This review aims to elucidate the neural mechanisms driving colorectal cancer (CRC) growth, metastasis, and therapeutic resistance, summarizing the roles of neurotransmitters, neurotrophic factors, and neural signaling in carcinogenesis. It further explores therapeutic strategies targeting neural dependencies in CRC.

A comprehensive PubMed search was conducted using the keywords colorectal cancer and tumor innervation, focusing on studies published between 2000 and 2024. The review synthesizes evidence across four domains: neurotransmitter-receptor interactions, gut-brain-microbiota axis dynamics, neuroimmune modulation, and neural regulation of cancer stem cells, discussing their collective impact on CRC pathophysiology.

Neural innervation significantly influences CRC progression. For instance, the neurotransmitter serotonin promotes tumor growth and metastasis via paracrine and autocrine stimulation, while neurotrophic mediators like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) activate oncogenic signaling through receptor tyrosine kinases (RTKs). Downstream pathways, such as Wnt/β-catenin signaling, are modulated by neural inputs, underscoring CRC's neurodevelopmental dependency and highlighting their potential as therapeutic targets.

Neural mechanisms are pivotal in CRC progression, revealing novel therapeutic avenues. Strategies targeting neurotransmitter synthesis, neurotrophic signaling, or neuroimmune crosstalk may disrupt tumorigenic loops while preserving systemic nervous system integrity. Future research must prioritize translating these insights into clinical interventions to improve patient outcomes. Elucidating the intricate interplay between neural mediators and cancer pathogenesis, coupled with developing therapies specifically targeting the neurogenic basis of CRC aggressiveness, represents a critical frontier in oncology.

Adult learning, memory, and social interaction partially depend on neurogenesis in two regions: the hippocampus and the subventricular zone. There is evidence that the immune system is important for these processes in pathological situations, but there is no review of its role in non-pathological or near-physiological conditions. Although further research is warranted in this area, some conclusions can be drawn. Intrusive LyC6hi monocytes and autoreactive CD4+ T cells have a positive impact on neurogenesis and behavior, but the latter are deleterious if specific to external antigens. Mildly activated microglia play a crucial role in promoting these processes, by eliminating apoptotic neuronal progenitors and producing low levels of interleukins, which increase if the cells are activated, leading to inhibition of neurogenesis. Chemokines are poorly studied, but progenitor cells and neurons express their receptors, which appear important for migration and maturation. The few works that jointly analyzed neurogenesis and behavior showed congruent effects of immune cells and cytokines. In conclusion, the immune system components -mostly local- seem of utmost importance for the control of behavior under non-pathological conditions.

BackgroundC1q is a promoter of the classical pathway of complement and its massive expression may be associated with the development of Alzheimer's disease (AD). However, the relationships between C1q and the major pathological challenges, including amyloid-β (Aβ) and tau deposition, remain undetermined in the preclinical AD phase.ObjectiveThis study aims to investigate the connections between plasma C1q and CSF AD biomarkers.MethodsThe cognitively intact participants (N = 1264) from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were categorized into four groups, including Stage 0 [normal Amyloid-β1-42 (Aβ1-42), Phosphorylated-tau (P-tau) and Total-tau (T-tau)], Stage 1 (abnormal Aβ1-42, but normal P-tau or T-tau), Stage 2 (abnormal Aβ1-42 and abnormal P-tau or T-tau), and suspected non-Alzheimer disease pathology (SNAP) (abnormal P-tau or T-tau, but normal amyloid levels). The changes in plasma C1q levels among these groups and the correlation between C1q levels and cerebrospinal fluid (CSF) AD biomarkers were performed.ResultsThe results demonstrated plasma C1q levels are lower in Stage 0 (p = 0.010) and SNAP (p < 0.001) compared with Stage 1. A significant association between C1q levels and CSF AD pathology, including Aβ1-42 (β = -0.143, p < 0.001), Aβ1-42/Aβ1-40 (β = -0.173, p < 0.001), P-tau/Aβ1-42 (β = 0.156, p < 0.001), and T-tau/Aβ1-42 (β = 0.130, p < 0.001) has been identified.ConclusionsThe current research elucidates a positive correlation between elevated plasma C1q levels and CSF Aβ pathology, with C1q amplifying concomitantly with the pathological and clinical progression of AD.

Sepsis is a syndrome of life-threatening acute organ dysfunction caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) refers to the diffuse brain dysfunction observed in sepsis cases, clinically characterized by a spectrum of neuropsychiatric manifestations ranging from delirium to coma. SAE is independently associated with increased short-term mortality and long-term neurological abnormalities, with currently no effective preventive or treatment strategies. The pathogenesis is intricate, involving disruptions in neurotransmitters, blood-brain barrier (BBB) breakdown, abnormal brain signal transmission, and oxidative stress, among others. These mechanisms interact or act in conjunction, contributing to the complexity of SAE. Scholars worldwide have made significant strides in understanding the pathogenesis of SAE, offering new perspectives for diagnosis and treatment. This review synthesizes recent mechanistic breakthroughs and clinical evidence to guide future research directions, particularly in targeting BBB restoration and oxidative stress.

This study investigated the neural correlates of perceiving visual contagion cues characteristic of respiratory infections through functional magnetic resonance imaging (fMRI). Sixty-two participants (32f/ 30 m; ∼25 years on average) watched short videos depicting either contagious or non-contagious everyday situations, while their brain activation was continuously measured. We further measured the release of secretory immunoglobulin A (sIgA) in saliva to examine the first-line defensive response of the mucosal immune system. Perceiving sneezing and sick individuals compared to non-contagious individuals triggered increased activation in the anterior insula and other regions of the neuroimmune axis, that have been implicated in the somatosensory representation of the respiratory tract, and further led to increased release of sIgA. In line with predictions, this contagion cue-related activation of the insula was positively correlated with both perceived contagiousness and disgust evoked by the videos, as well as with the mucosal sIgA response. In contrast, the amygdala exhibited heightened activation to all videos featuring humans, regardless of explicit signs of contagion, indicating a nonspecific alertness to human presence. Nevertheless, amygdala activation was also correlated with the disgust ratings of each video. Collectively, these findings outline a neuroimmune mechanism for the processing of respiratory contagion cues. While the insula coordinates central and peripheral immune activation to match the perceived contagion threat, supposedly by triggering both increased sIgA release and contagion-related cognitions, the amygdala may rather act as an alerting system for social situations with a heightened transmission risk. This proactive neuroimmune response may help humans to manage contagion risks, that are difficult to avoid, by activating physiological and cognitive countermeasures in reaction to typical symptoms of respiratory infection, which prepares the organism for subsequent pathogen exposure.

