Brain Sciences

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23 pages, 3518 KiB

Open AccessArticle

Mediation of Sinusoidal Network Oscillations in the Locus Coeruleus of Newborn Rat Slices by Pharmacologically Distinct AMPA and KA Receptors

by Bijal Rawal and Klaus Ballanyi

Brain Sci. 2022, 12(7), 945; https://doi.org/10.3390/brainsci12070945 - 19 Jul 2022

Viewed by 1690

Abstract

Brain control by locus coeruleus (LC) neurons involves afferent glutamate (Glu) inputs. In newborns, LC Glu receptors and responses may be sparse due to immaturity of the brain circuits providing such input. However, we reported, using newborn rat brain slices, that Glu and [...] Read more.

Brain control by locus coeruleus (LC) neurons involves afferent glutamate (Glu) inputs. In newborns, LC Glu receptors and responses may be sparse due to immaturity of the brain circuits providing such input. However, we reported, using newborn rat brain slices, that Glu and its ionotropic receptor (iGluR) agonist NMDA transform spontaneous local field potential (LFP) rhythm. Here, we studied whether α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-acid (AMPA) and kainate (KA) iGluR subtypes also transform the LFP pattern. AMPA (0.25–0.5 µM) and KA (0.5–2.5 µM) merged ~0.2 s-lasting bell-shaped LFP events occurring at ~1 Hz into ~40% shorter and ~4-fold faster spindle-shaped and more regular sinusoidal oscillations. The AMPA/KA effects were associated with a 3.1/4.3-fold accelerated phase-locked single neuron spiking due to 4.0/4.2 mV depolarization while spike jitter decreased to 64/42% of the control, respectively. Raising extracellular K⁺ from 3 to 9 mM increased the LFP rate 1.4-fold or elicited slower multipeak events. A blockade of Cl⁻-mediated inhibition with gabazine (5 μM) plus strychnine (10 μM) affected neither the control rhythm nor AMPA/KA oscillations. GYKI-53655 (25 μM) blocked AMPA (but not KA) oscillations whereas UBP-302 (25 μM) blocked KA (but not AMPA) oscillations. Our findings revealed that AMPA and KA evoke a similar novel neural network discharge pattern transformation type by acting on pharmacologically distinct AMPAR and KA receptors. This shows that already the neonatal LC can generate oscillatory network behaviors that may be important, for example, for responses to opioids. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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18 pages, 1793 KiB

Open AccessArticle

Feasibility of Canine Adenovirus Type 2 (CAV2) Based Vector for the Locus Coeruleus Optogenetic Activation in Non-Transgenic Rats: Implications for Functional Studies

by Anna Kabanova, Elena Cavani, Nikos K. Logothetis and Oxana Eschenko

Brain Sci. 2022, 12(7), 904; https://doi.org/10.3390/brainsci12070904 - 10 Jul 2022

Cited by 3 | Viewed by 2839

Abstract

The locus coeruleus norepinephrine (LC-NE) system modulates many visceral and cognitive functions, while LC-NE dysfunction leads to neurological and neurodegenerative conditions such as sleep disorders, depression, ADHD, or Alzheimer’s disease. Innovative viral-vector and gene-engineering technology combined with the availability of cell-specific promoters enabled [...] Read more.

