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The Locus Coeruleus. The figure in panel a shows two pictures at different magnifications (a and b) of a 10 µm-thick paraffin-embedded coronal section cut at the level of the pons from the brain of an adult C57 Black male mouse (Charles River). The section is collected at approximately at − 5.3 mm from the Bregma, according to the stereotactic mouse brain atlas by Paxinos and Franklin (2001). The section has been immune-stained with a primary antibody (#T1299 Sigma, U.S.A.) against the enzyme tyrosine hydroxylase (TH). Neurons immune-positive for the enzyme TH (brown color in the figure, due to DAB staining of biotin-coupled anti-mouse antibodies followed by exposure to Horseradish peroxidase streptavidin; Vector Laboratories), are neurons belonging to the nucleus Locus Coeruleus (LC); the section is counter-stained with Nissl Staining (Cresyl violet). The LC nucleus is placed right below the floor of the fourth ventricle of the pons (abbreviated as “f.v.” in the pictures) (scale bar: 200 µm). The graph in panel b shows the effects of the experimental lesion of LC-hypothalamic projections by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamin (DSP-4). The systemic administration of DSP-4 selectively lesions NA terminals originating from the LC in rodents. The figure shows the effect of the administration of DSP-4 50 mg/kg i.p. in adult Sprague Dawley Rats (DSP-4 N = 5; controls N = 5) on NA levels in homogenates collected from the hypothalamus (see legend to Table 2 for details on methodology). The NA levels (ng/mg protein) of the group “DSP-4” are expressed as % of “controls”. *p < 0.01 vs controls
Source publication
The hypothalamus and Locus Coeruleus (LC) share a variety of functions, as both of them take part in the regulation of the sleep/wake cycle and in the modulation of autonomic and homeostatic activities. Such a functional interplay takes place due to the dense and complex anatomical connections linking the two brain structures. In Alzheimer’s diseas...
Citations
... And reduced hypothalamic volume and gray matter loss was also observed [46]. Some post-mortem human studies showed that aberrant protein spreading and neuroinflammation may cause hypothalamus degeneration [47]. Zhang ...
Background
Previous research has underscored the correlation between Alzheimer’s disease (AD) and erectile dysfunction (ED). However, due to inherent limitations of observational studies, the causative relationship remains inconclusive.
Methods
Utilizing publicly available data from genome-wide association studies (GWAS) summary statistics, this study probed the potential causal association between AD and ED using univariate Mendelian randomization (MR). Further, the multivariable MR assessed the confounding effects of six cardiovascular diseases (CVDs). The primary approach employed was inverse variance weighted (IVW), supplemented by three additional methods. A series of sensitivity analyses were conducted to ensure the robustness of the results.
Results
In the forward MR analysis, the IVW method revealed causal evidence of genetically predicted AD being a risk factor for ED (OR = 1.077, 95% CI 1.007∼1.152, P = 0.031). Reverse analysis did not demonstrate any causal evidence linking ED to AD (OR = 1.018, 95% CI 0.974∼1.063, P = 0.430). Multivariable MR analysis showed that after adjusting for coronary heart disease (OR = 1.082, 95% CI 0.009∼1.160, P = 0.027), myocardial infarction (OR = 1.085, 95% CI 1.012∼1.163, P = 0.022), atrial fibrillation (OR = 1.076, 95% CI 1.002∼1.154, P = 0.043), heart failure (OR = 1.103, 95% CI 1.024∼1.188, P = 0.010), ischemic stroke (OR = 1.079, 95% CI 1.009∼1.154, P = 0.027), hypertension (OR = 1.092, 95% CI 1.011∼1.180, P = 0.025), and all models (OR = 1.115, 95% CI 1.024∼1.214, P = 0.012), the causal association between AD and ED persisted. Sensitivity analyses confirmed the absence of pleiotropy, heterogeneity, and outliers, validating the robustness of our results (P > 0.05).
Conclusions
This MR study consistently evidences a causal effect of genetically predicted AD on the risk of ED, independent of certain CVDs, yet offers no evidence for a reverse effect from ED.
... Altogether, these studies suggest an in vivo detectable association between LC-MRI integrity and sleep, but with a double pattern. On the one side, the progressive loss of integrity of LC alters daytime circadian rhythms [71] and impairs sleep quality [107], all processes in which the LC-NA system plays a key role [109]. On the other side, the disruption of this nucleus might be also associated with an abnormal and excessive LC-NA activation, which in turn might be responsible for "irritative symptoms" [44], as suggested by Koshmanova and colleagues [107], and also by Cassidy et al. for behavioral dyscontrol [63••]. ...
