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Photomicrographs at various magnifications of the locus coeruleus (A6) in the brain of the African elephant (Loxodonta africana) [18] revealed with tyrosine hydroxylase immunostaining. The standard mammalian diffuse portion of the locus coeruleus (A6d) is present in the ventrolateral periventricular grey matter of the rostral hindbrain (GC), but in addition, a medially located cluster of immunopositive neurons, the medial portion of the locus coeruleus (A6m), is observed and appears to be a lineage-specific addition to the locus coeruleus complex (A6). The neurons of the A6m (b,d) appear to have a slightly more arborized dendritic field than those of the A6d (c,e). In all images, dorsal is to the top and medial to the left. Scale bar in (a) = 1 mm. Scale bar in (c) = 500 µm and applies to (b,c). Scale bar in (e) = 50 µm and applies to (d,e). 4V-fourth ventricle; A7d-locus subcoeruleus, diffuse portion; GC-periventricular grey matter of the rostral hindbrain.
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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 th...
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Context 1
... the majority of mammals studied, the A6 nucleus is reported as being a moderate-to lowdensity cluster of noradrenergic neurons, which in the comparative neuroanatomical literature has been termed the A6 diffuse (A6d) nucleus ( Figure 3; Table 1). Despite this consistent appearance in most mammals, the form of this neuronal cluster varies from being absent in the tree pangolin (Figure 4) [25], to being comprised of relatively few neurons in the rock hyrax [17], having an additional medial nucleus in the African elephant (A6m; Figure 5) [18], being comprised of a single densely packed neuronal cluster (A6c, locus coeruleus, compact portion) in Murid rodents (A6cr, the rodent-type of the A6c, Figure 6a,b) [42], or being comprised of a combination of a high-density cluster bordered by a low-density cluster in primates (A6cp, the primate-type of A6c; Figure 7) and megachiropteran bats (A6cm, the megachiropteran-type of A6c; Figure 8). ...
Context 2
... date, the African elephant is the only species examined that shows a distinct topographically separated cluster of noradrenergic neurons in the periventricular grey matter; this cluster, comprised of relatively few neurons, is located medial to the standard A6d nucleus ( Figure 5) [18]. Within the order Rodentia, while the majority of species exhibit the typical moderate density of A6 neurons, the A6d (Figure 6c-f; Table 1), the Murid rodents, the lineage to which the commonly used laboratory rodents belong, show a distinctly different organization. ...
Citations
... El sistema noradrenérgico del núcleo cerúleo en el rombencéfalo de todos los vertebrados, mejor conocido en los mamíferos, constituye otro regulador del sueño(56,57), el núcleo cerúleo produce la noradrenalina (NA) la cual mantiene un perfil de aumento y disminución durante el sueño en sus dos fases; con niveles elevados de NA en el prosencéfalo durante NREM y supresión de NA en REM. Cambios disfuncionales en el núcleo cerúleo pueden conllevar al aumento de NA trayendo como consecuencia, primero, una hiper-excitabilidad la cual conduce a la fragmentación del sueño, característico de estados de estrés, envejecimiento o alteraciones del sueño por enfermedades neurodegenerativas como el Alzheimer; y segundo, puede cambiar la disminución de NA durante REM, trayendo como consecuencia la inhibición de la extinción de la M emocional(58).La dopamina parece jugar un papel modulador inhibidor/activador de diferentes N del cerebro de D. melanogaster, de manera que su señalización, aumenta el sueño nocturno, cuando inerva un tipo específico de N del centro del sueño del cerebro y promueve la vigilia en N del reloj circadiano(10). ...
Todos los animales disponen de mecanismos fisiológicos y homeostáticos para generar, mantener, ajustar y sincronizar los ciclos endógenos/exógenos del sueño. Varias áreas del cerebro intervienen en la activación y regulación de los ciclos sueño/vigilia y su sincronía con el ciclo luz/oscuridad. Toda esta actividad fisiológica está incluida en el reloj biológico (o ritmo circadiano) de cada animal, el cual está modulado por genes, proteínas, y neurotransmisores. El sueño se relaciona con los procesos de recuperación o reparación, mantenimiento y restauración de la eficacia de todos los sistemas del organismo, principalmente de los sistemas nervioso, endocrino e inmunológico. Dada la importancia del sueño tanto para los animales como para los humanos, esta revisión presenta una reseña sobre la fisiología y homeostasis del sueño, documentada a través de bibliografía científica publicada en los últimos cinco años (2017-2022), en revistas científicas como Science y Nature, de las bases de datos PubMed, Science Direct, o clasificadas en Scimago. El sueño está regulado por factores exógenos y endógenos, en estos últimos son actores principales los neurotransmisores (serotonina, histamina), neuromoduladores (noradrenalina), hormonas (sistema orexina/hipocretina, melatonina), el sistema glinfático y los genes que activan las diferentes vías de señalización para que funcione en forma óptima las neuronas y la glía del encéfalo.
