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Neuroinflammation, particularly in the dorsolateral prefrontal cortex, is well-established in a subset of people with schizophrenia, with significant increases in inflammatory markers including several cytokines. Yet the cause(s) of cortical inflammation in schizophrenia remains unknown. Clues as to potential microenvironmental triggers and/or intracellular deficits in immunoregulation may be gleaned from looking further upstream of effector immune molecules to transcription factors that control inflammatory gene expression. Here, we focus on the ‘master immune regulator’ nuclear factor kappa B (NF-κB) and review evidence in support of NF-κB dysregulation causing or contributing to neuroinflammation in patients. We discuss the utility of ‘immune biotyping’ as a tool to analyse immune-related transcripts and proteins in patient tissue, and the insights into cortical NF-κB in schizophrenia revealed by immune biotyping compared to studies treating patients as a single, homogenous group. Though the ubiquitous nature of NF-κB presents several hurdles for drug development, targeting this key immunoregulator with novel or repurposed therapeutics in schizophrenia is a relatively underexplored area that could aid in reducing symptoms of patients with active neuroinflammation.

Skeletal muscle dysfunction may contribute to the progression and severity of amyotrophic lateral sclerosis (ALS). In the present study, we characterized the skeletal muscle pathophysiology in an inducible transgenic mouse model (rNLS8) that develops a TAR-DNA binding protein (TDP-43) proteinopathy and ALS-like neuropathology and disease progression; representative of >90% of all familial and sporadic ALS cases. As we previously observed elevated levels of miR-23a in skeletal muscle of patients with familial and sporadic ALS, we also investigated the effect of miR-23a suppression on skeletal muscle pathophysiology and disease severity in rNLS8 mice. Five weeks after disease onset TDP-43 protein accumulation was observed in tibialis anterior (TA), quadriceps (QUAD) and diaphragm muscle lysates and associated with skeletal muscle atrophy. In the TA muscle TDP-43 was detected in muscle fibres that appeared atrophied and angular in appearance and that also contained β-amyloid aggregates. These fibres were also positive for neural cell adhesion molecule (NCAM), but not embryonic myosin heavy chain (eMHC), indicating TDP-43/ β-amyloid localization in denervated muscle fibres. There was an upregulation of genes associated with myogenesis and NMJ degeneration and a decrease in the MURF1 atrophy-related protein in skeletal muscle. Suppression of miR-23a impaired rotarod performance and grip strength and accelerated body weight loss during early stages of disease progression. This was associated with increased AchRα mRNA expression and decreased protein levels of PGC-1α. The TDP-43 proteinopathy-induced impairment of whole body and skeletal muscle functional performance is associated with muscle wasting and elevated myogenic and NMJ stress markers. Suppressing miR-23a in the rNLS8 mouse model of ALS contributes to an early acceleration of disease progression as measured by decline in motor function.

BackgroundCancer-related cognitive impairment (CRCI) has been reported in cancer survivors 20 years or more after cancer treatment, and has been associated with sustained increases in circulating inflammatory biomarkers. One of the major risk factors for CRCI is chemotherapy, and preclinical studies typically examine the impact of chemotherapy in cancer naïve mice to evaluate potential mechanisms However, clinical evaluation of the long-term effects of chemotherapy cannot avoid the potential cumulative impact of preceding factors on the brain including the cancer itself and cancer surgery. MethodsTo evaluate the cumulative impact of cancer-related factors on cognitive impairment and hippocampal cytokine expression, we evaluated the effect of paclitaxel chemotherapy vs. placebo on a background of 67NR mammary carcinoma and surgical resection of the primary tumour in mice. Memory was assessed using the Y maze test and novel object/novel place recognition test. Changes in hippocampal pro-inflammatory and anti-inflammatory cytokines, microglia and neuron markers were assessed using qRT-PCR. Results Cancer and cancer surgery was sufficient to induce long-term memory impairment and sustained increases in hippocampal pro-inflammatory cytokines. Paclitaxel prolonged spatial memory impairment in the Y maze test and exacerbated hippocampal Il6 and Tnfa mRNA expression compared with placebo treatment. ConclusionsThese findings suggest that cancer and cancer surgery can sensitise the brain to an exaggerated neuroinflammatory response to chemotherapy, and may contribute to sustained chemotherapy-induced cognitive impairment observed in cancer survivors.