Performing a thorough review of magnetic resonance imaging (MRI) studies assessing locus coeruleus (LC) integrity in ageing and Alzheimer’s disease (AD), and contextualizing them with current preclinical and neuropathological literature.
MRI successfully detected LC alterations in ageing and AD, identifying degenerative phenomena involving this nucleus even in the prodromal stages of the disorder. The degree of LC disruption was also associated with the severity of AD cortical pathology, cognitive and behavioral impairment, and the risk of clinical progression.
Locus coeruleus-MRI has proved to be a useful tool to assess the integrity of the central noradrenergic system in vivo in humans. It allowed to test in patients preclinical and experimental hypothesis, thus confirming the specific and marked involvement of the LC in AD and its key pathogenetic role. Locus coeruleus-MRI–related data might represent the theoretical basis on which to start developing noradrenergic drugs to target AD.
... Moreover, deposition of alpha-synuclein (α-syn) along the central autonomic network may also contribute to nOH (Coon et al. 2018). The nucleus of the solitary tract and rostral ventrolateral medulla have been shown to play an important role in the activation of the baroreflex system, receiving the modulation, among others, of the LC itself through both direct and indirect connections (Bockstaele et al. 1989;Sun 1995;Giorgi et al. 2021;Samuels and Szabadi 2008). Although the LC is among the first brain regions to degenerate in PD (Braak et al. 2003), few studies examined the structural degeneration of LC in the pathogenesis of PD non-motor symptoms (Malatt and Tagliati 2022), likely reflecting previous technical difficulties in visualizing in vivo the LC because of its small size and physiological inter-subject variability (Fernandes et al. 2012). ...
Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and degenerates early in Parkinson’s disease (PD). The objective of this study is to test whether degeneration of the LC is associated with orthostatic hypotension (OH) in PD. A total of 22 cognitively intact PD patients and 52 age-matched healthy volunteers underwent 3 T magnetic resonance (MRI) with neuromelanin-sensitive T1-weighted sequences (LC-MRI). For each subject, a template space-based LC-MRI was used to calculate LC signal intensity (LC contrast ratio—LCCR) and the estimated number of voxels (LCVOX) belonging to LC. Then, we compared the LC-MRI parameters in PD patients with OH (PDOH+) versus without OH (PDOH−) (matched for sex, age, and disease duration) using one-way analysis of variance followed by multiple comparison tests. We also tested for correlations between subject’s LC-MRI features and orthostatic drop in systolic blood pressure (SBP). PDOH− and PDOH+ did not differ significantly (p > 0.05) based on demographics and clinical characteristics, except for blood pressure measurements and SCOPA-AUT cardiovascular domain (p < 0.05). LCCR and LCVOX measures were significantly lower in PD compared to HC, while no differences were observed between PDOH− and PDOH+. Additionally, no correlation was found between the LC-MRI parameters and the orthostatic drop in SBP or the clinical severity of autonomic symptoms (p > 0.05). Conversely, RBD symptom severity negatively correlated with several LC-MRI parameters. Our results failed to indicate a link between the LC-MRI features and the presence of OH in PD but confirmed a marked alteration of LC signal in PD patients.
... Efferent projections have been grouped into three major noradrenergic pathways: 1) the cortical (or ascendant) pathway (Szabadi, 2013), which includes projections to the ventral tegmental area (VTA) (Alvarado et al., 2023;Mejias-Aponte, 2016), SN (Mejias-Aponte, 2016;Rommelfanger and Weinshenker, 2007), amygdala (McCall et al., 2017;Uematsu et al., 2017), hippocampus (Haring and Davis, 1985;Jones and Moore, 1977;Takeuchi et al., 2016), hypothalamus (Giorgi et al., 2021;Schwarz and Luo, 2015), thalamus (Beas et al., 2018;Rodenkirch et al., 2019), basal forebrain (España and Berridge, 2006), PFC and sensory cortices (McBurney-Lin et al., 2019;Schwarz and Luo, 2015;Szabadi, 2013), 2) the spinal pathway (or descendent) which includes brainstem nuclei such as the nervus vagi (Nosaka et al., 1982), sympathetic premotor nuclei (Head et al., 1998;Tavares et al., 1996) and the oculomotor nucleus (Carpenter et al., 1992) as well as various spinal nuclei via 3) cerebellar pathways (Fu et al., 2011), where it connects to both cerebellar cortex and nuclei (Dietrichs, 1988) and potentiates Purkinje cell spiking (Moises et al., 1981), for a comprehensive review on LC connections see Szabadi and colleagues (Szabadi, 2013). ...