The locus coeruleus norepinephrine (LC-NE) system modulates many visceral and cognitive functions, while LC-NE dysfunction leads to neurological and neurodegenerative conditions such as sleep disorders, depression, ADHD, or Alzheimer’s disease. Innovative viral-vector and gene-engineering technology combined with the availability of cell-specific promoters enabled regional targeting and selective control over phenotypically specific populations of neurons. We transduced the LC-NE neurons in adult male rats by delivering the canine adenovirus type 2-based vector carrying the NE-specific promoter PRSx8 and a light-sensitive channelrhodopsin-2 receptor (ChR2) directly in the LC or retrogradely from the LC targets. The highest ChR2 expression level was achieved when the virus was delivered medially to the trigeminal pathway and ~100 μm lateral to the LC. The injections close or directly in the LC compromised the tissue integrity and NE cell phenotype. Retrograde labeling was more optimal given the transduction of projection-selective subpopulations. Our results highlight a limited inference of ChR2 expression from representative cases to the entire population of targeted cells. The actual fraction of manipulated neurons appears most essential for an adequate interpretation of the study outcome. The actual fraction of manipulated neurons appears most essential for an adequate interpretation of the study outcome. Thus, besides the cell-type specificity and the transduction efficiency, the between-subject variability in the proportion of the remaining viral-transduced targeted cell population must be considered in any functional connectivity study. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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14 pages, 887 KiB

Open AccessArticle

Delta Opioid Receptors and Enkephalinergic Signaling within Locus Coeruleus Promote Stress Resilience

by John A. Tkaczynski, Olga Borodovitsyna and Daniel J. Chandler

Brain Sci. 2022, 12(7), 860; https://doi.org/10.3390/brainsci12070860 - 29 Jun 2022

Cited by 5 | Viewed by 2583

Abstract

The noradrenergic nucleus locus coeruleus is a key component of the stress circuitry of the brain. During stress, the neuropeptide corticotropin-releasing factor (CRF) is secreted onto LC, increasing LC output and norepinephrine concentration in the brain, which is thought to promote anxiety-like behavior. [...] Read more.

The noradrenergic nucleus locus coeruleus is a key component of the stress circuitry of the brain. During stress, the neuropeptide corticotropin-releasing factor (CRF) is secreted onto LC, increasing LC output and norepinephrine concentration in the brain, which is thought to promote anxiety-like behavior. LC is also innervated by several structures that synthesize and release the endogenous opioid peptide enkephalin onto LC upon stressor termination. While the role of CRF neurotransmission within LC in mediating anxiety-like behavior and the behavioral response to stress has been well characterized, the role of enkephalinergic signaling at LC-expressed δ-opioid receptors has been comparatively understudied. We have previously shown that acute stressor exposure increases LC activity and anxiety-like behavior for at least one week. Here, we extend these findings by showing that these effects may be mediated at least in part through stress-induced downregulation of DORs within LC. Furthermore, overexpression of DORs in LC blocks the effects of stress on both LC firing properties and anxiety-like behavior. In addition, intra-LC infusions of enkephalin blocked stress-induced freezing behavior and promoted conditioned place preference. These findings indicate that enkephalinergic neurotransmission at DORs within LC is an important component of the behavioral response to stress and may drive reward-related behavior as well. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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17 pages, 2860 KiB

Open AccessArticle

Spike-Dependent Dynamic Partitioning of the Locus Coeruleus Network through Noradrenergic Volume Release in a Simulation of the Nucleus Core

by Shristi Baral, Hassan Hosseini, Kaushik More, Thomaz M. C. Fabrin, Jochen Braun and Matthias Prigge

Brain Sci. 2022, 12(6), 728; https://doi.org/10.3390/brainsci12060728 - 1 Jun 2022

Viewed by 2998

Abstract

The Locus coeruleus (LC) modulates various neuronal circuits throughout the brain. Its unique architectural organization encompasses a net of axonal innervation that spans the entire brain, while its somatic core is highly compact. Recent research revealed an unexpected cellular input specificity within the [...] Read more.

