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![Coronal sections illustrating locus coeruleus nucleus (interaural À 1.04 mm; Bregma À 10.04 mm) [57] in the experimental groups. WM: Wistar males; WF: Wistar females; LEM: Long – Evans males; LEF: Long – Evans females Ce: cerebellum; LC: locus coeruleus; Me5: mesencephalic trigeminal nucleus. Scale bar: 200 A m.](profile/Eduardo-Pasaro/publication/7720807/figure/fig2/AS:280611408367616@1443914381261/Coronal-sections-illustrating-locus-coeruleus-nucleus-interaural-A-104-mm-Bregma-A.png)
Coronal sections illustrating locus coeruleus nucleus (interaural À 1.04 mm; Bregma À 10.04 mm) [57] in the experimental groups. WM: Wistar males; WF: Wistar females; LEM: Long – Evans males; LEF: Long – Evans females Ce: cerebellum; LC: locus coeruleus; Me5: mesencephalic trigeminal nucleus. Scale bar: 200 A m.
Source publication
Central nervous system sex differences have two morphological patterns. In one pattern, males show larger measurements (volume, number of neurons) than females (male > female; m > f) and, in the other, the opposite is true (female > male; f > m). The bed nucleus of the stria terminalis (BST) is a unique model for the study of sex differences becaus...
Context in source publication
Context 1
... effect for both volume [H(3) = 7.57; P < 0.05] and number of neurons in the LC [H(3) = 10.98; P < 0.01]. The Wistar rat LC is sexually dimorphic since the females show a larger LC volume (Figs. 3A and 4; P < 0.009) and greater number of neurons than do males ( Fig. 3B; Wistar: P < 0.01); the Long -Evans strain does not show these sex differences (Fig. 4). Males of both strains present a similar LC volume and number of neurons (Figs. 3A and B). However, the female Wistar rats have a larger volume and number of neurons than do female Long-Evans rats (volume: P < 0.01; number of neurons: P < 0.01). When the strains are compared, there is a statistically significant group effect for the ...
Citations
... Previous studies demonstrated sex differences in LC neurons, mainly in rats, and strain and age-dependent results were reported. While there were more neurons in the LC of female Wistar rats compared to males [48,49], this difference was not evident in Long-Evans rats [50,51]. Although there is little data from mice, no differences in TH + cells were found in the LC of adult female and male C57BL/6J mice [52]. ...
Background
In addition to social and cultural factors, sex differences in the central nervous system have a critical influence on behavior, although the neurobiology underlying these differences remains unclear. Interestingly, the Locus Coeruleus (LC), a noradrenergic nucleus that exhibits sexual dimorphism, integrates signals that are related to diverse activities, including emotions, cognition and pain. Therefore, we set-out to evaluate sex differences in behaviors related to LC nucleus, and subsequently, to assess the sex differences in LC morphology and function.
Methods
Female and male C57BL/6J mice were studied to explore the role of the LC in anxiety, depressive-like behavior, well-being, pain, and learning and memory. We also explored the number of noradrenergic LC cells, their somatodendritic volume, as well as the electrophysiological properties of LC neurons in each sex.
Results
While both male and female mice displayed similar depressive-like behavior, female mice exhibited more anxiety-related behaviors. Interestingly, females outperformed males in memory tasks that involved distinguishing objects with small differences and they also showed greater thermal pain sensitivity. Immunohistological analysis revealed that females had fewer noradrenergic cells yet they showed a larger dendritic volume than males. Patch clamp electrophysiology studies demonstrated that LC neurons in female mice had a lower capacitance and that they were more excitable than male LC neurons, albeit with similar action potential properties.
Conclusions
Overall, this study provides new insights into the sex differences related to LC nucleus and associated behaviors, which may explain the heightened emotional arousal response observed in females.
... As an additional finding, the latter and further studies noted a difference in the response of the SNS between female and male subjects, leading to the assumption that the male SNS is more reactive in an inflammatory context leading to overall pronounced neuromodulatory effects in males [29, 76,77]. A sexual dimorphism of the structure of the locus coeruleus as well as the bed nucleus of the stria terminalis has been described [78,79], which could be associated with these differences and might have further implications maybe contributing to sex-differences in incidence and severity of autoimmune diseases in general. Besides regulation of inflammation, many studies also investigated changes in local neurotransmitters, like noradrenaline (NA), by inflammation, e.g., in the EAE model [31,80,81]. ...