... In older age, significant variability in LC integrity has been observed (Betts et al., 2019a) and age-related differences in LC have not been consistently observed in cognitively intact older adults in the range of 60-80 (Betts et al., 2019b(Betts et al., , 2017Giorgi et al., 2021). ...
The locus coeruleus (LC) is a small brainstem structure located in the lower pons and is the main source of noradrenaline (NA) in the brain. Via its phasic and tonic firing, it modulates cognition and autonomic functions and is involved in the brain's immune response. The extent of degeneration to the LC in healthy ageing remains unclear, however, noradrenergic dysfunction may contribute to the pathogenesis of Alzheimer's (AD) and Parkinson's disease (PD). Despite their differences in progression at later disease stages, the early involvement of the LC may lead to comparable behavioural symptoms such as preclinical sleep problems and neuropsychiatric symptoms as a result of AD and PD pathology. In this review, we draw attention to the mechanisms that underlie LC degeneration in ageing, AD and PD. We aim to motivate future research to investigate how early degeneration of the noradrenergic system may play a pivotal role in the pathogenesis of AD and PD which may also be relevant to other neurodegenerative diseases.
... A recent report on the localization and morphology of hyperphosphorylated tau (AT8 +) LC neurons indicates the potential of dendritic spread of tau to LC-connected regions from as early as Braak stage 0, especially from the dorsal LC to neocortex and hippocampus [176]. Through connections with the thalamus, cerebral cortex, basal forebrain (BF), hippocampus and hypothalamus, including inhibition of sleep-promoting GABAergic neurons, LC noradrenergic neurons promote arousal and wakefulness and regulate memory [18,168,171,175,177], concomitant with the early onset of AD sleep deficits. Noradrenergic firing is low during NREM and quiescent during REM sleep, which is mediated via GABAergic inhibition from hypothalamic ventrolateral preoptic area (VLPO) and median preoptic nucleus, and hypothalamic galanin-(preoptic area (POA)) and melanin-concentrating hormone (MCH)-neuronal inhibition [168,170,171]. ...
Failed proteostasis is a well-documented feature of Alzheimer’s disease, particularly, reduced protein degradation and clearance. However, the contribution of failed proteostasis to neuronal circuit dysfunction is an emerging concept in neurodegenerative research and will prove critical in understanding cognitive decline. Our objective is to convey Alzheimer’s disease progression with the growing evidence for a bidirectional relationship of sleep disruption and proteostasis failure. Proteostasis dysfunction and tauopathy in Alzheimer’s disease disrupts neurons that regulate the sleep–wake cycle, which presents behavior as impaired slow wave and rapid eye movement sleep patterns. Subsequent sleep loss further impairs protein clearance. Sleep loss is a defined feature seen early in many neurodegenerative disorders and contributes to memory impairments in Alzheimer’s disease. Canonical pathological hallmarks, β-amyloid, and tau, directly disrupt sleep, and neurodegeneration of locus coeruleus, hippocampal and hypothalamic neurons from tau proteinopathy causes disruption of the neuronal circuitry of sleep. Acting in a positive-feedback-loop, sleep loss and circadian rhythm disruption then increase spread of β-amyloid and tau, through impairments of proteasome, autophagy, unfolded protein response and glymphatic clearance. This phenomenon extends beyond β-amyloid and tau, with interactions of sleep impairment with the homeostasis of TDP-43, α-synuclein, FUS, and huntingtin proteins, implicating sleep loss as an important consideration in an array of neurodegenerative diseases and in cases of mixed neuropathology. Critically, the dynamics of this interaction in the neurodegenerative environment are not fully elucidated and are deserving of further discussion and research. Finally, we propose sleep-enhancing therapeutics as potential interventions for promoting healthy proteostasis, including β-amyloid and tau clearance, mechanistically linking these processes. With further clinical and preclinical research, we propose this dynamic interaction as a diagnostic and therapeutic framework, informing precise single- and combinatorial-treatments for Alzheimer’s disease and other brain disorders.
Graphical Abstract
... Furthermore, LC takes part in the modulation of circadian rhythms, projecting to the hypothalamus [26]. The connections between these two areas of the CNS also underlie the regulation of many autonomic and endocrine pathways, such as heart rate, blood pressure, and release of steroid hormones [27]. Finally, the LC also plays a role in the regulation of the stress response, and its activity is altered in stress-related disorders such as anxiety and depression [28][29][30]. ...