The Locus coeruleus (LC) modulates various neuronal circuits throughout the brain. Its unique architectural organization encompasses a net of axonal innervation that spans the entire brain, while its somatic core is highly compact. Recent research revealed an unexpected cellular input specificity within the nucleus that can give rise to various network states that either broadcast norepinephrine signals throughout the brain or pointedly modulate specific brain areas. Such adaptive input–output functions likely surpass our existing network models that build upon a given synaptic wiring configuration between neurons. As the distances between noradrenergic neurons in the core of the LC are unusually small, neighboring neurons could theoretically impact each other via volume transmission of NE. We therefore set out to investigate if such interaction could be mediated through noradrenergic alpha2-receptors in a spiking neuron model of the LC. We validated our model of LC neurons through comparison with experimental patch-clamp data and identified key variables that impact alpha2-mediated inhibition of neighboring LC neurons. Our simulation confirmed a reliable autoinhibition of LC neurons after episodes of high neuronal activity that continue even after neuronal activity subsided. Additionally, dendro-somatic synapses inhibited spontaneous spiking in the somatic compartment of connected neurons in our model. We determined the exact position of hundreds of LC neurons in the mouse brain stem via a tissue clearing approach and, based on this, further determined that 25 percent of noradrenergic neurons have a neighboring LC neuron within less than a 25-micrometer radius. By modeling NE diffusion, we estimated that more than 15 percent of the alpha2-adrenergic receptors fraction can bind NE within such a diffusion radius. Our spiking neuron model of LC neurons predicts that repeated or long-lasting episodes of high neuronal activity induce partitioning of the gross LC network and reduce the spike rate in neighboring neurons at distances smaller than 25 μm. As these volume-mediating neighboring effects are challenging to test with the current methodology, our findings can guide future experimental approaches to test this phenomenon and its physiological consequences. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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24 pages, 3160 KiB

Open AccessArticle

NMDA Enhances and Glutamate Attenuates Synchrony of Spontaneous Phase-Locked Locus Coeruleus Network Rhythm in Newborn Rat Brain Slices

by Bijal Rawal, Vladimir Rancic and Klaus Ballanyi

Brain Sci. 2022, 12(5), 651; https://doi.org/10.3390/brainsci12050651 - 16 May 2022

Cited by 2 | Viewed by 2148

Abstract

Locus coeruleus (LC) neurons are controlled by glutamatergic inputs. Here, we studied in brain slices of neonatal rats NMDA and glutamate effects on phase-locked LC neuron spiking at ~1 Hz summating to ~0.2 s-lasting bell-shaped local field potential (LFP). NMDA: 10 μM accelerated [...] Read more.

Locus coeruleus (LC) neurons are controlled by glutamatergic inputs. Here, we studied in brain slices of neonatal rats NMDA and glutamate effects on phase-locked LC neuron spiking at ~1 Hz summating to ~0.2 s-lasting bell-shaped local field potential (LFP). NMDA: 10 μM accelerated LFP 1.7-fold, whereas 25 and 50 μM, respectively, increased its rate 3.2- and 4.6-fold while merging discrete events into 43 and 56% shorter oscillations. After 4–6 min, LFP oscillations stopped every 6 s for 1 s, resulting in ‘oscillation trains’. A dose of 32 μM depolarized neurons by 8.4 mV to cause 7.2-fold accelerated spiking at reduced jitter and enhanced synchrony with the LFP, as evident from cross-correlation. Glutamate: 25–50 μM made rhythm more irregular and the LFP pattern could transform into 2.7-fold longer-lasting multipeak discharge. In 100 μM, LFP amplitude and duration declined. In 25–50 μM, neurons depolarized by 5 mV to cause 3.7-fold acceleration of spiking that was less synchronized with LFP. Both agents: evoked ‘post-agonist depression’ of LFP that correlated with the amplitude and kinetics of V_m hyperpolarization. The findings show that accelerated spiking during NMDA and glutamate is associated with enhanced or attenuated LC synchrony, respectively, causing distinct LFP pattern transformations. Shaping of LC population discharge dynamics by ionotropic glutamate receptors potentially fine-tunes its influence on brain functions. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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17 pages, 2237 KiB

