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Current Biology : CB Nov 2015The release of the neurotransmitter norepinephrine throughout the mammalian brain is important for modulating attention, arousal, and cognition during many behaviors.... (Review)
Review
The release of the neurotransmitter norepinephrine throughout the mammalian brain is important for modulating attention, arousal, and cognition during many behaviors. Furthermore, disruption of norepinephrine-mediated signaling is strongly associated with several psychiatric and neurodegenerative disorders in humans, emphasizing the clinical importance of this system. Most of the norepinephrine released in the brain is supplied by a very small, bilateral nucleus in the brainstem called the locus coeruleus. The goal of this minireview is to emphasize the complexity of the locus coeruleus beyond its primary definition as a norepinephrine-producing nucleus. Several recent studies utilizing innovative technologies highlight how the locus coeruleus-norepinephrine system can now be targeted with increased accuracy and resolution, in order to better understand its role in modulating diverse behaviors.
Topics: Animals; Attention; Brain; Brain Stem; Cognition; Humans; Locus Coeruleus; Norepinephrine
PubMed: 26528750
DOI: 10.1016/j.cub.2015.09.039 -
Nature Reviews. Neuroscience Nov 2020The locus coeruleus (LC), or 'blue spot', is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the... (Review)
Review
The locus coeruleus (LC), or 'blue spot', is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.
Topics: Animals; Cognition; Humans; Locus Coeruleus; Neural Pathways; Neuronal Plasticity; Neurons; Nucleus Accumbens
PubMed: 32943779
DOI: 10.1038/s41583-020-0360-9 -
Brain : a Journal of Neurology Mar 2022There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining...
There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining immunohistochemistry, tracing studies and western blotting, with the use of different DREADDS (designer receptor exclusively activated by designer drugs) and behavioural approaches in a rat model of neuropathic pain (chronic constriction injury), we explore how this comorbidity arises. To this end, we evaluated the time-dependent plasticity of noradrenergic locus coeruleus neurons relative to the site of injury: ipsilateral (LCipsi) or contralateral (LCcontra) locus coeruleus at three different time points: short (2 days), mid (7 days) and long term (30-35 days from nerve injury). Nerve injury led to sensorial hypersensitivity from the onset of injury, whereas depressive-like behaviour was only evident following long-term pain. Global chemogenetic blockade of the LCipsi system alone increased short-term pain sensitivity while the blockade of the LCipsi or LCcontra relieved pain-induced depression. The asymmetric contribution of locus coeruleus modules was also evident as neuropathy develops. Hence, chemogenetic blockade of the LCipsi→spinal cord projection, increased pain-related behaviours in the short term. However, this lateralized circuit is not universal as the bilateral chemogenetic inactivation of the locus coeruleus-rostral anterior cingulate cortex pathway or the intra-rostral anterior cingulate cortex antagonism of alpha1- and alpha2-adrenoreceptors reversed long-term pain-induced depression. Furthermore, chemogenetic locus coeruleus to spinal cord activation, mainly through LCipsi, reduced sensorial hypersensitivity irrespective of the time post-injury. Our results indicate that asymmetric activation of specific locus coeruleus modules promotes early restorative analgesia, as well as late depressive-like behaviour in chronic pain and depression comorbidity.
Topics: Animals; Comorbidity; Depression; Humans; Locus Coeruleus; Neuralgia; Neurons; Rats
PubMed: 34373893
DOI: 10.1093/brain/awab239 -
Neuron Oct 2022Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and...
Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on a temporary increase in excitability that drives the overlap between dorsal CA1 (dCA1) hippocampal ensembles that encode the linked memories. Here, we show that locus coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine. Additionally, we found that LC-to-dCA1-projecting neurons modulate the excitability of dCA1 neurons and the extent of overlap between dCA1 memory ensembles as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation reveals a fundamental separation between the brain mechanisms modulating these two distinct processes.
Topics: Locus Coeruleus; Dopamine; Memory; Hippocampus; Neurons
PubMed: 36041433
DOI: 10.1016/j.neuron.2022.08.001 -
Neuron Aug 2015The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE...