Recently, the non-intestinal functions of human milk oligosaccharides (HMOs) have been widely documented, including their roles in promoting brain development and growth, as well as ameliorating anxiety, allergies, and obesity. Understanding their mechanisms of action is becoming increasingly critical. Furthermore, these effects are frequently associated with the type and structure of HMOs. As an innovative technology, "plant factory" is expected to complement traditional synthesis technology. This study reviews the novel "plant factory" synthesis techniques. Particular emphasis is placed on the processes, advantages, and limitations of "plant factory" synthesis of HMOs. This technology can express genes related to HMO synthesis instantaneously in plant leaves, thereby enabling the rapid and cost-effective generation of HMOs. However, "plant factory" technology remains underdeveloped, and challenges related to low yield and unsustainable production must be addressed. Furthermore, we present an overview of the most recent clinical and preclinical studies on the non-intestinal functions of HMOs. This review emphasizes the mechanisms of action underlying the non-intestinal functions of HMOs. HMOs primarily exert non-intestinal functions through the cleavage of beneficial monomer components, metabolism to produce advantageous metabolites, and regulation of immune responses.

For a long time, traditional medicine has acknowledged the gut's impact on general health. Contemporary science substantiates this association through investigations of the gut microbiota, the extensive community of microorganisms inhabiting our gastrointestinal system. These microscopic residents considerably improve digestive processes, nutritional absorption, immunological function, and pathogen defense. Nevertheless, a variety of gastrointestinal and extra-intestinal disorders can result from dysbiosis, an imbalance of the microbial composition of the gut microbiota. A groundbreaking discovery is the gut-brain axis, a complex communication network that links the enteric and central nervous system (CNS). This bidirectional communication allows the brain to influence gut activities and vice versa, impacting mental health and mood disorders like anxiety and depression. The gut microbiota can influence this communication by creating neurotransmitters and short-chain fatty acids, among other biochemical processes. These factors may affect our mental state, our ability to regulate our emotions, and the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to explore the complex interrelationships between the brain and the gut microbiota. We also conducted a thorough examination of the existing understanding in the area of how microbiota affects social behaviors, including emotions, stress responses, and cognitive functions. We also explored the potential of interventions that focus on the connection between the gut and the brain, such as using probiotics to treat diseases of the CNS. This research opens up new possibilities for addressing mental health and neurological conditions in an innovative manner.

A 39-year-old male patient was admitted to hospital with abdominal distension, unconsciousness, and anuria. Head computed tomography (CT) showed subarachnoid hemorrhage and diffuse cerebral edema. The high-density area of contrast accumulation region in the high-density CT plaque was 38 HU, and the preliminary diagnosis was SAH, incomplete intestinal obstruction, and sepsis caused by acute cerebrovascular disease. After admission, the patient displayed upturned eyes, limb convulsions, serum procalcitonin level exceeding 100 ng/mL, low blood pressure and septic shock. Imipenem was given for intensive anti-infection therapy. After treatment, procalcitonin levels showed a slow decline, renal function, and intra-abdominal pressure returned to normal, urine volume gradually increased, but platelets still showed a downward trend. Lumbar puncture showed colorless and clear cerebrospinal fluid, and the biochemical and routine results of cerebrospinal fluid were normal. SAH and intracranial infection were excluded, and it was considered that the head CT showed pseudo-subarachnoid hemorrhage. On the 3rd day of admission, laparoscopic exploratory laparotomy+appendectomy+abdominal drainage under general anesthesia were performed. During surgery, purulent gangrene in the appendix was found, with pus adhering to the surface of the intestines and a large amount of pus present in the abdominal cavity. Rhabdomyolysis syndrome developed after surgery. After continuous renal replacement therapy, the indicators gradually returned to normal. The patient was conscious, and the head CT results were normal. The patient was discharged from the hospital on the 19th day after surgery, and no special discomfort and abdominal pain and distension occurred during the 3-month follow-up.

Nerve signaling within the tumor microenvironment (TME) plays a critical role in the initiation, progression, and metastasis of solid tumors. Due to their highly responsive behavior and activation upon injury and cancer onset, this review specifically focuses on how sympathetic nerves rewire the TME. Within tumors, sympathetic nerves closely interact with various TME components, and their combined signaling often shifts tumor-intrinsic physiology toward tumor-supportive phenotypes. In turn, the TME components, such as myeloid cells, lymphoid cells, extracellular matrix (ECM), endothelial cells, cancer associated fibroblasts (CAFs), and Schwann cells, secrete neurotrophic and axon guidance factors that influence both sympathetic outgrowth and tumor cell behavior, further exacerbating tumor progression and metastasis. Here, we review the current evidence on the multidirectional impacts of sympathetic nerves and both immune and non-immune TME components, the nature of these communication processes, and how exploring these interactions may inform future therapeutics to impair cancer progression and metastasis.

Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons, resulting in muscle atrophy, spasticity, hyperreflexia, and paralysis. Inflammation plays an important role in the development of ALS, and associated with rapid disease progression. Current observational studies indicate the thinning of cortical thickness in patients with ALS is associated with rapid disease progression and cognitive changes. However, the effects of inflammatory cytokines on cortical thickness in patients with ALS are unclear. Here, we investigated the relationship between inflammatory cytokines and cortical thickness in patients with ALS.

We evaluated 51 patients with ALS for inflammatory cytokines including interleukin (IL)-4, interferon (IFN)-α, IL-1β, IL-2, IL-5, IL-12, tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-8, IL-17, and IFN-γ and analyzed the correlation between these indicators and the ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score). Twenty-six patients with ALS and 26 controls were studied using whole-cortex analysis, and post-hoc analyses were performed to examine the correlation between brain cortical thickness and ALSFRS-R or ΔFS scores.