Open AccessArticle

Worry Modifies the Relationship between Locus Coeruleus Activity and Emotional Mnemonic Discrimination

by Linda H. G. Pagen, Benedikt A. Poser, Martin P. J. van Boxtel, Nikos Priovoulos, Roy W. E. van Hooren, Frans R. J. Verhey and Heidi I. L. Jacobs

Brain Sci. 2022, 12(3), 381; https://doi.org/10.3390/brainsci12030381 - 12 Mar 2022

Viewed by 2672

Abstract

Background: The locus coeruleus (LC) plays a critical role in modulating emotional memory performance via widespread connections to the medial temporal lobe (MTL). Interestingly, both the LC and MTL are affected during aging. Therefore, we aimed to investigate whether worry during cognitive aging [...] Read more.

Background: The locus coeruleus (LC) plays a critical role in modulating emotional memory performance via widespread connections to the medial temporal lobe (MTL). Interestingly, both the LC and MTL are affected during aging. Therefore, we aimed to investigate whether worry during cognitive aging changes the relationship between memory performance and the neural activity patterns during an emotional memory task. Methods: Twenty-eight participants aged 60–83 years from the Maastricht Aging study conducted an emotional mnemonic discrimination task during a 7T fMRI-scan. We performed a robust multiple linear regression to examine the association between worry and mnemonic memory performance under different levels of arousal. Subsequently, we examined if worry modifies the relationship between neuronal activity and mnemonic memory performance. Results: We observed that under low arousal, only participants with low compared to high levels of worry benefitted from additional LC activity. Under high arousal, additional LC activity was associated with lower mnemonic memory performance. Conclusion: Our results suggest there might be an optimal involvement of the NA-system for optimal memory discrimination performance, as we observed that under low levels of worry and with lower levels of arousal, higher LC activity might be needed to achieve similar levels of optimal memory performance as achieved under higher arousal when LC activity remained lower. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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15 pages, 781 KiB

Open AccessArticle

Functional Coupling of the Locus Coeruleus Is Linked to Successful Cognitive Control

by Marcus Grueschow, Birgit Kleim and Christian Carl Ruff

Brain Sci. 2022, 12(3), 305; https://doi.org/10.3390/brainsci12030305 - 24 Feb 2022

Cited by 10 | Viewed by 4760

Abstract

The locus coeruleus (LC) is a brainstem structure that sends widespread efferent projections throughout the mammalian brain. The LC constitutes the major source of noradrenaline (NE), a modulatory neurotransmitter that is crucial for fundamental brain functions such as arousal, attention, and cognitive control. [...] Read more.

The locus coeruleus (LC) is a brainstem structure that sends widespread efferent projections throughout the mammalian brain. The LC constitutes the major source of noradrenaline (NE), a modulatory neurotransmitter that is crucial for fundamental brain functions such as arousal, attention, and cognitive control. This role of the LC-NE is traditionally not believed to reflect functional influences on the frontoparietal network or the striatum, but recent advances in chemogenetic manipulations of the rodent brain have challenged this notion. However, demonstrations of LC-NE functional connectivity with these areas in the human brain are surprisingly sparse. Here, we close this gap. Using an established emotional stroop task, we directly compared trials requiring response conflict control with trials that did not require this, but were matched for visual stimulus properties, response modality, and controlled for pupil dilation differences across both trial types. We found that LC-NE functional coupling with the parietal cortex and regions of the striatum is substantially enhanced during trials requiring response conflict control. Crucially, the strength of this functional coupling was directly related to individual reaction time differences incurred by conflict resolution. Our data concur with recent rodent findings and highlight the importance of converging evidence between human and nonhuman neurophysiology to further understand the neural systems supporting adaptive and maladaptive behavior in health and disease. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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15 pages, 2927 KiB

Open AccessArticle

Using Inhibitory DREADDs to Silence LC Neurons in Monkeys

by Pauline Perez, Estelle Chavret-Reculon, Philippe Ravassard and Sebastien Bouret

Brain Sci. 2022, 12(2), 206; https://doi.org/10.3390/brainsci12020206 - 31 Jan 2022

Cited by 9 | Viewed by 3557

Abstract

Understanding the role of the noradrenergic nucleus locus coeruleus (LC) in cognition and behavior is critical: It is involved in several key behavioral functions such as stress and vigilance, as well as in cognitive processes such as attention and decision making. In recent [...] Read more.