The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of in vivo chemogenetics, optogenetics, and retrograde tracing, we determine that increased tonic activity of the LC-NE system is necessary and sufficient for stress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin-releasing hormone(+) (CRH(+)) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders.
Topics: Adrenergic Neurons; Animals; Anxiety; Corticotropin-Releasing Hormone; Locus Coeruleus; Male; Mice; Mice, Inbred C57BL; Norepinephrine; Optogenetics; Stress, Psychological
PubMed: 26212712
DOI: 10.1016/j.neuron.2015.07.002 -
Nature Aug 2015Deciphering how neural circuits are anatomically organized with regard to input and output is instrumental in understanding how the brain processes information. For...
Deciphering how neural circuits are anatomically organized with regard to input and output is instrumental in understanding how the brain processes information. For example, locus coeruleus noradrenaline (also known as norepinephrine) (LC-NE) neurons receive input from and send output to broad regions of the brain and spinal cord, and regulate diverse functions including arousal, attention, mood and sensory gating. However, it is unclear how LC-NE neurons divide up their brain-wide projection patterns and whether different LC-NE neurons receive differential input. Here we developed a set of viral-genetic tools to quantitatively analyse the input-output relationship of neural circuits, and applied these tools to dissect the LC-NE circuit in mice. Rabies-virus-based input mapping indicated that LC-NE neurons receive convergent synaptic input from many regions previously identified as sending axons to the locus coeruleus, as well as from newly identified presynaptic partners, including cerebellar Purkinje cells. The 'tracing the relationship between input and output' method (or TRIO method) enables trans-synaptic input tracing from specific subsets of neurons based on their projection and cell type. We found that LC-NE neurons projecting to diverse output regions receive mostly similar input. Projection-based viral labelling revealed that LC-NE neurons projecting to one output region also project to all brain regions we examined. Thus, the LC-NE circuit overall integrates information from, and broadcasts to, many brain regions, consistent with its primary role in regulating brain states. At the same time, we uncovered several levels of specificity in certain LC-NE sub-circuits. These tools for mapping output architecture and input-output relationship are applicable to other neuronal circuits and organisms. More broadly, our viral-genetic approaches provide an efficient intersectional means to target neuronal populations based on cell type and projection pattern.
Topics: Animals; Axons; Brain; Female; Locus Coeruleus; Male; Mice; Neural Pathways; Neuroanatomical Tract-Tracing Techniques; Neurons; Norepinephrine; Pilot Projects; Purkinje Cells; Rabies virus; Rats; Rats, Wistar; Reproducibility of Results; Synapses
PubMed: 26131933
DOI: 10.1038/nature14600 -
Neuron Sep 2016Neurons transmit information to distant brain regions via long-range axonal projections. In the mouse, area-to-area connections have only been systematically mapped...
Neurons transmit information to distant brain regions via long-range axonal projections. In the mouse, area-to-area connections have only been systematically mapped using bulk labeling techniques, which obscure the diverse projections of intermingled single neurons. Here we describe MAPseq (Multiplexed Analysis of Projections by Sequencing), a technique that can map the projections of thousands or even millions of single neurons by labeling large sets of neurons with random RNA sequences ("barcodes"). Axons are filled with barcode mRNA, each putative projection area is dissected, and the barcode mRNA is extracted and sequenced. Applying MAPseq to the locus coeruleus (LC), we find that individual LC neurons have preferred cortical targets. By recasting neuroanatomy, which is traditionally viewed as a problem of microscopy, as a problem of sequencing, MAPseq harnesses advances in sequencing technology to permit high-throughput interrogation of brain circuits.