ObjectiveSince the first report of CHCHD10 gene mutations in amyotrophiclateral sclerosis (ALS)/frontotemporaldementia (FTD) patients, genetic variation in CHCHD10 has been inconsistently linked to disease. A pathological assessment of the CHCHD10 protein in patient neuronal tissue also remains to be reported. We sought to characterise the genetic and pathological contribution of CHCHD10 to ALS/FTD in Australia.MethodsWhole-exome and whole-genome sequencing data from 81 familial and 635 sporadic ALS, and 108 sporadic FTD cases, were assessed for genetic variation in CHCHD10. CHCHD10 protein expression was characterised by immunohistochemistry, immunofluorescence and western blotting in control, ALS and/or FTD postmortem tissues and further in a transgenic mouse model of TAR DNA-binding protein 43 (TDP-43) pathology.ResultsNo causal, novel or disease-associated variants in CHCHD10 were identified in Australian ALS and/or FTD patients. In human brain and spinal cord tissues, CHCHD10 was specifically expressed in neurons. A significant decrease in CHCHD10 protein level was observed in ALS patient spinal cord and FTD patient frontal cortex. In a TDP-43 mouse model with a regulatable nuclear localisation signal (rNLS TDP-43 mouse), CHCHD10 protein levels were unaltered at disease onset and early in disease, but were significantly decreased in cortex in mid-stage disease.ConclusionsGenetic variation in CHCHD10 is not a common cause of ALS/FTD in Australia. However, we showed that in humans, CHCHD10 may play a neuron-specific role and a loss of CHCHD10 function may be linked to ALS and/or FTD. Our data from the rNLS TDP-43 transgenic mice suggest that a decrease in CHCHD10 levels is a late event in aberrant TDP-43-induced ALS/FTD pathogenesis.

The impact of psychosocial factors on cancer is established from clinical studies. These findings offer novel points of intervention to improve patient wellbeing and survival using both behavioral and pharmacologic strategies. Pre-clinical in vivo models of cancer have been essential tools for defining a mechanistic understanding of how psychosocial factors impact cancer. Their use has allowed discovery and characterization of bi-directional signalling pathways that transmit information between the brain and the body to affect cancer progression. In vivo cancer models have demonstrated that signalling from the brain has direct effects on tumor cells, and also modulates anti-cancer immunity and the tumor microenvironment to impact cancer progression. By describing the molecular and cellular mechanisms of psychosocial influences on cancer, preclinical studies are now motivating and guiding prospective clinical studies to evaluate novel biobehavioral and pharmacologic interventions to slow cancer progression and improve treatment response.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, 'rNLS8', mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.

© Copyright © 2020 Chang, Chung, Lawther, Ziegler, Shackleford, Sloan and Walker. Inflammation has been proposed to play a causal role in chemobrain which—if true—would represent an opportunity to repurpose existing anti-inflammatory drugs for the prevention and treatment of chemobrain. Here, we show that the chemoagent paclitaxel induces memory impairment and anhedonia in mice within 24 h of treatment cessation, but inflammation is not present until 2 weeks after treatment. We find no evidence of brain inflammation as measured by cytokine analysis at any time point. Furthermore, treating with aspirin to block inflammation did not affect paclitaxel-induced memory impairment. These findings suggest that inflammation may not be responsible for memory impairment induced by paclitaxel. These results contrast with recent findings of a causal role for inflammation in cancer-induced memory deficits in mice that were prevented by treatment with oral aspirin, suggesting that cognitive impairment in cancer patients undergoing treatment may arise from multiple convergent mechanisms.