Understanding the role of the noradrenergic nucleus locus coeruleus (LC) in cognition and behavior is critical: It is involved in several key behavioral functions such as stress and vigilance, as well as in cognitive processes such as attention and decision making. In recent years, the development of viral tools has provided a clear insight into numerous aspects of brain functions in rodents. However, given the specificity of primate brains and the key benefit of monkey research for translational applications, developing viral tools to study the LC in monkeys is essential for understanding its function and exploring potential clinical strategies. Here, we describe a pharmacogenetics approach that allows to selectively and reversibly inactivate LC neurons using Designer Receptors Exclusively Activated by Designer Drugs (DREADD). We show that the expression of the hM4Di DREADD can be restricted to noradrenergic LC neurons and that the amount of LC inhibition can be adjusted by adapting the dose of the specific DREADD activator deschloroclozapine (DCZ). Indeed, even if high doses (>0.3 mg/kg) induce a massive inhibition of LC neurons and a clear decrease in vigilance, smaller doses (<0.3 mg/kg) induce a more moderate decrease in LC activity, but it does not affect vigilance, which is more compatible with an assessment of subtle cognitive functions such as decision making and attention. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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10 pages, 1192 KiB

Open AccessArticle

by Inuk Song, Joshua Neal and Tae-Ho Lee

Brain Sci. 2021, 11(11), 1485; https://doi.org/10.3390/brainsci11111485 - 10 Nov 2021

Cited by 10 | Viewed by 2726

Abstract

The locus coeruleus is critical for selective information processing by modulating the brain’s connectivity configuration. Increasingly, studies have suggested that LC controls sensory inputs at the sensory gating stage. Furthermore, accumulating evidence has shown that young children and older adults are more prone [...] Read more.

The locus coeruleus is critical for selective information processing by modulating the brain’s connectivity configuration. Increasingly, studies have suggested that LC controls sensory inputs at the sensory gating stage. Furthermore, accumulating evidence has shown that young children and older adults are more prone to distraction and filter out irrelevant information less efficiently, possibly due to the unoptimized LC connectivity. However, the LC connectivity pattern across the life span is not fully examined yet, hampering our ability to understand the relationship between LC development and the distractibility. In this study, we examined the intrinsic network connectivity of the LC using a public fMRI dataset with wide-range age samples. Based on LC-seed functional connectivity maps, we examined the age-related variation in the LC connectivity with a quadratic model. The analyses revealed two connectivity patterns explicitly. The sensory-related brain regions showed a positive quadratic age effect (u-shape), and the frontal regions for the cognitive control showed a negative quadratic age effect (inverted u-shape). Our results imply that such age-related distractibility is possibly due to the impaired sensory gating by the LC and the insufficient top-down controls by the frontal regions. We discuss the underlying neural mechanisms and limitations of our study. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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21 pages, 2379 KiB

Open AccessArticle

A Bridge between the Breath and the Brain: Synchronization of Respiration, a Pupillometric Marker of the Locus Coeruleus, and an EEG Marker of Attentional Control State

by Michael Christopher Melnychuk, Ian H. Robertson, Emanuele R. G. Plini and Paul M. Dockree

Brain Sci. 2021, 11(10), 1324; https://doi.org/10.3390/brainsci11101324 - 6 Oct 2021

Cited by 9 | Viewed by 6597

Abstract

Yogic and meditative traditions have long held that the fluctuations of the breath and the mind are intimately related. While respiratory modulation of cortical activity and attentional switching are established, the extent to which electrophysiological markers of attention exhibit synchronization with respiration is [...] Read more.

