Locus Coeruleus AND immunity

Aging and age-related diseases are associated with cellular stress, metabolic imbalance, oxidative stress, and neuroinflammation, accompanied by cognitive impairment. Lifestyle factors such as diet, sleep fragmentation, and stress can potentiate damaging cellular cascades and lead to an acceleration of brain aging and cognitive impairment. High-fat diet (HFD) has been associated with obesity, metabolic disorders like diabetes, and cardiovascular disease. HFD also induces neuroinflammation, impairs learning and memory, and may increase anxiety-like behavior...

INTRODUCTION: Methylmercury (MeHg) is an environmental contaminant that is of particular concern in Northern Arctic Canadian populations. Specifically, organic mercury compounds such as MeHg are potent toxicants that affect multiple bodily systems including the nervous system. Developmental exposure to MeHg is a major concern, as the developing fetus and neonate are thought to be especially vulnerable to the toxic effects of MeHg. The objective of this study was to examine developmental exposure to low doses of MeHg and effects upon the adult central nervous system (CNS)...

In Alzheimer's disease (AD) pathophysiology, plaque and tangle accumulation trigger an inflammatory response that mounts positive feed-back loops between inflammation and protein aggregation, aggravating neurite damage and neuronal death. One of the earliest brain regions to undergo neurodegeneration is the locus coeruleus (LC), the predominant site of norepinephrine (NE) production in the central nervous system (CNS). In animal models of AD, dampening the impact of noradrenergic signaling pathways, either through administration of beta blockers or pharmacological ablation of the LC, heightened neuroinflammation through increased levels of pro-inflammatory mediators...

Maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of gestation increased susceptibility to neurodevelopmental disorders, including autism, in the offspring. In the present work, we aimed to provide characterization of the long-term consequences on anxiety-like behavior and cardiovascular stress response of MIA in the offspring. This study aimed to evaluate the effect of MIA by lipopolysaccharide (LPS) in adult male offspring. In our study, the animals were subjected to a range of behavioral and physiological tests, including the elevated plus maze, social interaction, cat odor response, open field behavior, contextual fear conditioning, and cardiovascular responses during restraint stress...

BACKGROUND: Most current disease-modifying therapies approved for multiple sclerosis (MS) are immunomodulatory drugs that counteract the aberrant activity of the immune system. Hence, new pharmacological interventions that drive anti-inflammatory activity and neuroprotection would represent interesting alternative therapeutic approaches or complementary strategies to treat progressive forms of MS. There is evidence of reduced noradrenaline levels and alterations to locus coeruleus (LC) noradrenergic neurons in MS patients, as well as in animal models of this disease, potentially factors contributing to the pathophysiology...

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...

Alzheimer's disease (AD) is a neurodegenerative disease and the most common example of dementia. The neuropathological features of AD are the abnormal deposition of extracellular amyloid-β (Aβ) and intraneuronal neurofibrillary tangles with hyperphosphorylated tau protein. It is recognized that AD starts in the frontal cerebral cortex, and then it progresses to the entorhinal cortex, the hippocampus, and the rest of the brain. However, some studies on animals suggest that AD could also progress in the reverse order starting from the midbrain and then spreading to the frontal cortex...

The dysfunction of descending noradrenergic (NAergic) modulation in second-order neurons has long been observed in neuropathic pain. In clinical practice, antidepressants that increase noradrenaline levels in the synaptic cleft are used as first-line agents, although adequate analgesia has not been occasionally achieved. One of the hallmarks of neuropathic pain in the orofacial regions is microglial abnormalities in the trigeminal spinal subnucleus caudalis (Vc). However, until now, the direct interaction between descending NAergic system and Vc microglia in orofacial neuropathic pain has not been explored...

Neuroinflammatory disorders preferentially impair the higher cognitive and executive functions of the prefrontal cortex (PFC). This includes such challenging disorders as delirium, perioperative neurocognitive disorder, and the sustained cognitive deficits from "long-COVID" or traumatic brain injury. There are no FDA-approved treatments for these symptoms; thus, understanding their etiology is important for generating therapeutic strategies. The current review describes the molecular rationale for why PFC circuits are especially vulnerable to inflammation, and how α2A-adrenoceptor (α2A-AR) actions throughout the nervous and immune systems can benefit the circuits in PFC needed for higher cognition...