The aim of this article is to highlight the potential role of the locus-coeruleus–noradrenergic (LC-NA) system in neurodevelopmental disorders (NdDs). The LC is the main brain noradrenergic nucleus, key in the regulation of arousal, attention, and stress response, and its early maturation and sensitivity to perinatal damage make it an interesting target for translational research. Clinical data shows the involvement of the LC-NA system in several NdDs, suggesting a pathogenetic role in the development of such disorders. In this context, a new neuroimaging tool, LC Magnetic Resonance Imaging (MRI), has been developed to visualize the LC in vivo and assess its integrity, which could be a valuable tool for exploring morphological alterations in NdD in vivo in humans. New animal models may be used to test the contribution of the LC-NA system to the pathogenic pathways of NdD and to evaluate the efficacy of NA-targeting drugs. In this narrative review, we provide an overview of how the LC-NA system may represent a common pathophysiological and pathogenic mechanism in NdD and a reliable target for symptomatic and disease-modifying drugs. Further research is needed to fully understand the interplay between the LC-NA system and NdD.
... As said, the LC is part of the reticular formation and is a key station of the ascending reticular activating system (ARAS), the system first described by Moruzzi and Magoun in 1949, which orchestrates the wake/sleep cycle (Moruzzi and Magoun, 1949). In line with this, LC shows also a strong interconnection with the hypothalamus, thus playing a key role also in the modulation of circadian rhythms (Giorgi et al., 2021a). LC is a wake-promoting nucleus, and it sends projections to, and receives afferences from, other wake-promoting nuclei, such as the cholinergic pedunculopontine and latero-dorsal tegmental nuclei, the serotoninergic dorsal raphe nucleus, the dopaminergic ventral tegmental area, the histaminergic tuberomammillary nucleus and the orexinergic lateral hypothalamic area (Szabadi, 2013). ...
... All these brain structures are densely interconnected, finely orchestrating the balance between sleep and wake and interplaying with the neuronal network modulating circadian rhythms. Indeed, the LC projects also to the suprachiasmatic nucleus of the hypothalamus, which is the masterclock of circadian rhythm regulation (Giorgi et al., 2021a). Through this connection, which the LC shares also with the other sleep-regulating nuclei, the sleep/wake cycle is tuned with circadian rhythm (González and Aston-Jones, 2006). ...
... LC projects to the rostroventral lateral medulla and to the caudal raphe nucleus in the medulla oblungata, as well as to the paraventricular nucleus of the hypothalamus. LC plays a relevant role in the modulation of cardiovascular functions, participating in the regulation of heart frequency and blood pressure; moreover, it influences hypothalamus-driven activities, such as thermoregulation and appetite (Giorgi et al., 2021a). For the sake of completeness, it should be mentioned that LC influences also the hypothalamic regulation of the endocrine system, acting especially on sexual hormones control and vasopressin release (Anselmo-Franci et al., 1997;Rodovalho et al., 2006). ...
... Furthermore, the defective long-term potentiation (LTP) found in the prefrontal cortex of prenatally malnourished rats was restored to normal levels by antagonizing or generating knockdown of α 2C -adrenoceptors, which suggests that the observed LTP neuroplastic deficit is generated by an excess of noradrenaline in the brain [82]. There are good reasons to consider central noradrenergic hyperactivity as a likely causal factor for both the increased levels of hypothalamic CRF and the downstream hypertensive effect developed by animals suffering from fetal malnutrition: (i) Axonal noradrenergic neurons from the A1, A2, A5, A6 (locus coeruleus) and A7 brainstem areas project densely to magnocellular and parvocellular regions of the PVN [83][84][85]; for in-depth review see [86]. (ii) In the PVN, noradrenaline stimulates transcription of the CRF gene very rapidly [87] by activating α 1 -adrenoceptors [88], with subsequent increase in cytosolic calcium in PVN neurons [89] and CRF release [90]. ...
A crucial etiological component in fetal programming is early nutrition. Indeed, early undernutrition may cause a chronic increase in blood pressure and cardiovascular diseases, including stroke and heart failure. In this regard, current evidence has sustained several pathological mechanisms involving changes in central and peripheral targets. In the present review, we summarize the neuroendocrine and neuroplastic modifications that underlie maladaptive mechanisms related to chronic hypertension programming after early undernutrition. First, we analyzed the role of glucocorticoids on the mechanism of long-term programming of hypertension. Secondly, we discussed the pathological plastic changes at the paraventricular nucleus of the hypothalamus that contribute to the development of chronic hypertension in animal models of prenatal undernutrition, dissecting the neural network that reciprocally communicates this nucleus with the locus coeruleus. Finally, we propose an integrated and updated view of the main neuroendocrine and central circuital alterations that support the occurrence of chronic increases of blood pressure in prenatally undernourished animals.