IL-4, IFN-α, IL-1β, and IL-2 levels were significantly correlated with ALSFRS-R scores, and the IL-2 level was significantly correlated with ΔFS scores. After controlling for age and sex, the ALS group had thinner cortexes in multiple clusters across the brain than the control group. Further analyses revealed that cortical thickness in the right superior temporal and lingual gyrus regions was inversely correlated with ΔFS scores. There was a significant positive correlation between the clusters in the right lingual cortex and IL-2 level.

These results suggest cortical thickness was reduced in patients with ALS in motor and non-motor cortical areas. Inflammatory factors (especially IL-2) were correlated with cortical thickness, and both were related to the disease progression rate, suggesting IL-2 plays an important role in ALS.

Food allergy is classically characterized by an inappropriate type-2 immune response to allergenic food antigens. However, how allergens are detected and how that detection leads to the initiation of allergic immunity is poorly understood. In addition to the gastrointestinal tract, the barrier epithelium of the skin may also act as a site of food allergen sensitization. These barrier epithelia are densely innervated by sensory neurons, which respond to diverse physical environmental stimuli. Recent findings suggest that sensory neurons can directly detect a broad array of immunogens, including allergens, triggering sensory responses and the release of neuropeptides that influence immune cell function. Reciprocally, immune mediators modulate the activation or responsiveness of sensory neurons, forming neuroimmune feedback loops that may impact allergic immune responses. By utilizing cutaneous allergen exposure as a model, this review explores the pivotal role of sensory neurons in allergen detection and their dynamic bidirectional communication with the immune system, which ultimately orchestrates the type-2 immune response. Furthermore, it sheds light on how peripheral signals are integrated within the central nervous system to coordinate hallmark features of allergic reactions. Drawing from this emerging evidence, we propose that atopy arises from a dysregulated neuroimmune circuit.

Cannabis (marijuana) is a leafy plant that has medical, recreational, and other uses. Cannabis is socially accepted and widely used throughout the United States. Though cannabis use is increasingly gaining popularity, studies detail the deleterious effects of chronic cannabis smoking on mental health, as well as the immunosuppressive properties of cannabinoids. Additionally, oral dysbiosis induced by cannabis smoking serves as a novel catalyst for neurological abnormalities, potentially possible through microbial translocation via the oral-brain axis. This review summarizes the effects and link of smoking cannabis on neurological abnormalities, immunity, and oral microbiome.

The study aimed to investigate whether an exercise-induced pro-inflammatory response alters the perception as well as visual exploration of emotional body language in social interactions.

In a within-subject design, 19 male, healthy adults aged between 19 and 33 years performed a downhill run for 45 min at 70% of their VO2max on a treadmill to induce maximal myokine blood elevations, leading to a pro-inflammatory status. Two control conditions were selected: a control run with no decline and a rest condition without physical exercise. Blood samples were taken before (T0), directly after (T1), 3 h after (T3), and 24 h after (T24) each exercise for analyzing the inflammatory response. 3 h after exercise, participants observed point-light displays (PLDs) of human interactions portraying four emotions (happiness, affection, sadness, and anger). Participants categorized the emotional content, assessed the emotional intensity of the stimuli, and indicated their confidence in their ratings. Eye movements during the entire paradigm and self-reported current mood were also recorded.

The downhill exercise condition resulted in significant elevations of measured cytokines (IL6, CRP, MCP-1) and markers for muscle damage (Myoglobin) compared to the control running condition, indicating a pro-inflammatory state after the downhill run. Emotion recognition rates decreased significantly after the downhill run, whereas no such effect was observed after control running. Participants' sensitivity to emotion-specific cues also declined. However, the downhill run had no effect on the perceived emotional intensity or the subjective confidence in the given ratings. Visual scanning behavior was affected after the downhill run, with participants fixating more on sad stimuli, in contrast to the control conditions, where participants exhibited more fixations while observing happy stimuli.

Our study demonstrates that inflammation, induced through a downhill running model, impairs perception and emotional recognition abilities. Specifically, inflammation leads to decreased recognition rates of emotional content of social interactions, attributable to diminished discrimination capabilities across all emotional categories. Additionally, we observed alterations in visual exploration behavior. This confirms that inflammation significantly affects an individual's responsiveness to social and affective stimuli.

The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.

Major depressive disorder (MDD) affects millions of individuals worldwide, leading to considerable social and economic costs. Despite advancements in pharmacological treatments, achieving remission remains a key challenge, with a substantial number of patients showing resistance to existing therapies. This resistance is often associated with elevated levels of proinflammatory cytokines, suggesting a connection between inflammation, MDD pathophysiology, and treatment efficacy. The observation of increased immune activation in about a quarter of patients with MDD resulted in the distinction between inflammatory and noninflammatory endotypes. Although anti-inflammatory treatments show promise in alleviating depression-like symptoms, responses are heterogeneous, thus highlighting the importance of identifying distinct inflammatory endotypes to tailor effective therapeutic strategies. The intestinal microbiome emerges as a crucial modulator of mental health, mediating its effects partially through different immune pathways. Microbiota-derived short-chain fatty acids (SCFAs) significantly impact innate and adaptive immune cells, regulating their differentiation, function, and cellular response. Furthermore, gut-educated immune cells reach the border regions of the central nervous system (CNS), regulating glial cell functions. Although the CNS modulates immune responses via efferent parts of the vagus nerve, afferent tracts concurrently transport information on peripheral inflammation back to the brain. This bidirectional communication is particularly relevant in depression, allowing for therapeutic stimulation of the vagus nerve in the context of inflammatory depression endotypes. In this review, we explore the intricate relationship between inflammation and depression, discuss how inflammatory signals are translated into depressive-like symptoms, and highlight immune-modulating therapeutic avenues.