Atopic dermatitis is a common chronic inflammatory skin disease, with most cases experiencing skin barrier dysfunction and enhanced allergen entry, accompanied by cytokine production which evokes predominantly type-2-skewed immune responses, itch, and scratching behavior. Although intense itch and excessive scratching behavior affect progression of skin lesions, it is unclear what causes them. Data suggest that scratching behavior stimulates brain dopaminergic reward and habit learning systems, strengthening habitual scratching behavior, while nocturnal scratching behavior presumably increases locus coeruleus-noradrenergic system activity, prompting sleep disturbances...

BACKGROUND: Women are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. METHODS: Microglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways...

Alzheimer's disease is a progressive neurodegenerative disorder characterized histologically in postmortem human brains by the presence of dense protein accumulations known as amyloid plaques and tau tangles. Plaques and tangles develop over decades of aberrant protein processing, post-translational modification, and misfolding throughout an individual's lifetime. We present a foundation of evidence from the literature that suggests chronic stress is associated with increased disease severity in Alzheimer's patient populations...

Following acute infection, herpes simplex virus 1 (HSV-1) establishes lifelong latency in neurons. The latency associated transcript (LAT) is the only viral gene abundantly expressed during latency. Wild-type (WT) HSV-1 reactivates more efficiently than LAT mutants because LAT promotes establishment and maintenance of latency. While sensory neurons in trigeminal ganglia (TG) are important sites for latency, brainstem is also a site for latency and reactivation from latency. The principal sensory nucleus of the spinal trigeminal tract (Pr5) likely harbors latent HSV-1 because it receives afferent inputs from TG...

Alzheimer's Disease (AD) is a complex neurodegenerative disease and remains the most common form of dementia. The pathological features include amyloid (Aβ) accumulation, neurofibrillary tangles (NFTs), neural and synaptic loss, microglial cell activation, and an increased blood-brain barrier permeability. One longstanding hypothesis suggests that a microbial etiology is key to AD initiation. Among the various periodontal microorganisms, Porphyromonas gingivalis has been considered the keystone agent to potentially correlate with AD, due to its influence on systemic inflammation...

BACKGROUND: Under inflammatory conditions, the activation of corticotropin-releasing factor (CRF) receptor has been shown to inhibit pain through opioid peptide release from immune cells or neurons. CRF's effects on human and animal pain modulation depend, however, on the distribution of its receptor subtypes 1 and 2 (CRF-R1 and CRF-R2) along the neuraxis of pain transmission. The objective of this study is to investigate the respective role of each CRF receptor subtype on centrally administered CRF-induced antinociception during inflammatory pain...

As we all know, dexmedetomidine (DEX), as a highly selective α2 adrenergic receptor agonist, exerts sedative, anti-anxiety and hypnotic effects by inhibiting the discharge of norepinephrine neurons in locus coeruleus and GABA-related hypnotic pathways. However, the role of DEX in anti-inflammatory and immune regulation has gradually attracted the attention of researchers in recent years. The α2 adrenergic receptor is one of the members of the adrenergic receptor family, which is widely present in a variety of immune cells and mediates the biological behavior of the inflammatory immune system...

BACKGROUND: Amyloid β oligomers (AβO) are potent modulators of Alzheimer's pathology, yet their impact on one of the earliest brain regions to exhibit signs of the condition, the locus coeruleus (LC), remains to be determined. Of particular importance is whether AβO impact the spontaneous excitability of LC neurons. This parameter determines brain-wide noradrenaline (NA) release, and thus NA-mediated brain functions, including cognition, emotion and immune function, which are all compromised in Alzheimer's...

The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease...

Postoperative cognitive dysfunction (POCD) is a common postoperative neurocognitive complication in elderly patients. However, the specific pathogenesis is unknown, and it has been demonstrated that neuroinflammation plays a key role in POCD. Recently, increasing evidence has proven that the locus coeruleus noradrenergic (LCNE) system participates in regulating neuroinflammation in some neurodegenerative disorders. We hypothesize that LCNE plays an important role in the neuroinflammation of POCD. In this study, 400 μg of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was injected intracerebroventricularly into each rat 7 days before anesthesia/surgery to deplete the locus coeruleus (LC) noradrenaline (NE)...

Modulation of the aquaporin 4 (AQP4) water-regulatory channel or production of autoantibodies against this protein have been implicated in a variety of neuropsychiatric conditions, and possible mechanisms have been proposed. However, the nature of the interaction between AQP4 expression and its implications in depression remain elusive. To our knowledge, this is the first review summarising data for the involvement of AQP4 in the context of depression and related mechanisms across a wide range of experimental studies: pre-clinical (KO and wild-type), post-mortem, ex vivo, and clinical studies in depression...