In this review article the current model of the interaction between the sympathetic nervous system (SNS) and the immune system in the context of chronic inflammation is presented. Mechanisms in the interaction between the SNS and the immune system are shown, which are similar for all disease entities: 1) the biphasic effect of the sympathetic system on the inflammatory response with a proinflammatory, stimulating effect before and during the activation of the immune system (early) and a more inhibitory effect in late phases of immune activation (chronic). 2) The interruption of communication between immune cells and the brain by withdrawal of sympathetic nerve fibers from areas of inflammation, such as the spleen, lymph nodes or peripheral foci of inflammation. 3) The local replacement of catecholamines by neurotransmitter-producing cells to fine-tune the local immune response independently of the brain. 4) Increased activity of the SNS due to an imbalance of the autonomic nervous system at the systemic level, which provides an explanation for known disease sequelae and comorbidities due to the long duration of chronic inflammatory reactions, such as increased cardiovascular risk with hypertension, diabetes mellitus and catabolic metabolism. The understanding of neuroimmune interactions can lead to new therapeutic approaches, e.g., a stimulation of beta-adrenergic and even more an inhibition of alpha-adrenergic receptors or a restoration of the autonomic balance in the context of arthritis ) can make an anti-inflammatory contribution (more influence of the vagus nerve); however, in order to translate the theoretical findings into clinical action that is beneficial for the patient, controlled interventional studies are required.
... As an additional finding, the latter and further studies noted a difference in the response of the SNS between female and male subjects, leading to the assumption that the male SNS is more reactive in an inflammatory context leading to overall pronounced neuromodulatory effects in males [29, 76,77]. A sexual dimorphism of the structure of the locus coeruleus as well as the bed nucleus of the stria terminalis has been described [78,79], which could be associated with these differences and might have further 6-OHDA, 6-hydroxydopamine; early phase = transition phase; AR, adrenoceptor; CNS, central nervous system; ECP, endogenous catecholamine production; IFN, interferon; IL, interleukin; i.p., intraperitoneal; late phase = post-induction phase; ln, lymph node; p.i., postimmunization; SLO, secondary lymphoid organ; SNS, sympathetic nervous system; TH, tyrosine hydroxylase; TNF, tumor necrosis factor; wt, wild type. ...
The immune system is embedded in a network of regulatory systems to keep homeostasis in case of an immunologic challenge. Neuroendocrine immunologic research revealed several aspects of these interactions over the past decades, e.g. between the autonomic nervous system and the immune system. This review will focus on evidence revealing the role of the sympathetic nervous system (SNS) in chronic inflammation, like colitis, multiple sclerosis, systemic sclerosis, lupus erythematodes, and arthritis with a focus on animal models supported by human data. A theory of the contribution of the SNS in chronic inflammation will be presented that spans these disease entities. One major finding is the biphasic nature of the sympathetic contribution to inflammation with proinflammatory effects until the point of disease outbreak and mainly anti-inflammatory influence thereafter. Since sympathetic nerve fibers are lost from sites of inflammation during inflammation, local cells and immune cells achieve the capability to endogenously produce catecholamines to fine-tune the inflammatory response independent of brain control. On a systemic level, it has been shown across models that the SNS is activated in inflammation as opposed to the parasympathetic nervous system. Permanent overactivity of the SNS contributes many of the known disease sequelae. One goal of neuroendocrine immune research is defining new therapeutic targets. In this respect, it will be discussed that at least in arthritis, it might be beneficial to support β-adrenergic and inhibit α-adrenergic activity besides restoring autonomic balance. Overall, in the clinical setting we now need controlled interventional studies to successfully translate the theoretical knowledge into benefits for patients.
... Regions with volume/density sexual dimorphism in C57BL/6J mice To examine whether differences in overall brain volume or density (Fig. 1H) are 280 isotropic, we conducted a region-specific analysis of volume, density, and cell count. Differences between males and females in regional neuroanatomy have been extensively described, including dimorphic 285 volume and cell count in the medial amygdala (MEA) 17,18 and in the bed nuclei of the stria terminalis (BST) 19 . We first compared C57BL/6J males (n=140) with females (n=152). ...
