nora..."
...The regions that were activated after social defeat are integrated in catecholaminergic pathways and implicated in fear and threat appraisal (Samuels and Szabadi, 2008; Roozendaal et al., 2009; Ulrich-Lai and Herman, 2009)....
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TL;DR: GANE not only reconciles apparently contradictory findings in the emotion-cognition literature but also extends previous influential theories of LC neuromodulation by proposing specific mechanisms for how LC-NE activity increases neural gain.
Abstract: Emotional arousal enhances perception and memory of high-priority information but impairs processing of other information. Here, we propose that, under arousal, local glutamate levels signal the current strength of a representation and interact with norepinephrine (NE) to enhance high priority representations and out-compete or suppress lower priority representations. In our "glutamate amplifies noradrenergic effects" (GANE) model, high glutamate at the site of prioritized representations increases local NE release from the locus coeruleus (LC) to generate "NE hotspots." At these NE hotspots, local glutamate and NE release are mutually enhancing and amplify activation of prioritized representations. In contrast, arousal-induced LC activity inhibits less active representations via two mechanisms: 1) Where there are hotspots, lateral inhibition is amplified; 2) Where no hotspots emerge, NE levels are only high enough to activate low-threshold inhibitory adrenoreceptors. Thus, LC activation promotes a few hotspots of excitation in the context of widespread suppression, enhancing high priority representations while suppressing the rest. Hotspots also help synchronize oscillations across neural ensembles transmitting high-priority information. Furthermore, brain structures that detect stimulus priority interact with phasic NE release to preferentially route such information through large-scale functional brain networks. A surge of NE before, during, or after encoding enhances synaptic plasticity at NE hotspots, triggering local protein synthesis processes that enhance selective memory consolidation. Together, these noradrenergic mechanisms promote selective attention and memory under arousal. GANE not only reconciles apparently contradictory findings in the emotion-cognition literature but also extends previous influential theories of LC neuromodulation by proposing specific mechanisms for how LC-NE activity increases neural gain.
458 citations
Cites background from "Functional neuroanatomy of the nora..."
...The LC is the primary source of cortical NE and helps determine arousal levels (Berridge & Waterhouse 2003; Berridge et al. 2012; Samuels & Szabadi 2008a; 2008b)....
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TL;DR: This work demonstrates that the pupil does not signal expected reward or uncertainty per se, but instead signals surprise, that is, errors in judging uncertainty, and analyses this effect with respect to a specific mathematical model of uncertainty and surprise, namely risk and risk prediction error.
Abstract: Our decisions are guided by the rewards we expect. These expectations are often based on incomplete knowledge and are thus subject to uncertainty. While the neurophysiology of expected rewards is well understood, less is known about the physiology of uncertainty. We hypothesize that uncertainty, or more specifically errors in judging uncertainty, are reflected in pupil dilation, a marker that has frequently been associated with decision-making, but so far has remained largely elusive to quantitative models. To test this hypothesis, we measure pupil dilation while observers perform an auditory gambling task. This task dissociates two key decision variables – uncertainty and reward – and their errors from each other and from the act of the decision itself. We first demonstrate that the pupil does not signal expected reward or uncertainty per se, but instead signals surprise, that is, errors in judging uncertainty. While this general finding is independent of the precise quantification of these decision variables, we then analyze this effect with respect to a specific mathematical model of uncertainty and surprise, namely risk and risk prediction error. Using this quantification, we find that pupil dilation and risk prediction error are indeed highly correlated. Under the assumption of a tight link between noradrenaline (NA) and pupil size under constant illumination, our data may be interpreted as empirical evidence for the hypothesis that NA plays the same role for uncertainty as dopamine does for reward, namely the encoding of error signals.
422 citations
Cites background from "Functional neuroanatomy of the nora..."
...First, converging evidence from electrophysiology (Rajkowski et al., 1993, 1994), pharmacology (Phillips et al., 2000), anatomy (Samuels and Szabadi, 2008 for review), and human imaging (Sterpenich et al., 2006; but see Astafiev et al., 2010) points to a tight link between pupil dilation under…...
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...Several lines of evidence converge in favor of a link between pupil dilation and NA levels (Samuels and Szabadi, 2008 for review), including anatomy (Nieuwenhuis et al., 2011 for review), pharmacology in healthy observers and patients (Koss, 1986; Phillips et al., 2000; Jepma et al., 2011), monkey…...
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TL;DR: Eyetracking measures provide non-invasive and rich indices of brain function and cognition and gaze analysis reveals current attentional focus and cognitive strategies.
412 citations
Cites background from "Functional neuroanatomy of the nora..."
...The LC is a small ucleus in the brainstem that plays a central role in the regulation f physiological arousal (Samuels and Szabadi, 2008) and cognitive unctioning (Sara, 2009)....
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...…and pupil dilation has been established with a variety of methods, including human and animal studies with pharmacological manipulations and brain imaging techniques (Samuels and Szabadi, 2008; Sara, 2009), allowing researchers to draw inferences about neural processes from pupillometry data....