Yogic and meditative traditions have long held that the fluctuations of the breath and the mind are intimately related. While respiratory modulation of cortical activity and attentional switching are established, the extent to which electrophysiological markers of attention exhibit synchronization with respiration is unknown. To this end, we examined (1) frontal midline theta-beta ratio (TBR), an indicator of attentional control state known to correlate with mind wandering episodes and functional connectivity of the executive control network; (2) pupil diameter (PD), a known proxy measure of locus coeruleus (LC) noradrenergic activity; and (3) respiration for evidence of phase synchronization and information transfer (multivariate Granger causality) during quiet restful breathing. Our results indicate that both TBR and PD are simultaneously synchronized with the breath, suggesting an underlying oscillation of an attentionally relevant electrophysiological index that is phase-locked to the respiratory cycle which could have the potential to bias the attentional system into switching states. We highlight the LC’s pivotal role as a coupling mechanism between respiration and TBR, and elaborate on its dual functions as both a chemosensitive respiratory nucleus and a pacemaker of the attentional system. We further suggest that an appreciation of the dynamics of this weakly coupled oscillatory system could help deepen our understanding of the traditional claim of a relationship between breathing and attention. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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Review

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21 pages, 438 KiB

Open AccessReview

The Neuromodulatory Role of the Noradrenergic and Cholinergic Systems and Their Interplay in Cognitive Functions: A Focused Review

by Cody Slater, Yuxiang Liu, Evan Weiss, Kunpeng Yu and Qi Wang

Brain Sci. 2022, 12(7), 890; https://doi.org/10.3390/brainsci12070890 - 7 Jul 2022

Cited by 17 | Viewed by 6075

Abstract

The noradrenergic and cholinergic modulation of functionally distinct regions of the brain has become one of the primary organizational principles behind understanding the contribution of each system to the diversity of neural computation in the central nervous system. Decades of work has shown [...] Read more.

The noradrenergic and cholinergic modulation of functionally distinct regions of the brain has become one of the primary organizational principles behind understanding the contribution of each system to the diversity of neural computation in the central nervous system. Decades of work has shown that a diverse family of receptors, stratified across different brain regions, and circuit-specific afferent and efferent projections play a critical role in helping such widespread neuromodulatory systems obtain substantial heterogeneity in neural information processing. This review briefly discusses the anatomical layout of both the noradrenergic and cholinergic systems, as well as the types and distributions of relevant receptors for each system. Previous work characterizing the direct and indirect interaction between these two systems is discussed, especially in the context of higher order cognitive functions such as attention, learning, and the decision-making process. Though a substantial amount of work has been done to characterize the role of each neuromodulator, a cohesive understanding of the region-specific cooperation of these two systems is not yet fully realized. For the field to progress, new experiments will need to be conducted that capitalize on the modular subdivisions of the brain and systematically explore the role of norepinephrine and acetylcholine in each of these subunits and across the full range of receptors expressed in different cell types in these regions. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

15 pages, 7690 KiB

Open AccessReview

Locus Coeruleus in Non-Mammalian Vertebrates

by Sijia Wang, Zhirong Wang and Yu Mu

Brain Sci. 2022, 12(2), 134; https://doi.org/10.3390/brainsci12020134 - 20 Jan 2022

Cited by 8 | Viewed by 6259

Abstract

The locus coeruleus (LC) is a vertebrate-specific nucleus and the primary source of norepinephrine (NE) in the brain. This nucleus has conserved properties across species: highly homogeneous cell types, a small number of cells but extensive axonal projections, and potent influence on brain [...] Read more.