The mouse brain is by far the most intensively studied among mammalian brains, yet basic measures of its cytoarchitecture remain obscure. For example, quantifying cell numbers, and the interplay of sex-, strain-, and individual variability in cell density and volume is out of reach for many regions. The Allen Mouse Brain Connectivity project produces high-resolution full brain images of hundreds of brains. Although these were created for a different purpose, they reveal details of neuroanatomy and cytoarchitecture. Here, we used this population to systematically characterize cell density and volume for each anatomical unit in the mouse brain. We developed a deep neural network-based segmentation pipeline that uses the auto-fluorescence intensities of images to segment cell nuclei even within the densest regions, such as the dentate gyrus. We applied our pipeline to 537 brains of males and females from C57BL/6J and FVB.CD1 strains. Globally, we found that increased overall brain volume does not result in uniform expansion across all regions. Moreover, region-specific density changes are often negatively correlated with the volume of the region, therefore cell count does not scale linearly with volume. Many regions, including layer 2/3 across several cortical areas, showed distinct lateral bias. We identified the greatest strain-specific or sex-specific differences in the medial amygdala (MEA), bed nuclei (BST), lateral septum and olfactory system (e.g., MOB, AOB, TR) and prefrontal areas (e.g., ORB) - yet, inter-individual variability was always greater than the effect size of a single qualifier. We provide the results of this analysis as an accessible resource for the community.
... Due to the key role in regulating mammal neural networks, multiple studies have focused on LC and employed LC-NE neurons as paradigms for elucidating the underlying mechanisms of sex differences with regard to the effects of sex hormones, structural differences, and molecular mechanisms (Pinos et al., 2001;Garcia-Falgueras et al., 2005;Bangasser et al., 2011Bangasser et al., , 2016De Carvalho et al., 2016;Mulvey et al., 2018). Among them, sex hormones have been shown to have a differential influence on the activities of LC-NE neurons in rats of different sexes (De Carvalho et al., 2016). ...
... Furthermore, previous structural studies generally focused on somal and dendritic differences of LC-NE neurons. For instance, female rats exhibit a larger LC size and more LC-NE neurons than male subjects, though these are defined to a limited strain or species (e.g., Wistar strain; Pinos et al., 2001;Garcia-Falgueras et al., 2005). The dendritic appearance of LC-NE neurons in female rats is morphologically more complex, with a higher density of dendrites, prolonged dendritic extensions leading to a larger coverage, and more dendritic branch points and ends for increased number of synaptic contacts (Bangasser et al., 2011). ...
... With brain-wide quantitative analysis of input sources to LC-NE neurons, we identified multiple sexually differentiated anatomical brain regions, including the hippocampus, MSC in basal forebrain, thalamus, PVH in hypothalamus, and cerebellar cortex. The findings are consistent with previous studies in rats showing that somal and dendritic differences exist within different sexes (Pinos et al., 2001;Garcia-Falgueras et al., 2005;Bangasser et al., 2011). For the hippocampus, its connections with LC play important roles in the regulation of learning/memory and different performances. ...
As the most important organ in our bodies, the brain plays a critical role in deciding sex-related differential features; however, the underlying neural circuitry basis remains unclear. Here, we used a cell-type-specific rabies virus-mediated monosynaptic tracing system to generate a sex differences-related whole-brain input atlas of locus coeruleus noradrenaline (LC-NE) neurons. We developed custom pipelines for brain-wide comparisons of input sources in both sexes with the registration of the whole-brain data set to the Allen Mouse Brain Reference Atlas. Among 257 distinct anatomical regions, we demonstrated the differential proportions of inputs to LC-NE neurons in male and female mice at different levels. Locus coeruleus noradrenaline neurons of two sexes showed general similarity in the input patterns, but with differentiated input proportions quantitatively from major brain regions and diverse sub-regions. For instance, inputs to male LC-NE neurons were found mainly in the cerebrum, interbrain, and cerebellum, whereas inputs to female LC-NE neurons were found in the midbrain and hindbrain. We further found that specific subsets of nuclei nested within sub-regions contributed to overall sex-related differences in the input circuitry. Furthermore, among the totaled 123 anatomical regions with proportion of inputs >0.1%, we also identified 11 sub-regions with significant statistical differences of total inputs between male and female mice, and seven of them also showed such differences in ipsilateral hemispheres. Our study not only provides a structural basis to facilitate our understanding of sex differences at a circuitry level but also provides clues for future sexually differentiated functional studies related to LC-NE neurons.