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...By inhibiting the Edinger-Westphal nucleus and the pupil’s constricting muscle, LC activity therefore indirectly dilates the pupil (Beatty and Lucero-Wagoner, 2000; Loewenfeld and Lowenstein, 1993; Samuels and Szabadi, 2008)....
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...At the same time, LC activity suppresses sleepiness through its substantial inhibitory projections to sleep-promoting GABAergic neurons in the basal forebrain and to other structures related to low arousal throughout the central nervous system (Samuels and Szabadi, 2008)....
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...Samuels and Szabadi (2008) have provided a comprehensive review of the anatomical structures underlying the LC’s role in arousal and autonomic function....
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References
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Journal Article•
4,814 citations
"Functional neuroanatomy of the nora..." refers background in this paper
...The LC, a pontine nucleus located near the pontomesencephalic junction, is the largest group of noradrenergic neurones in the central nervous system [70, 174, 261]....
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TL;DR: In this paper, it was shown that reticular activation is associated with the activation of the reticular formation of the brain stem, and that reticulus activation can be induced by low frequency stimulation of the diffuse thalamic projection system, rather than intra-cortical spread following the arrival of afferent impulses at the sensory receiving areas of the cortex.
4,014 citations
TL;DR: The ascending monoamine pathways in the rat brain are demonstrated by the pile up of fluorescent material occurring in the axons after various types of lesions, indicating a unique role for the locus coeruleus in influencing the activity of the entire brain.
Abstract: The ascending monoamine pathways in the rat brain are demonstrated by the pile up of fluorescent material occurring in the axons after various types of lesions. The anatomy of the pathways is outlined in drawings of frontal sections of the brain and the origin and termination of several pathways is determined by studying the anterograde and retrograde degeneration occurring after well localised lesions. It is possible to separate the ascending NA pathways into a dorsal and a ventral bundle of axons. The dorsal bundle innervates the cortex and the hippocampus and the ventral bundle supplies NA nerve terminals to the medulla, the pons, the mesencephalon and the diencephalon. The dorsal bundle is found to originate in the locus coeruleus. Lesions of this nucleus abolish the nerve terminals in all cortical areas and in several other areas of the brain indicating a unique role for the locus coeruleus in influencing the activity of the entire brain. The 5-HT pathways have a distribution similar to the ventral NA pathyway. The course of the nigro-striatal and the meso-limbic DA pathways is presented in detail.
3,758 citations
"Functional neuroanatomy of the nora..." refers background in this paper
...The LC projects to areas throughout the cerebellum [208, 210, 261, 268, 369] and in particular to the cerebellar cortex [301, 320]....
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...The LC also innervates the hippocampus, providing the sole source of noradrenaline to the hippocampal neurones [110, 174, 204, 208, 210, 261, 277, 369]....
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TL;DR: A hypothalamus-specific mRNA is described that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin, suggesting that the hypocretins function within the CNS as neurotransmitters.
Abstract: We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies of the dorsal and lateral hypothalamic areas. The fibers of these neurons are widespread throughout the posterior hypothalamus and project to multiple targets in other areas, including brainstem and thalamus. Hcrt immunoreactivity is associated with large granular vesicles at synapses. One of the Hcrt peptides was excitatory when applied to cultured, synaptically coupled hypothalamic neurons, but not hippocampal neurons. These observations suggest that the hypocretins function within the CNS as neurotransmitters.
3,558 citations
"Functional neuroanatomy of the nora..." refers background in this paper
...The orexin system originates solely in the LH/PF, with fibres projecting widely throughout the brainstem and thalamus [78]....
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TL;DR: The results of this immunohistochemical study suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep–waking cycle.
Abstract: The novel neuropeptides called hypocretins (orexins) have recently been identified as being localized exclusively in cell bodies in a subregion of the tuberal part of the hypothalamus. The structure of the hypocretins, their accumulation in vesicles of axon terminals, and their excitatory effect on cultured hypothalamic neurons suggest that the hypocretins function in intercellular communication. To characterize these peptides further and to help understand what physiological functions they may serve, we undertook an immunohistochemical study to examine the distribution of preprohypocretin-immunoreactive neurons and fibers in the rat brain. Preprohypocretin-positive neurons were found in the perifornical nucleus and in the dorsal and lateral hypothalamic areas. These cells were distinct from those that express melanin-concentrating hormone. Although they represent a restricted group of cells, their projections were widely distributed in the brain. We observed labeled fibers throughout the hypothalamus. The densest extrahypothalamic projection was found in the locus coeruleus. Fibers were also seen in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central gray, the substantia nigra, the raphe nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Less prominent projections were found in cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. These results suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep–waking cycle.
3,255 citations
"Functional neuroanatomy of the nora..." refers background in this paper
...The LH/PF densely innervates the neurones of the LC [54, 193, 261] with fibres that contain the orexin peptides [74, 97, 138, 280] (see Fig....
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