... Eagleman and Vaughn (2021) present supporting data from evolutionary history, non-human primate brain and human brain. The LC is an ancient brain structure thought to have been involved in early amphibian diving response (Amaral and Sinnamon, 1977) and is quite similar in human and non-human primate brain (Manger and Eschenko, 2021). Nevertheless, we have limited the scope of our survey to the LC in the present-day human brain. ...
The defensive activation theory (DAT) was recently proposed to explain the biological function of dreaming. Briefly, DAT states that dreams are primarily visual to prevent plastic take-over of an otherwise inactive visual cortex during sleep. Evidence to support the DAT revolve around the interplay between dream activity (REM%) and cortical plasticity found in evolutionary history, primate studies, and coinciding decline in human cortical plasticity and REM% with age. As the DAT may prove difficult to test experimentally, we investigate whether further support for the DAT can be found in the literature. Plasticity and REM sleep are closely linked to functions of the Locus Coeruleus (LC). We therefore review existing knowledge about the LC covering LC stability with age, and the role of the LC in the plasticity of the visual cortex. Recent studies show the LC to be more stable than previously believed and therefore, the LC likely supports the REM% and plasticity in the same manner throughout life. Based on this finding, we review the effect of aging on REM% and visual cortex plasticity. Here, we find that recent, weighty studies are not in complete agreement with the data originally provided as support for DAT. Results from these studies, however, are not in themselves irreconcilable with the DAT. Our findings therefore do not disprove the DAT. Importantly, we show that the LC is involved in all mechanisms central to the DAT. The LC may therefore provide an experimental window to further explore and test the DAT.
... Due to the consistent presence of the locus coeruleus in mammalian species, scientific findings in laboratory animals have been extrapolated to the human physiology-but the inter-species variability has not been systematically analyzed. Manger and Eschenko reviewed the available information from approximately 80 mammalian species across different subclasses and orders and created a comparative analysis of the nuclear organization of the locus coeruleus complex [8]. The described variations in nuclear organization have to be accounted for in the cross-species conclusions and practical implications, as the potential homology may or may not be correct. ...
Many years ago, before the Internet and the introduction of the electronic publications, bibliographical research was conducted in physical libraries, and the most commonly used source of information was the regularly updated Index Medicus, a multi-volume treatise that for 125 years summarized and indexed all published medical literature, classifying it by keywords and subject headings [...]
... In the current description the nuclei are referred to using the nomenclature of Dahlström and Fuxe (1964), and no putatively catecholaminergic nuclei outside the classically defined nuclei (e.g., Smeets & Gonz alez, 2000) were observed. The rodent typical C3 nucleus (rostral dorsal midline medullary nucleus) and the Murid rodent/primate/megabat A6c nucleus (compact portion of locus coeruleus) (e.g., Manger & Eschenko, 2021) were absent in the lesser hedgehog tenrec. ...
... | Rostral rhombencephalic catecholaminergic nuclei -The locus coeruleus complex (A7-A4) Within the rostral rhombencephalon, or rostral hindbrain (Watson et al., 2019), of lesser hedgehog tenrec, a substantive number of TH+ neurons formed the locus coeruleus complex. The mammalian locus coeruleus complex is typically subdivided into five nuclei (Manger & Eschenko, 2021), these being: the subcoeruleus compact portion (A7sc), subcoeruleus diffuse portion (A7d), locus coeruleus compact portion (A6c), fifth arcuate nucleus (A5), and the dorsolateral division of locus coeruleus (A4). All subdivisions were noted in the lesser hedgehog tenrec (Figures 2q-s, 13). ...
... These A6d neurons were separated from the A7sc neurons by the passage of the tract of the fifth mesencephalic nucleus. No compact division of the locus coeruleus (A6c) (Manger & Eschenko, 2021) was observed in the lesser hedgehog tenrec. A small cluster of multipolar and bipolar TH+ neurons located dorsal to the A6d, within the periventricular gray matter, adjacent to the lateral walls of the fourth ventricle were assigned to the A4 (Figures 2s, 13a,d). ...