... This system is often activated along with the HPA axis and at least partially regulated by CRF [136][137][138]. Animal studies show that female rats have more LC neurons than male rats, which could play a role in the differences in the manifestation of stress-related disorders [139,140]. LC dendrites appear to be more complex and extensive in female rats, with morphological analysis indicating longer and further radiating LC dendritic trees in females compared to males [141]. With denser, branching, and more complex dendrites, female rodents, and by extrapolation, human females are probably better equipped to process more emotional stimuli and initiate a greater arousal response. ...
No organ in the body is impervious to the effects of stress, and a coordinated response from all organs is essential to deal with stressors. A dysregulated stress response that fails to bring systems back to homeostasis leads to compromised function and ultimately a diseased state. The components of the corticotropin-releasing factor (CRF) family, an ancient and evolutionarily conserved stress hormone-receptor system, helps both initiate stress responses and bring systems back to homeostasis once the stressors are removed. The mammalian CRF family comprises of four known agonists, CRF and urocortins (UCN1–3), and two known G protein-coupled receptors (GPCRs), CRF1 and CRF2. Evolutionarily, precursors of CRF- and urocortin-like peptides and their receptors were involved in osmoregulation/diuretic functions, in addition to nutrient sensing. Both CRF and UCN1 peptide hormones as well as their receptors appeared after a duplication event nearly 400 million years ago. All four agonists and both CRF receptors show sex-specific changes in expression and/or function, and single nucleotide polymorphisms are associated with a plethora of human diseases. CRF receptors harbor N-terminal cleavable peptide sequences, conferring biased ligand properties. CRF receptors have the ability to heteromerize with each other as well as with other GPCRs. Taken together, CRF receptors and their agonists due to their versatile functional adaptability mediate nuanced responses and are uniquely positioned to orchestrate sex-specific signaling and function in several tissues.
... Lastly, we explored the effects of BPA on the volume of the locus coeruleus (LC), a nucleus located in the pons and selected because one laboratory has generated data suggesting perinatal BPA exposure can have sex-specific effects on LC volume in Wistar rats (Kubo et al., 2001;Kubo et al., 2003). A female biased sexual dimorphism in rodent LC volume has been reported, however, this appears to be strain-and species-dependent (Babstock et al., 1997;Garcia-Falgueras et al., 2005). Thus, whether or not a sex difference exists, and might be vulnerable to BPA, was of interest in our animal model. ...
... In Wistar rats the female LC contains more neurons and has a greater overall volume than the male LC. This, however, appears to be strain-specific, as sex differences have not been observed in Long Evans or Sprague-Dawley rats (Babstock et al., 1997;Garcia-Falgueras et al., 2005;Garcia-Falgueras et al., 2006;Guillamon et al., 1988;Pinos et al., 2001). Here we found no sex difference in LC and no effect of BPA exposure at any of the exposure levels examined. ...
... Taken together, these studies suggest that stressful events would cause a greater increase in the arousal network of women than men, because women have lower resting state LC functional connectivity, but greater activation of LC circuits following aversive stimuli. Beyond functional differences, there is structural evidence that the LC contains more neurons in females than males, an effect consistent in humans and certain rat strains [53][54][55][56][57][58][59]. Collectively, these studies provide support for the idea that stress-inducing negative stimuli would have a greater impact on arousal in women than in men. ...
... Animal studies have revealed further sex differences in the LC and its regulation by stress (for review see [60]). In addition to its larger size in females than males of certain rat strains [55,56], we found that dendrites of LC neurons are longer and more complex in female compared to male rats [61] (Fig. 1a,b). LC dendrites are present within the nuclear core of the LC, but they also extend into the ventromedial and dorsolateral pericoerulear (peri-LC) regions [62,63]. ...