Some recent publications have used the term "vagal-adrenal axis" to account for mechanisms involved in the regulation of inflammation by electroacupuncture. This concept proposes that efferent parasympathetic nerve fibers in the vagus directly innervate the adrenal glands to influence catecholamine secretion. Here, we discuss evidence for anatomical and functional links between the vagi and adrenal glands that may be relevant in the context of inflammation and its neural control by factors, including acupuncture. First, we find that evidence for any direct vagal parasympathetic efferent innervation of the adrenal glands is weak and likely artifactual. Second, we find good evidence that vagal afferent fibers directly innervate the adrenal gland, although their function is uncertain. Third, we highlight a wealth of evidence for indirect pathways, whereby vagal afferent signals act via the central nervous system to modify adrenal-dependent anti-inflammatory responses. Vagal afferents, not efferents, are thus the likely key to these phenomena.

The nervous and immune systems are highly developed, and each performs specialized physiological functions. However, they work together, and their dysfunction is associated with various diseases. Specialized molecules, such as neurotransmitters, cytokines, and more general metabolites, are essential for the appropriate regulation of both systems. Tryptophan, an essential amino acid, is converted into functional molecules such as serotonin and kynurenine, both of which play important roles in the nervous and immune systems. The role of kynurenine metabolites in neurodegenerative and psychiatric diseases has recently received particular attention. Recently, we found that hyperactivity of the kynurenine pathway is a critical risk factor for septic shock. In this review, we first outline neuroimmune interactions and tryptophan derivatives and then summarized the changes in tryptophan metabolism in neurological disorders. Finally, we discuss the potential of tryptophan derivatives as therapeutic targets for neuroimmune disorders.

Depressed patients have an increased incidence of pain. A pathophysiological connection between depression and pain is still not revealed. Immunological activation has been found in both depression and pain. There are few studies of pain and immune activation in patients with depression, without inflammatory and autoimmune disorders.

This is a naturalistic follow-up study of 50 patients with a major depressive disorder (MDD) depressive episode, without any inflammatory or autoimmune conditions. We have previously reported on the relationship between depression and cytokine levels. In this study, we obtained data of depression, pain and cytokine levels before and after 12 weeks of depression treatment. All patients were medication-free at inclusion.

At inclusion three out of four patients experienced pain, and the pain scores correlated with the depression scores. After treatment, as depression was relieved, the pain scores dropped significantly and were no longer correlated to the depression scores. There were no correlations between pain scores and cytokine levels. Pain level at inclusion did not correlate with depression treatment outcome.

Our findings indicate that pain is a feature of depression. Pain levels and cytokine values didn't correlate. Pain at inclusion did not predict depression treatment outcome.

Dietary fasting markedly influences the distribution and function of immune cells and exerts potent immunosuppressive effects. However, the mechanisms through which fasting regulates immunity remain obscure. Here we report that catecholaminergic (CA) neurons in the ventrolateral medulla (VLM) are activated during fasting in mice, and we demonstrate that the activity of these CA neurons impacts the distribution of T cells and the development of autoimmune disease in an experimental autoimmune encephalomyelitis (EAE) model. Ablation of VLM CA neurons largely reversed fasting-mediated T cell redistribution. Activation of these neurons drove T cell homing to bone marrow in a CXCR4/CXCL12 axis-dependent manner, which may be mediated by a neural circuit that stimulates corticosterone secretion. Similar to fasting, the continuous activation of VLM CA neurons suppressed T cell activation, proliferation, differentiation and cytokine production in autoimmune mouse models and substantially alleviated disease symptoms. Collectively, our study demonstrates neuronal control of inflammation and T cell distribution, suggesting a neural mechanism underlying fasting-mediated immune regulation.

AbstractLocomotion is essential for survival, but it requires resources such as energy and metabolites and therefore may conflict with other physiological processes that also demand resources, particularly expensive processes such as immunological responses. This possible trade-off may impose limits on either the magnitude of immune responses or the patterns of activity and performance. Previous studies have shown that invasive species may have a depressed immune response, allowing them to maintain locomotor function and reproduction even when sick. This may contribute to the ecological success of invasive species in colonization and dispersal. In contrast, noninvasive species tend to reduce activity as a response to infection. Here, we studied the impact of a simulated infection on locomotor performance and voluntary movement in the anurans Xenopus laevis (a globally invasive species) and Xenopus allofraseri (a noninvasive congeneric). We found that a simulated infection reduces locomotor performance in both species, with an accentuated effect on X. allofraseri. Voluntary movement was marginally different between species. Our data suggest that a simulated infection leads to behavioral depression and reduced locomotor performance in anurans and show that this effect is limited in the invasive X. laevis. Contrasting responses to an immune challenge have been reported in the few amphibian taxa analyzed to date and suggest relationships between ecology and immunology that deserve further investigation. Specifically, a depressed immune response may underlie a propension to invasion in some species. Whether this is a general trend for invasive species remains to be tested, but our data add to the growing body of work documenting depressed immune systems in invasive species.

Infections are often accompanied by weight loss caused by alterations in host behavior and metabolism, also known as sickness behaviors. Recent studies have revealed that sickness behaviors can either promote or impede survival during infections depending on factors such as the type of infectious pathogen. Nevertheless, we have an incomplete understanding of the underlying mechanisms of sickness behaviors. Furthermore, although the host immune responses to infections have long been known to contribute to the induction of sickness behaviors, recent studies have identified emerging cytokines that are also key regulators of host metabolism during infection and inflammation, such as growth differentiation factor 15 (GDF-15). GDF-15 is a distant member of the TGF-β superfamily that causes weight loss by suppressing appetite and food consumption and causing emesis. These effects require activation of neurons that express the only known GDF-15 receptor, the GFRAL receptor. GDF-15 also functions in the periphery including the induction of ketogenesis and immunoregulation. Nevertheless, the functions and regulation of GDF-15 during live infections is not yet known. Murine infection with avirulent Toxoplasma gondii is an established model to understand infection-induced weight loss. Past studies have determined that acute T. gondii infection causes weight loss due to diminished food consumption and increased energy expenditure through unknown mechanisms. Additionally, our lab previously demonstrated that T. gondii causes upregulation in serum GDF-15 in an IFN-γ-dependent manner during the post-acute phase of the infection. In this study, we interrogated the in-vivo functions and immune regulation of GDF-15 during Toxoplasma gondii infection. First, we found that in wild-type mice, acute T. gondii infection caused a significant weight loss that is preceded by elevation of serum levels of IFN-γ and GDF-15. To determine whether IFN-γ regulates GDF-15, we neutralized IFN-γ on days 5 and 6 and measured GDF-15 on day 7 and found that serum but not tissue levels of GDF-15 decreased after IFN-γ neutralization. Additionally, exogenous IFN-γ was sufficient to elevate serum GDF-15 in the absence of infection. Next, we compared the outcomes of T. gondii infection between WT and Gdf15-/- mice. We observed that the weight trajectories were declining in WT mice while they were increasing in Gdf15-/-mice during the acute phase of the infection. This difference in trajectories extended throughout the chronic infection resulting to an overall weight loss relative to initial weights in WT mice but not Gdf15-/-mice. Then, we determined that GDF-15 is not essential for survival and immunoregulation during T. gondii infection. We also demonstrated that GDF-15 is required for the induction of FGF21, stress-induced cytokine with prominent roles in regulating host metabolism. Finally, we discovered a cytokine cascade IFN-γ-GDF-15-FGF21 that is likely involved in the regulation of host metabolism. Overall, our study provides evidence that IFN-γ contributes to the regulation of host metabolism during infection by inducing GDF-15 and FGF21. GDF-15 orchestrates changes in host metabolism that supports the host immune response in clearing the infection. These physiological alterations induce FGF21, which in turn, orchestrates the adaptive responses to the effects of GDF-15, which can be detrimental when protracted.