Topics: Animals; Brain Mapping; Cerebral Cortex; High-Throughput Nucleotide Sequencing; Locus Coeruleus; Mice; Neural Pathways; Neuroanatomical Tract-Tracing Techniques; Neurons; RNA; Sequence Analysis, RNA
PubMed: 27545715
DOI: 10.1016/j.neuron.2016.07.036 -
Proceedings of the National Academy of... Nov 2021The last decade has seen significant progress identifying genetic and brain differences related to intelligence. However, there remain considerable gaps in our... (Review)
Review
The last decade has seen significant progress identifying genetic and brain differences related to intelligence. However, there remain considerable gaps in our understanding of how cognitive mechanisms that underpin intelligence map onto various brain functions. In this article, we argue that the locus coeruleus-norepinephrine system is essential for understanding the biological basis of intelligence. We review evidence suggesting that the locus coeruleus-norepinephrine system plays a central role at all levels of brain function, from metabolic processes to the organization of large-scale brain networks. We connect this evidence with our executive attention view of working-memory capacity and fluid intelligence and present analyses on baseline pupil size, an indicator of locus coeruleus activity. Using a latent variable approach, our analyses showed that a common executive attention factor predicted baseline pupil size. Additionally, the executive attention function of disengagement--not maintenance--uniquely predicted baseline pupil size. These findings suggest that the ability to control attention may be important for understanding how cognitive mechanisms of fluid intelligence map onto the locus coeruleus-norepinephrine system. We discuss how further research is needed to better understand the relationships between fluid intelligence, the locus coeruleus-norepinephrine system, and functionally organized brain networks.
Topics: Animals; Attention; Brain; Executive Function; Humans; Individuality; Intelligence; Locus Coeruleus; Memory, Short-Term; Norepinephrine; Pupil
PubMed: 34764223
DOI: 10.1073/pnas.2110630118 -
Brain Connectivity Apr 2022Locus coeruleus (LC) is the primary source of norepinephrine to the brain and its efferent projections innervate many brain regions, including the thalamus. The LC...
Locus coeruleus (LC) is the primary source of norepinephrine to the brain and its efferent projections innervate many brain regions, including the thalamus. The LC degrades with normal aging, but not much is known regarding whether its structural connectivity evolves with age or predicts aspects of cognition. Here, we use high-resolution diffusion tensor imaging-based tractography to examine structural connectivity between LC and the thalamus in younger and older adults. We found LC projections to be bundled in a fiber tract anatomically consistent with the central tegmental tract (CTT) and branched from this tract into the thalamus. The older cohort exhibited a significant reduction in mean and radial diffusivity within CTT, as compared with the young cohort. We also observed a significant correlation between CTT mean, axial, and radial diffusivities and memory performance (delayed recall) in the older adult cohort. These observations suggest that although LC projections degrade with age, the degree of degradation is associated with cognitive abilities in older adults. Impact statement Locus coeruleus (LC) modulates several cognitive processes, including modulating arousal, attention modulation, and memory. Sustaining the integrity of LC neurons is hypothesized to play a key role in staving off age-related cognitive decline. However, less is known about how efferent projections of LC change with age or cognition. Here, we examine how age affects the microstructure of the central tegmental tract, a fiber tract in which LC efferent projections are bundled, and whether age-related changes in the microstructure of this tract are associated with cognitive decline.
Topics: Aged; Aging; Brain; Cognition; Diffusion Tensor Imaging; Humans; Locus Coeruleus
PubMed: 34139886
DOI: 10.1089/brain.2020.0947 -
Neuron Jul 2021Dysregulation in contextual processing is believed to affect several forms of psychopathology, such as post-traumatic stress disorder (PTSD). The dentate gyrus (DG), a...
Dysregulation in contextual processing is believed to affect several forms of psychopathology, such as post-traumatic stress disorder (PTSD). The dentate gyrus (DG), a subregion of the hippocampus, is thought to be an important brain region for disambiguating new experiences from prior experiences. Noradrenergic (NE) neurons in the locus coeruleus (LC) are more tonically active during stressful events and send dense projections to the DG, yet an understanding of their function in DG-dependent contextual discrimination has not been established. Here, we isolate a key function of the LC-NE-DG circuit in contextual aversive generalization using selective manipulations and in vivo single-cell calcium imaging. We report that activation of LC-NE neurons and terminal activity results in contextual generalization. We found that these effects required β-adrenergic-mediated modulation of hilar interneurons to ultimately promote aversive generalization, suggesting that disruption of noradrenergic tone may serve as an important avenue for treating stress-induced disorders.
Topics: Adrenergic Neurons; Animals; Conditioning, Classical; Dentate Gyrus; Fear; Female; Generalization, Psychological; Locus Coeruleus; Male; Mice, Inbred C57BL; Mice
PubMed: 34081911
DOI: 10.1016/j.neuron.2021.05.006