There are sex differences in the prevalence and presentation of many psychiatric disorders. For example, posttraumatic stress disorder (PTSD) and major depression are more common in women than men, and women with these disorders present with more hyperarousal symptoms than men. In contrast, attention deficit hyperactivity (ADHD) and schizophrenia are more common in men than women, and men with these disorders have increased cognitive deficits compared to women. A shared feature of the aforementioned psychiatric disorders is the contribution of stressful events to their onset and/or severity. Here we propose that sex differences in stress responses bias females towards hyperarousal and males towards cognitive deficits. Evidence from clinical and preclinical studies is detailed. We also describe underlying neurobiological mechanisms. For example, sex differences in stress receptor signaling and trafficking in the locus coeruleus-arousal center are detailed. In learning circuits, evidence for sex differences in dendritic morphology is provided. Finally, we describe how evaluating sex-specific mechanisms for responding to stress in female and male rodents can lead to better treatments for stress-related psychiatric disorders.
... The sex difference in rodent LC size and neuronal number is dependent on strain (Garcia-Falgueras et al., 2005). Specifically, sex differences in LC size are observed in the ancestral Wistar strain, but not in the Long-Evans strain, an effect attributed to a loss of the sex difference as a result of inbreeding for other traits (Garcia-Falgueras et al., 2005. ...
... The sex difference in rodent LC size and neuronal number is dependent on strain (Garcia-Falgueras et al., 2005). Specifically, sex differences in LC size are observed in the ancestral Wistar strain, but not in the Long-Evans strain, an effect attributed to a loss of the sex difference as a result of inbreeding for other traits (Garcia-Falgueras et al., 2005. Currently, behavioral data on the consequences of sex differences in LC size in Wistar, but not Long-Evans rats is lacking, but future studies addressing this issue could illuminate the consequences of a larger LC in females. ...
Women are more likely than men to suffer from and post-traumatic stress disorder (PTSD) and major depression. In addition to their sex bias, these disorders share stress as an etiological factor and hyperarousal as a symptom. Thus, sex differences in brain arousal systems and their regulation by stress could help explain increased vulnerability to these disorders in women. Here we review preclinical studies that have identified sex differences in the locus coeruleus (LC)-norepinephrine (NE) arousal system. First, we detail how structural sex differences in the LC can bias females towards increased arousal in response to emotional events. Second, we highlight studies demonstrating that estrogen can increase NE in LC target regions by enhancing the capacity for NE synthesis, while reducing NE degradation, potentially increasing arousal in females. Third, we review data revealing how sex differences in the stress receptor, corticotropin releasing factor 1 (CRF1), can increase LC neuronal sensitivity to CRF in females compared to males. This effect could translate into hyperarousal in women under conditions of CRF hypersecretion that occur in PTSD and depression. The implications of these sex differences for the treatment of stress-related psychiatric disorders are discussed. Moreover, the value of using information regarding biological sex differences to aid in the development of novel pharmacotherapies to better treat men and women with PTSD and depression also is highlighted.
... The LC has long been recognized as a sexually dimorphic structure, both in terms of volume, neuron number and cellular morphology [304][305][306]. LC and NTS both contain estrogen receptors (both ERα and ERβ) and androgen receptors [307][308][309]. ...
In this review we propose that there are sex differences in how men and women enter onto the path that can lead to addiction. Males are more likely than females to engage in risky behaviors that include experimenting with drugs of abuse, and in susceptible individuals, they are drawn into the spiral that can eventually lead to addiction. Women and girls are more likely to begin taking drugs as self-medication to reduce stress or alleviate depression. For this reason women enter into the downward spiral further along the path to addiction, and so transition to addiction more rapidly. We propose that this sex difference is due, at least in part, to sex differences in the organization of the neural systems responsible for motivation and addiction. Additionally, we suggest that sex differences in these systems and their functioning are accentuated with addiction. In the current review we discuss historical, cultural, social and biological bases for sex differences in addiction with an emphasis on sex differences in the neurotransmitter systems that are implicated.