... The plastic effects of LC activation are activity-dependent and produce a synergism with ionotropic glutamate receptor excitation (Kasamatsu et al., 1991). The plasticityinducing effects of LC are extended to a variety of physiological and pathological conditions Galgani et al., 2020;Gesi et al., 2000;Giorgi et al., 2003;Giorgi et al., 2006;Giorgi et al., 2008;Giorgi et al., 2017;Giorgi et al., 2019;Giorgi et al., 2020a;Giorgi et al., 2020b;Giorgi et al., 2021a;Giorgi et al., 2021b;Giorgi et al., 2022;Ruffoli et al., 2011), which include learning and memory and seizures. In all these cases a prominent role is exerted by beta receptors, which modulate specific intracellular signaling pathways (Lazzeri et al., 2021;Biagioni et al., 2022). ...
The occurrence of pure light exerts a variety of effects in the human body, which span from behavioral alterations, such as light-driven automatic motor activity, cognition and mood to more archaic vegetative functions, which encompass most organs of the body with remarkable effects on the cardiovascular system. Although empirical evidence clearly indicates occurrence of these widespread effects, the anatomical correlates and long-lasting changes within putatively specific neuronal circuitries remain largely unexplored. A specific role is supposed to take place for catecholamine containing neurons in the core of the brainstem reticular formation, which produces a widespread release of noradrenaline in the forebrain while controlling the vegetative nervous system. An indirect as well as a direct (mono-synaptic) retino-brainstem pathway is hypothesized to rise from a subtype of intrinsically photosensitive retinal ganglion cells (iPRGCs), subtype M1, which do stain for Brn3b, and project to the pre-tectal region (including the olivary pre-tectal nucleus). This pathway provides profuse axon collaterals, which spread to the periacqueductal gray and dorsal raphe nuclei. According to this evidence, a retino-reticular monosynaptic system occurs, which powerfully modulate the noradrenergic hub of reticular nuclei in the lateral column of the brainstem reticular formation. These nuclei, which are evidenced in the present study, provide the anatomical basis to induce behavioral and cardiovascular modulation. The occurrence of a highly interconnected network within these nuclei is responsible for light driven plastic effects, which may alter persistently behavior and vegetative functions as the consequence of long-lasting alterations in the environmental light stimulation of the retina. These changes, which occur within the core of an archaic circuitry such as the noradrenaline-containing neurons of the reticular formation, recapitulate, within the CNS, ancestral effects of light-driven changes, which can be detected already within the retina itself at the level of multipotent photic cells.
... Of note, the specificity of the LC-NE system in the aforementioned relationships will have to be tested against the isolated role of other wake-promoting neuronal populations that also exhibit marked neurodegeneration in AD, such as the orexinergic cells of the lateral hypothalamus or the histaminergic neurons from the TMN [95,116]. In particular, as the LC-NE system has been suggested to act as an effector of the wake-promoting inputs from the orexinergic neurons [41], the structural and functional connections between the LC and these hypothalamic neurons warrant further attention to disentangle their respective contributions to age-and AD-related sleep-wake disruption [117]. ...
Five decades ago, seminal studies positioned the brainstem locus coeruleus (LC) norepinephrine (NE) system as a key substrate for the regulation of wakefulness and sleep, and this picture has recently been elaborated thanks to methodological advances in the precise investigation and experimental modulation of LC structure and functions. This review presents and discusses findings that support the major role of the LC-NE system at different levels of sleep-wake organization, ranging from its involvement in the overall architecture of the sleep-wake cycle to its associations with sleep microstructure, while accounting for the intricate neuroanatomy surrounding the LC. Given the particular position held by the LC-NE system by being at the intersection of sleep-wake dysregulation and initial pathophysiological processes of Alzheimer’s disease (AD), we conclude by examining emerging opportunities to investigate LC-NE mediated relationships between sleep-wake alteration and AD in human aging. We further propose several research perspectives that could support the LC-NE system as a promising target for the identification of at-risk individuals in the preclinical stages of AD, and for the development of novel preventive interventions.