For many brain disorders, a subset of patients jointly exhibit alterations in cortical brain structure and elevated levels of circulating immune markers. This may be driven in part by shared genetic architecture. Therefore, we investigated the phenotypic and genetic associations linking global cortical surface area and thickness with blood immune markers (i.e., white blood cell counts and plasma C-reactive protein levels).

Linear regression was used to assess phenotypic associations in 30,823 UK Biobank participants. Genome-wide and local genetic correlations were assessed using linkage disequilibrium score regression and local analysis of covariance annotation. The number of shared trait-influencing genetic variants was estimated using MiXeR. Shared genetic architecture was assessed using a conjunctional false discovery rate framework, and mapped genes were included in gene-set enrichment analyses.

Cortical structure and blood immune markers exhibited predominantly inverse phenotypic associations. There were modest genome-wide genetic correlations, the strongest of which were for C-reactive protein levels (rg_surface_area = -0.13, false discovery rate-corrected p = 4.17 × 10-3; rg_thickness = -0.13, false discovery rate-corrected p = 4.00 × 10-2). Meanwhile, local genetic correlations showed a mosaic of positive and negative associations. White blood cells shared on average 46.24% and 38.64% of trait-influencing genetic variants with surface area and thickness, respectively. Additionally, surface area shared 55 unique loci with the blood immune markers while thickness shared 15. Overall, monocyte count exhibited the largest genetic overlap with cortical brain structure. A series of gene enrichment analyses implicated neuronal-, astrocytic-, and schizophrenia-associated genes.

The findings indicate shared genetic underpinnings for cortical brain structure and blood immune markers, with implications for neurodevelopment and understanding the etiology of brain-related disorders.

This narrative review aimed at identifying the existing scientific literature investigating periodontitis and neuropathic diseases.

A search of the literature published between 2000 and 2022 was carried out in the electronic databases of Scopus and PubMed. Studies in which the eligible articles were mainly published in English were included. Descriptive correlational studies, case-control studies, comparative studies, and cohort studies were also included. The following main keywords were used: "Neuropathic diseases," "Periodontitis," "Alzheimer's disease," and "Porphyromonas gingivalis."

This narrative review found that cognitively impaired persons with severe periodontitis had a higher prevalence and incidence of periodontal diseases than the rest of the population. A significant positive correlation of salivary interleukin (IL)-1beta and immediate recall scores involved in cognition was also evident. It indicates that the most investigated parameter was whether there is any common link between periodontal disease and neurodegeneration. No randomized controlled clinical studies were found in the current literature review.

Based on the literature reviewed, there is currently no strong scientific evidence to support or discourage the cause-effect relationship of periodontal diseases and neurodegenerative diseases.

Depression is a common and disabling comorbidity in rheumatoid arthritis that not only decreases the likelihood of remission and treatment adherence but also increases the risk of disability and mortality in patients with rheumatoid arthritis. Compelling data that link immune mechanisms to major depressive disorder indicate possible common mechanisms that drive the pathology of the two conditions. Preclinical evidence suggests that pro-inflammatory cytokines, which are prevalent in rheumatoid arthritis, have various effects on monoaminergic neurotransmission, neurotrophic factors and measures of synaptic plasticity. Neuroimaging studies provide insight into the consequences of inflammation on the brain (for example, on neural connectivity), and clinical trial data highlight the beneficial effects of immune modulation on comorbid depression. Major depressive disorder occurs more frequently in patients with rheumatoid arthritis than in the general population, and major depressive disorder also increases the risk of a future diagnosis of rheumatoid arthritis, further highlighting the link between rheumatoid arthritis and major depressive disorder. This Review focuses on interactions between peripheral and central immunobiological mechanisms in the context of both rheumatoid arthritis and major depressive disorder. Understanding these mechanisms will provide a basis for future therapeutic development, not least in depression.

A series of symptoms, including fever, widespread pain, fatigue, and even ageusia, have frequently been reported in the context of various infections, such as COVID-19. Although the pathogenic mechanisms underlying an infection causing fever and pain have been well established, the mechanisms of fatigue induced by infection in specific brain regions remain unclear.

To elucidate whether and how the peripheral infection cause fatigue via regional neuroinflammation, we performed a brain-wide investigation of neuroinflammation in a peripheral pseudoinfection rat model using [18F]DPA-714 positron emission tomography (PET) imaging analysis, in which the polyriboinosinic: polyribocytidylic acid (poly I:C) was intraperitoneally injected.

Transient fever lasting for several hours and subsequent suppression of spontaneous activity lasting a few days were induced by poly I:C treatment. Significant increase in plasma interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were observed at 2 and 4 h following poly I:C treatment. PET imaging analysis revealed that the brain uptake of [18F]DPA-714 was significantly increased in several brain regions one day after poly I:C treatment, such as the dorsal raphe (DR), parvicellular part of red nucleus (RPC), A5 and A7 noradrenergic nucleus, compared with the control group. The accumulation of [18F]DPA-714 in the DR, RPC and A5 was positively correlated with subsequent fatigue-like behavior, and that in the A7 tended to positively correlate with fever.