The locus coeruleus (LC) is a vertebrate-specific nucleus and the primary source of norepinephrine (NE) in the brain. This nucleus has conserved properties across species: highly homogeneous cell types, a small number of cells but extensive axonal projections, and potent influence on brain states. Comparative studies on LC benefit greatly from its homogeneity in cell types and modularity in projection patterns, and thoroughly understanding the LC-NE system could shed new light on the organization principles of other more complex modulatory systems. Although studies on LC are mainly focused on mammals, many of the fundamental properties and functions of LC are readily observable in other vertebrate models and could inform mammalian studies. Here, we summarize anatomical and functional studies of LC in non-mammalian vertebrate classes, fish, amphibians, reptiles, and birds, on topics including axonal projections, gene expressions, homeostatic control, and modulation of sensorimotor transformation. Thus, this review complements mammalian studies on the role of LC in the brain. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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23 pages, 14175 KiB

Open AccessReview

The Mammalian Locus Coeruleus Complex—Consistencies and Variances in Nuclear Organization

by Paul R. Manger and Oxana Eschenko

Brain Sci. 2021, 11(11), 1486; https://doi.org/10.3390/brainsci11111486 - 10 Nov 2021

Cited by 18 | Viewed by 3331

Abstract

Descriptions of the nuclear parcellation of the locus coeruleus complex have been provided in approximately 80 mammal species spanning the phylogenetic breadth of this class. Within the mammalian rostral hindbrain, noradrenergic neurons (revealed with tyrosine hydroxylase and dopamine-ß-hydroxylase immunohistochemistry) have been observed within [...] Read more.

Descriptions of the nuclear parcellation of the locus coeruleus complex have been provided in approximately 80 mammal species spanning the phylogenetic breadth of this class. Within the mammalian rostral hindbrain, noradrenergic neurons (revealed with tyrosine hydroxylase and dopamine-ß-hydroxylase immunohistochemistry) have been observed within the periventricular grey matter (A4 and A6 nuclei) and parvicellular reticular nucleus (A5 and A7 nuclei), with the one exception to date being the tree pangolin, where no A4/A6 neurons are observed. The alphanumeric nomenclature system, developed in laboratory rodent brains, has been adapted to cover the variation observed across species. Cross-species homology is observed regarding the nuclear organization of noradrenergic neurons located in the parvicellular reticular nucleus (A5 and A7). In contrast, significant variations are observed in the organization of the A6 neurons of the locus coeruleus proper. In most mammals, the A6 is comprised of a moderate density of neurons, but in Murid rodents, primates, and megachiropteran bats, the A6 exhibits a very high density of neurons. In primates and megachiropterans, there is an additional moderate density of A6 neurons located rostromedial to the high-density portion. These variations are of importance in understanding the translation of findings in laboratory rodents to humans. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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Other

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7 pages, 1125 KiB

Open AccessOpinion

Challenges and Perspectives of Mapping Locus Coeruleus Activity in the Rodent with High-Resolution fMRI

by Xiaoqing Alice Zhou, Yuanyuan Jiang, Vitaly Napadow and Xin Yu

Brain Sci. 2022, 12(8), 1085; https://doi.org/10.3390/brainsci12081085 - 16 Aug 2022

Viewed by 2324

Abstract

The locus coeruleus (LC) is one of the most commonly studied brainstem nuclei when investigating brain–behavior associations. The LC serves as a major brainstem relay for both ascending bottom-up and descending top-down projections. Specifically, noradrenergic (NA) LC neurons not only connect globally to [...] Read more.

The locus coeruleus (LC) is one of the most commonly studied brainstem nuclei when investigating brain–behavior associations. The LC serves as a major brainstem relay for both ascending bottom-up and descending top-down projections. Specifically, noradrenergic (NA) LC neurons not only connect globally to higher-order subcortical nuclei and cortex to mediate arousal and attention but also directly project to other brainstem nuclei and to the spinal cord to control autonomic function. Despite the extensive investigation of LC function using electrophysiological recordings and cellular/molecular imaging for both cognitive research and the contribution of LC to different pathological states, the role of neuroimaging to investigate LC function has been restricted. For instance, it remains challenging to identify LC-specific activation with functional MRI (fMRI) in animal models, due to the small size of this nucleus. Here, we discuss the complexity of fMRI applications toward LC activity mapping in mouse brains by highlighting the technological challenges. Further, we introduce a single-vessel fMRI mapping approach to elucidate the vascular specificity of high-resolution fMRI signals coupled to LC activation in the mouse brainstem. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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26 pages, 10041 KiB