The current study provides an analysis of the cholinergic, catecholaminergic, serotonergic, and orexinergic neuronal populations, or nuclei, in the brain of the lesser hedgehog tenrec, as revealed with immunohistochemical techniques. For all four of these neuromodulatory systems, the nuclear organization was very similar to that observed in other Afrotherian species and is broadly similar to that observed in other mammals. The cholinergic system shows the most variation, with the lesser hedgehog tenrec exhibiting palely immunopositive cholinergic neurons in the ventral portion of the lateral septal nucleus, and the possible absence of cholinergic neurons in the parabigeminal nucleus and the medullary tegmental field. The nuclear complement of the catecholaminergic, serotonergic and orexinergic systems showed no specific variances in the lesser hedgehog tenrec when compared to other Afrotherians, or broadly with other mammals. A striking feature of the lesser hedgehog tenrec brain is a significant mesencephalic flexure that is observed in most members of the Tenrecoidea, as well as the closely related Chrysochlorinae (golden moles), but is not present in the greater otter shrew, a species of the Potomogalidae lineage currently incorporated into the Tenrecoidea. In addition, the cholinergic neurons of the ventral portion of the lateral septal nucleus are observed in the golden moles, but not in the greater otter shrew. This indicates that either complex parallel evolution of these features occurred in the Tenrecoidea and Chrysochlorinae lineages, or that the placement of the Potomogalidae within the Tenrecoidea needs to be re‐examined.
... This has predominantly been shown in rats [60], although some evidence points to a similar function in mice [61]. Furthermore, these neurons become part of the parvocellular reticular nucleus (PARN) (r7-r11) [7], similarly hallmarked by the expression of VGlut2 [7] and involved in the regulation of visceral and motor systems [62] (Figures 3 and 4). It has recently been shown by Schinzel et al. (2021) that a subset of neurons found within the dorsal cochlear nucleus (DCN) of the cochlear nucleus (CN) (r7-r9), arise from a Ptf1a-expressing lineage of progenitors and express Lbx1, suggesting that these neurons potentially arise from the dB1 progenitor domain [63] (Figures 3 and 4). ...
The medulla oblongata, located in the hindbrain between the pons and the spinal cord, is an important relay center for critical sensory, proprioceptive, and motoric information. It is an evolutionarily highly conserved brain region, both structural and functional, and consists of a multitude of nuclei all involved in different aspects of basic but vital functions. Understanding the functional anatomy and developmental program of this structure can help elucidate potential role(s) of the medulla in neurological disorders. Here, we have described the early molecular patterning of the medulla during murine development, from the fundamental units that structure the very early medullary region into 5 rhombomeres (r7–r11) and 13 different longitudinal progenitor domains, to the neuronal clusters derived from these progenitors that ultimately make-up the different medullary nuclei. By doing so, we developed a schematic overview that can be used to predict the cell-fate of a progenitor group, or pinpoint the progenitor domain of origin of medullary nuclei. This schematic overview can further be used to help in the explanation of medulla-related symptoms of neurodevelopmental disorders, e.g., congenital central hypoventilation syndrome, Wold–Hirschhorn syndrome, Rett syndrome, and Pitt–Hopkins syndrome. Based on the genetic defects seen in these syndromes, we can use our model to predict which medullary nuclei might be affected, which can be used to quickly direct the research into these diseases to the likely affected nuclei.
... The brainstem locus coeruleus norepinephrine (LC-NE) system comprises a set of small neuronal clusters (nuclei) located in the pons and medulla [1]. Among these NEproducing brainstem nuclei, the LC presents a primary source of NE in the forebrain [2,3]. ...
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 ~100μm 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.
... Noradrenaline (NA) is a monoamine neurotransmitter that acts in the brain and body to induce and coordinate states of wakefulness, and to facilitate adaptive behaviors in response to environmental novelty. The mammalian brainstem contains a cluster of up to seven NA-synthetizing nuclei (A1-A7) that have been anatomically identified in >80 mammals [1], from rat [2], to cat [3], to human [4]. The tightly appositioned A4 and A6 nuclei stand out as the largest, often densest, and predominant forebrain-projecting nuclei that share a common embryonic origin [5] and in which activity levels correlate with the degree of wakefulness (for review, see [6][7][8][9]). ...