These findings suggest that peripheral infection may trigger regional neuroinflammation, which may cause specific symptoms such as fatigue. A similar mechanism might be involved in COVID-19.

Sepsis induces neuroinflammation, BBB disruption, cerebral hypoxia, neuronal mitochondrial dysfunction, and cell death causing sepsis-associated encephalopathy (SAE). These pathological consequences lead to short- and long-term neurobehavioural deficits. Till now there is no specific treatment that directly improves SAE and its associated behavioural impairments. In this review, we discuss the underlying mechanisms of sepsis-induced brain injury with a focus on the latest progress regarding neuroprotective effects of SIRT1 (silent mating type information regulation-2 homologue-1). SIRT1 is an NAD+ -dependent class III protein deacetylase. It is able to modulate multiple downstream signals (including NF-κB, HMGB, AMPK, PGC1α and FoxO), which are involved in the development of SAE by its deacetylation activity. There are multiple recent studies showing the neuroprotective effects of SIRT1 in neuroinflammation related diseases. The proposed neuroprotective action of SIRT1 is meant to bring a promising therapeutic strategy for managing SAE and ameliorating its related behavioural deficits.

Alzheimer's disease (AD) is a chronic neurodegenerative disease and the common cause of dementia. The aggregation of beta-amyloid (Aβ peptide) leading to excessive neuroinflammation is considered to be the neuropathological hallmark of AD, although the precise mechanisms remain unclear. Oligomerization of these peptides may be associated with their 42 amino acid residue arrangement. However, the process of amyloid plaque formation is still not well known. The protein folding-shape code (PFSC) method is a powerful tool to analyze protein confirmation which could exhibit the local structural folding features in detail. In our study, we utilized the PFSC to analyze Aβ peptide in humans and mice and found that mouse Aβ42 is less likely to polymerize than human's. Subsequently, we used the PFSC method to analyze the 42 amino acids of Aβ, transformed some species in human Aβ42 and obtained 7 mutants. We showed that it was not easy to aggregate Aβ in mutants. Herein, inflammatory responses were decreased, as indicated by the expression of cytokines. We confirmed that the neurotoxicity of mutant human Aβ was decreased by preventing peptide aggregation. This may represent a new therapeutic approach for treating AD.

This study evaluated the effects of previous exposure to Transcranial Direct Current Stimulation (tDCS) on nociceptive, neuroinflammatory, and neurochemical parameters, in rats subjected to an incisional pain model. Forty adult male Wistar rats (60 days old; weighing ∼ 250 g) were divided into five groups: 1. control (C); 2. drugs (D); 3. surgery (S); 4. surgery + sham-tDCS (SsT) and 5. surgery + tDCS (ST). Bimodal tDCS (0.5 mA) was applied for 20 min/day/8 days before the incisional model. Mechanical allodynia (von Frey) was evaluated at different time points after surgery. Cytokines and BDNF levels were evaluated in the cerebral cortex, hippocampus, brainstem, and spinal cord. Histology and activity of myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAGase) were evaluated in the surgical lesion sites in the right hind paw. The results demonstrate that the surgery procedure increased BDNF and IL-6 levels in the spinal cord levels in the hippocampus, and decreased IL-1β and IL-6 levels in the cerebral cortex, IL-6 levels in the hippocampus, and IL-10 levels in the brainstem and hippocampus. In addition, preemptive tDCS was effective in controlling postoperative pain, increasing BDNF, IL-6, and IL-10 levels in the spinal cord and brainstem, increasing IL-1β in the spinal cord, and decreasing IL-6 levels in the cerebral cortex and hippocampus, IL-1β and IL-10 levels in the hippocampus. Preemptive tDCS also contributes to tissue repair, preventing chronic inflammation, and consequent fibrosis. Thus, these findings imply that preemptive methods for postoperative pain management should be considered an interesting pain management strategy, and may contribute to the development of clinical applications for tDCS in surgical situations.

Animal models of selective breeding for extremes in emotionality are a strong experimental approach to model psychopathologies. They became indispensable in order to increase our understanding of neurobiological, genetic, epigenetic, hormonal, and environmental mechanisms contributing to anxiety disorders and their association with depressive symptoms or social deficits. In the present review, we extensively discuss Wistar rats selectively bred for high (HAB) and low (LAB) anxiety-related behaviour on the elevated plus-maze. After 30 years of breeding, we can confirm the prominent differences between HAB and LAB rats in trait anxiety, which are accompanied by consistent differences in depressive-like, social and cognitive behaviours. We can further confirm a single nucleotide polymorphism in the vasopressin promotor of HAB rats causative for neuropeptide overexpression, and show that low (or high) anxiety and fear levels are unlikely due to visual dysfunctions. Thus, HAB and LAB rats continue to exist as a reliable tool to study the multiple facets underlying the pathology of high trait anxiety and its comorbidity with depression-like behaviour and social dysfunctions.

To date, 72 % of the world's population has received at least one COVID-19 vaccination. The number of antibodies produced by some individuals is exponentially higher than in others, for various mostly unknown reasons. This variation causes great diversity in the future susceptibility to infection by the original or variants of the SARS-CoV-2 virus. The following study investigated whether individuals were able to estimate the strength of their antibody response after their COVID-19 vaccinations. 166 recently vaccinated participants provided a blood sample for determination of antibody titers. Participants were asked to estimate how many antibodies they thought they had produced, and were further asked how protected they felt from COVID-19 due to vaccination. Both self-rated antibody levels, and feelings of protection against COVID-19 were significantly related to their actual IgG spike antibody titers, after controlling for age, days since vaccination, BMI and cross vaccination. These results suggest that individuals may have a form of "immune interoception" which relates to their response to their COVID-19 vaccination.

Peripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer's disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory insults that take place outside the central nervous system. Herein, we define acute inflammatory insults as an immune challenge in the form of pathogen exposure (e.g., viral infection) or tissue damage (e.g., surgery) that causes a large, yet time-limited, inflammatory response. We provide an overview of the clinical and translational research that has examined the connection between acute inflammatory insults and Alzheimer's disease, focusing on three categories of peripheral inflammatory insults that have received considerable attention in recent years: acute infection, critical illness, and surgery. Additionally, we review immune and neurobiological mechanisms which facilitate the neural response to acute inflammation and discuss the potential role of the blood-brain barrier and other components of the neuro-immune axis in Alzheimer's disease. After highlighting the knowledge gaps in this area of research, we propose a roadmap to address methodological challenges, suboptimal study design, and paucity of transdisciplinary research efforts that have thus far limited our understanding of how pathogen- and damage-mediated inflammatory insults may contribute to Alzheimer's disease. Finally, we discuss how therapeutic approaches designed to promote the resolution of inflammation may be used following acute inflammatory insults to preserve brain health and limit progression of neurodegenerative pathology.

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with "brain fog," arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

Findings from numerous laboratories and across neuroimaging modalities have consistently shown that exogenous administration of cytokines or inflammatory stimuli that induce cytokines disrupts circuits and networks involved in motivation and motor activity, threat detection, anxiety, and interoceptive and emotional processing. While inflammatory effects on neural circuits and relevant behaviors may represent adaptive responses promoting conservation of energy and heightened vigilance during immune activation, chronically elevated inflammation may contribute to symptoms of psychiatric illnesses. Indeed, biomarkers of inflammation such as cytokines and acute phase reactants are reliably elevated in a subset of patients with unipolar or bipolar depression, anxiety-related disorders, and schizophrenia and have been associated with differential treatment responses and poor clinical outcomes. A growing body of literature also describes higher levels of endogenous inflammatory markers and altered, typically lower functional or structural connectivity within these circuits in association with transdiagnostic symptoms such as anhedonia and anxiety in psychiatric and at-risk populations. This review presents recent evidence that inflammation and its effects on the brain may serve as one molecular and cellular mechanism of dysconnectivity within anatomically and/or functionally connected cortical and subcortical regions in association with transdiagnostic symptoms. We also discuss the need to establish reproducible methods to assess inflammation-associated dysconnectivity in relation to behavior for use in translational studies or biomarker-driven clinical trials for novel pharmacological or behavioral interventions targeting inflammation or its effects on the brain.

The long-term effects of cyclooxygenase 1 and 2 (COX-1/2) inhibitors are usually tested in terms of the periphery of the organism. Therefore, we studied the effects of SC560 (selective COX-1 inhibitor) and celecoxib (selective COX-2 inhibitor) on the activity of brain monoaminergic systems and animal behaviour. Additionally, we tested the effect of these inhibitors during inflammation. We have observed that long-term administration of celecoxib reduces the activity of the noradrenergic system, increases the activity of dopaminergic and serotonergic systems, increases locomotor activity, and enhances the exploratory behaviour of rats. Administration of SC560 also increases the activity of dopaminergic and serotonergic systems but reduces locomotor activity and impairs the exploratory behaviour of rats. The mechanism responsible for decreased activity of the noradrenergic system may be related to the weakening of activity of the positive feedback loop between the paraventricular nucleus and coeruleus locus. We suggest that the effect of used inhibitors on the dopaminergic system is associated with a possible increase in anandamide concentration and its effect on dopamine reuptake in synaptic clefts. It also appears that cyclooxygenase peroxidase activity may play a role in this process. In turn, changes in the activity of the serotonergic system may be related to the activity of indoleamine-2,3-dioxygenase, which decreases because of the decreased concentration of pro-inflammatory compounds. We believe that behavioural changes induced by COX inhibitors are the result of the modified activity of monoaminergic CNS systems in the brainstem, hypothalamus, and medial prefrontal cortex.

Sepsis associated encephalopathy (SAE) is a common but poorly understood complication during sepsis. Currently, there are no preventive or therapeutic agents available for this neurological disorder. The present study was designed to determine the potential protective effects of β-patchoulene (β-PAE) in a mouse model of SAE and explore the putative mechanisms underpinning the beneficial effects.

SAE was induced in C57BL/6 mice by cecal ligation and puncture(CLP). Mice were administrated with β-PAE or saline by intra-cerebral ventricle(i.c.v) injection immediately after CLP surgery. The inhibitory avoidance tests and open field tests were performed at 24h, 48h and 7days after procedures. Cytokines expression, oxidative parameters, microglia polarization and apoptosis in the brain tissue were assessed. Sirt1, Nrf2, HO-1and cleaved-caspase3 expression in hippocampus was determined by western-blotting. Further, serum cytokines expression and spleen lymphocytes apoptosis were evaluated, and survival study was performed.

Septic mice suffered severe cognitive decline following CLP as evidenced by decreased memory latency time and lower frequency of line crossing in the behavioral tests. A high dose of β-PAE(1mg/kg) improved the cognitive impairment in SAE mice, which was accompanied by reduced cytokines expression and oxidative stress. Immunofluorescence assay showed that β-PAE inhibited the expression of Iba-1 and iNOS in microglia. The mechanistic study indicated that β-PAE could promote the nuclear expression of Sirt1/Nrf2 and enhance cytoplasmic HO-1 expression. Furthermore, i.c.v administration of β-PAE decreased the expression of serum cytokines and apoptosis in the spleen, thus leading to an improved 7-day survival of septic mice. Finally, blockade of Nrf2 activation with ML385 largely mitigated the protective effects of β-PAE on the cognitive function, neuroinflammation and survival in SAE mice.

In this study, we found that β-PAE significantly altered sepsis induced neuroinflammation and microglia activation, thus reversed the cognitive decline and improved the peripheral immune function. The neuroprotective effects were possibly mediated by the activation of Sirt1/Nrf2/HO-1 pathway. β-PAE might serve as a promising therapeutic agent for SAE prevention and treatment.