Open AccessPerspective

Autocrine Neuromodulation and Network Activity Patterns in the Locus Coeruleus of Newborn Rat Slices

by Quinn Waselenchuk and Klaus Ballanyi

Brain Sci. 2022, 12(4), 437; https://doi.org/10.3390/brainsci12040437 - 25 Mar 2022

Cited by 2 | Viewed by 2661

Abstract

Already in newborns, the locus coeruleus (LC) controls multiple brain functions and may have a complex organization as in adults. Our findings in newborn rat brain slices indicate that LC neurons (i) generate at ~1 Hz a ~0.3 s-lasting local field potential (LFP) [...] Read more.

Already in newborns, the locus coeruleus (LC) controls multiple brain functions and may have a complex organization as in adults. Our findings in newborn rat brain slices indicate that LC neurons (i) generate at ~1 Hz a ~0.3 s-lasting local field potential (LFP) comprising summated phase-locked single spike discharge, (ii) express intrinsic ‘pacemaker’ or ‘burster’ properties and (iii) receive solely excitatory or initially excitatory–secondary inhibitory inputs. μ-opioid or ɑ₂ noradrenaline receptor agonists block LFP rhythm at 100–250 nM whereas slightly lower doses transform its bell-shaped pattern into slower crescendo-shaped multipeak bursts. GABA_A and glycine receptors hyperpolarize LC neurons to abolish rhythm which remains though unaffected by blocking them. Rhythm persists also during ionotropic glutamate receptor (iGluR) inhibition whereas <10 mV depolarization during iGluR agonists accelerates spiking to cause subtype-specific fast (spindle-shaped) LFP oscillations. Similar modest neuronal depolarization causing a cytosolic Ca²⁺ rise occurs (without effect on neighboring astrocytes) during LFP acceleration by CNQX activating a TARP-AMPA-type iGluR complex. In contrast, noradrenaline lowers neuronal Ca²⁺ baseline via ɑ₂ receptors, but evokes an ɑ₁ receptor-mediated ‘concentric’ astrocytic Ca²⁺ wave. In summary, the neonatal LC has a complex (possibly modular) organization to enable discharge pattern transformations that might facilitate discrete actions on target circuits. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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18 pages, 3952 KiB

Open AccessPerspective

Locus Coeruleus Optogenetic Modulation: Lessons Learned from Temporal Patterns

by Carolyn W. Harley and Qi Yuan

Brain Sci. 2021, 11(12), 1624; https://doi.org/10.3390/brainsci11121624 - 9 Dec 2021

Cited by 10 | Viewed by 3831

Abstract

After reviewing seminal studies using optogenetics to interrogate the functional role of the locus coeruleus in behavior, we conclude that differences in firing rates and firing patterns of locus coeruleus neurons contribute to locus coeruleus nucleus heterogeneity by recruiting different output circuitry, and [...] Read more.

After reviewing seminal studies using optogenetics to interrogate the functional role of the locus coeruleus in behavior, we conclude that differences in firing rates and firing patterns of locus coeruleus neurons contribute to locus coeruleus nucleus heterogeneity by recruiting different output circuitry, and differentially modifying behavior. The outcomes initiated by different optogenetic input activation patterns and frequencies can have opposite consequences for behavior, activate different neurons in the same target structure, be supported by distinct adrenoceptors and vary with behavioral state. Full article

(This article belongs to the Special Issue Towards Understanding the Functional Connectivity of the Locus Coeruleus)

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