... In tissue sections, these nuclei appear sky-blue because of their pigmentation with neuromelanin, a by-product of catecholamine metabolism, which gave it the name locus coeruleus (LC, Latin for "sky-blue spot"). The LC lies in the pontine brainstem as an anteroposteriorly extended tube with a central ventral extension along the fourth ventricle (for review, see [1,8]) and it is part of the ascending arousal systems, together with other monoaminergic and cholinergic nuclei (for review, see [10,11]). The LC provides brain-wide axonal arborizations and fine meshworks of varicose fibers that arise from a comparatively small number of NA-synthetizing neurons (thousands in rodents [12,13], tens of thousands in humans [14]). ...
... Novel anatomical and physiological technologies, together with advanced behavioral measures, are about to bring fundamentally renewed insights into the LC's functions. The LC shows a genetic and/or functional heterogeneity at multiple levels from its embryonic and evolutionary origins (for review, see [1,5]), its synaptic interactions with the pericoerulear area (for review, see [30]), its input-output connectivity (for review, see [31]), to its cellular identities and neurotransmitter release (for review, see [6,30]), neuronal ensemble formation (for review, see [32]), regulation of whole-brain states [33], brain-statedependent firing patterns (for review, see [7,30]), and behavioral roles (for review, see [34]). The LC emerges as a dynamic and plastic assembly of functionally specialized LC neuronal subgroups that act locally or globally according to recently lived experiences, ongoing demands, and future challenges (for review, see [30,35]). ...
For decades, numerous seminal studies have built our understanding of the locus coeruleus (LC), the vertebrate brain’s principal noradrenergic system. Containing a numerically small but broadly efferent cell population, the LC provides brain-wide noradrenergic modulation that optimizes network function in the context of attentive and flexible interaction with the sensory environment. This review turns attention to the LC’s roles during sleep. We show that these roles go beyond down-scaled versions of the ones in wakefulness. Novel dynamic assessments of noradrenaline signaling and LC activity uncover a rich diversity of activity patterns that establish the LC as an integral portion of sleep regulation and function. The LC could be involved in beneficial functions for the sleeping brain, and even minute alterations in its functionality may prove quintessential in sleep disorders.
... The recent development of pharmacogenetics has allowed key advances in understanding neuromodulatory functions [10][11][12]. Indeed, pharmacogenetics allow researchers to reversibly and reliably manipulate the activity of entire populations of neurons, with a high level of specificity [13]. The development of this approach in monkeys is critical for several reasons: First, it allows us to study behavioral and cognitive processes (and corresponding brain regions) that relay upon brain regions that are specific to primates [14,15]. ...
... We did not verify the subcellular localization, but the functional effects of DCZ injection indicates that a sufficient amount of hM4Di receptors was present in the membrane of LC neurons to respond to DCZ. Lastly, even if the coverage of LC neurons seemed relatively homogenous, this remains difficult to assess given the anatomical heterogeneity of the nucleus in monkeys [13,35]. Even if a finer characterization of that heterogeneity would be critical to better understand the specific functions of LC in primates, we believe that the current method is sufficient to induce a reliable activation of LC neurons, and along with a finer anatomical characterization of the effects, further functional testing would also be critical to evaluate its efficacy. ...
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.
... The locus coeruleus (LC) is a vertebrate-specific norepinephrinergic (NE) nucleus [1][2][3][4]. The LC locates deeply in the dorsal part of the brainstem [5], where a small number of neurons extensively branch their axons and provide the main source of NE to the brain [6]. ...
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.
The locus coeruleus (LC) is the primary source of noradrenergic transmission in the mammalian central nervous system. This small pontine nucleus consists of a densely packed nuclear core—which contains the highest density of noradrenergic neurons—embedded within a heterogeneous surround of non‐noradrenergic cells. This local heterogeneity, together with the small size of the LC, has made it particularly difficult to infer noradrenergic cell identity based on extracellular sampling of in vivo spiking activity. Moreover, the relatively high cell density, background activity and synchronicity of LC neurons have made spike identification and unit isolation notoriously challenging. In this study, we aimed at bridging these gaps by performing juxtacellular recordings from single identified neurons within the mouse LC complex. We found that noradrenergic neurons (identified by tyrosine hydroxylase, TH, expression; TH‐positive) and intermingled putatively non‐noradrenergic (TH‐negative) cells displayed similar morphologies and responded to foot shock stimuli with excitatory responses; however, on average, TH‐positive neurons exhibited more prominent foot shock responses and post‐activation firing suppression. The two cell classes also displayed different spontaneous firing rates, spike waveforms and temporal spiking properties. A logistic regression classifier trained on spontaneous electrophysiological features could separate the two cell classes with 76% accuracy. Altogether, our results reveal in vivo electrophysiological correlates of TH‐positive neurons, which can be useful for refining current approaches for the classification of LC unit activity.