Sickness behavior was conceptualized initially as the behavioral counterpart of the fever response to infectious pathogens. It helps to raise body temperature to its higher setpoint and to maintain it at this new level and it has the additional benefit of enabling a weakened organism to protect itself from other dangers. The discovery of the behavioral effects of proinflammatory cytokines produced by activated immune cells provided a cellular and molecular basis to this phenomenon. The administration of cytokines or cytokine inducers like lipopolysaccharide to healthy rodents allowed to reveal the similarities and differences between inflammation-induced sickness behavior and the fever response. It also led to the understanding of how the inflammatory response that is triggered at the periphery can propagate into the brain and induce the behavioral manifestations of sickness. At the behavioral level, the demonstration that sickness behavior is the expression of a motivational state that reorganizes perception and action in face of a microbial pathogen just like fear in face of a predator appeared at first glance to strengthen the adaptive value of this behavior. However, all aspects of sickness behavior are not always favorable for the organism. This is the case for anorexia that is beneficial in the context of bacterial infection but detrimental in the context of viral infection. In addition, studies of sickness behavior in natural conditions revealed that like any other defensive behavior, sickness behavior requires trade-offs between its survival benefits for the sick individual and the costs incurred especially in the context of gregarious groups. Thanks to these studies, evidence is emerging that sickness behavior is much more variable in its expression than initially thought, and that part of this variability depends not only on the pathogen and the social context in which the infection develops but also on individual factors including species, sex, age, nutrition, and physiological status.

In recent years, it has been convincingly demonstrated that acute brain injury may cause severe cardiac complications-such as neurogenic stress cardiomyopathy (NSC), a specific form of takotsubo cardiomyopathy. The pathophysiology of these brain-heart interactions is complex and involves sympathetic hyperactivity, activation of the hypothalamic-pituitary-adrenal axis, as well as immune and inflammatory pathways. There have been great strides in our understanding of the axis from the brain to the heart in patients with isolated acute brain injury and more specifically in patients with stroke. On the other hand, in patients with NSC, research has mainly focused on hemodynamic dysfunction due to arrhythmias, regional wall motion abnormality, or left ventricular hypokinesia that leads to impaired cerebral perfusion pressure. Comparatively little is known about the underlying secondary and delayed cerebral complications. The aim of the present review is to describe the stroke-heart-brain axis and highlight the main pathophysiological mechanisms leading to secondary and delayed cerebral injury in patients with concurrent hemorrhagic or ischemic stroke and NSC as well as to identify further areas of research that could potentially improve outcomes in this specific patient population.

Mounting evidence shows that the complex gut microbial ecosystem in the human gastrointestinal (GI) tract regulates the physiology of the central nervous system (CNS) via microbiota and the gut-brain (MGB) axis. The GI microbial ecosystem communicates with the brain through the neuroendocrine, immune, and autonomic nervous systems. Recent studies have bolstered the involvement of dysfunctional MGB axis signaling in the pathophysiology of several neurodegenerative, neurodevelopmental, and neuropsychiatric disorders (NPDs). Several investigations on the dynamic microbial system and genetic-environmental interactions with the gut microbiota (GM) have shown that changes in the composition, diversity and/or functions of gut microbes (termed "gut dysbiosis" (GD)) affect neuropsychiatric health by inducing alterations in the signaling pathways of the MGB axis. Interestingly, both preclinical and clinical evidence shows a positive correlation between GD and the pathogenesis and progression of NPDs. Long-term GD leads to overstimulation of hypothalamic-pituitary-adrenal (HPA) axis and the neuroimmune system, along with altered neurotransmitter levels, resulting in dysfunctional signal transduction, inflammation, increased oxidative stress (OS), mitochondrial dysfunction, and neuronal death. Further studies on the MGB axis have highlighted the significance of GM in the development of brain regions specific to stress-related behaviors, including depression and anxiety, and the immune system in the early life. GD-mediated deregulation of the MGB axis imbalances host homeostasis significantly by disrupting the integrity of the intestinal and blood-brain barrier (BBB), mucus secretion, and gut immune and brain immune functions. This review collates evidence on the potential interaction between GD and NPDs from preclinical and clinical data. Additionally, we summarize the use of non-therapeutic modulators such as pro-, pre-, syn- and post-biotics, and specific diets or fecal microbiota transplantation (FMT), which are promising targets for the management of NPDs.

Both psychosocial and physical environmental stressors have been linked to chronic mental health and chronic medical conditions. The psycho-immune-neuroendocrine (PINE) network details metabolomic pathways which are responsive to varied stressors and link chronic medical conditions with mental disorders, such as major depressive disorder via a network of pathophysiological pathways. The primary objective of this review is to explore evidence of relationships between airborne particulate matter (PM, as a concrete example of a physical environmental stressor), the PINE network and chronic non-communicable diseases (NCDs), including mental health sequelae, with a view to supporting the assertion that physical environmental stressors (not only psychosocial stressors) disrupt the PINE network, leading to NCDs. Biological links have been established between PM exposure, key sub-networks of the PINE model and mental health sequelae, suggesting that in theory, long-term mental health impacts of PM exposure may exist, driven by the disruption of these biological networks. This disruption could trans-generationally influence health; however, long-term studies and information on chronic outcomes following acute exposure event are still lacking, limiting what is currently known beyond the acute exposure and all-cause mortality. More empirical evidence is needed, especially to link long-term mental health sequelae to PM exposure, arising from PINE pathophysiology. Relationships between physical and psychosocial stressors, and especially the concept of such stressors acting together to impact on PINE network function, leading to linked NCDs, evokes the concept of syndemics, and these are discussed in the context of the PINE network.

The will to live and the ability to maintain one's well-being are crucial for survival. Yet, almost a million people die by suicide globally each year (Aleman and Denys, 2014), making premature deaths due to suicide a significant public health problem (Saxena et al., 2013). The expression of suicidal behaviors is a complex phenotype with documented biological, psychological, clinical, and sociocultural risk factors (Turecki et al., 2019). From a brain disease perspective, suicide is associated with neuroanatomical, neurophysiological, and neurochemical dysregulations of brain networks involved in integrating and contextualizing cognitive and emotional regulatory behaviors. From a symptom perspective, diagnostic measures of dysregulated mood states like major depressive symptoms are associated with over sixty percent of suicide deaths worldwide (Saxena et al., 2013). This paper reviews the neurobiological and clinical phenotypic correlates for mood dysregulations and suicidal phenotypes. We further propose machine learning approaches to integrate neurobiological measures with dysregulated mood symptoms to elucidate the role of inflammatory processes as neurobiological risk factors for suicide.