IntroductionCancer-related cognitive impairment (CRCI) is a distressing and disabling side-effect of cancer treatments affecting up to 75% of patients. For some patients, their cognitive impairment may be transient, but for a subgroup, these symptoms can be long-standing and have a major impact on the quality of life. This paper describes the protocol for a study: (1) to assess the feasibility of collecting longitudinal data on cognition via self-report, neuropsychological testing, peripheral markers of inflammation and neuroimaging and (2) to explore and describe patterns of cancer-related cognitive impairment over the course of treatment and recovery in patients with newly diagnosed, aggressive lymphoma undergoing standard therapy with curative intent.Methods and analysisThis is a prospective, longitudinal, feasibility study in which 30 newly diagnosed, treatment-naive patients with aggressive lymphoma will be recruited over a 12-month period. Patients will complete comprehensive assessments at three time points: baseline (time 1, pre-treatment) and two post-baseline follow-up assessments (time 2, mid-treatment and time 3, 6–8 weeks post-treatment completion). All patients will be assessed for self-reported cognitive difficulties and objective cognitive function using Stroop Colour and Word, Trail Making Test Part A and B, Hopkins Verbal Learning Test-Revised, Controlled Oral Word Association and Digit Span. Blood cell-based inflammatory markers and neuroimaging including a positron emission tomography (PET) with 18F-labelled fluoro-2-deoxyglucose (18F-FDG) and CT (18F-FDG-PET/CT) and a MRI will explore potential inflammatory and neuroanatomical or functional mechanisms and biomarkers related to CRCI. The primary intent of analysis will be to assess the feasibility of collecting longitudinal data on cognition using subjective reports and objective tasks from patients during treatment and recovery for lymphoma. These data will inform the design of a larger-scale investigation into the patterns of cognitive change over the course of treatment and recovery, adding to an underexplored area of cancer survivorship research.Ethics and disseminationEthical approval has been granted by Austin Health Human Rights Ethics Committee (HREC) in Victoria Australia. Peer reviewed publications and conference presentations will report the findings of this novel study.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12619001649101).

Publisher's version (útgefin grein), Background: Cancer patients have a highly increased risk of psychiatric disorders following diagnosis, compared with cancer-free individuals. Inflammation is involved in the development of both cancer and psychiatric disorders. The role of non-steroidal anti-inflammatory drugs (NSAIDs) in the subsequent risk of psychiatric disorders after cancer diagnosis is however unknown. Methods: We performed a cohort study of all patients diagnosed with a first primary malignancy between July 2006 and December 2013 in Sweden. Cox proportional hazards models were used to assess the association of NSAID use during the year before cancer diagnosis with the risk of depression, anxiety, and stress-related disorders during the first year after cancer diagnosis. Results: Among 316,904 patients identified, 5613 patients received a diagnosis of depression, anxiety, or stress-related disorders during the year after cancer diagnosis. Compared with no use of NSAIDs, the use of aspirin alone was associated with a lower rate of depression, anxiety, and stress-related disorders (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.81 to 0.97), whereas the use of non-aspirin NSAIDs alone was associated with a higher rate (HR, 1.24; 95% CI, 1.15 to 1.32), after adjustment for sociodemographic factors, comorbidity, indications for NSAID use, and cancer characteristics. The association of aspirin with reduced rate of depression, anxiety, and stress-related disorders was strongest for current use (HR, 0.84; 95% CI, 0.75 to 0.93), low-dose use (HR, 0.88; 95% CI, 0.80 to 0.98), long-term use (HR, 0.84; 95% CI, 0.76 to 0.94), and among patients with cardiovascular disease (HR, 0.81; 95% CI, 0.68 to 0.95) or breast cancer (HR, 0.74; 95% CI, 0.56 to 0.98). Conclusion: Pre-diagnostic use of aspirin was associated with a decreased risk of depression, anxiety, and stress-related disorders during the first year following cancer diagnosis., This study was supported by grants awarded to FF by Swedish Cancer Society (No. CAN 2017/322) and the Swedish Research Council for Health, Working Life and Welfare (No. 2017-00531), to KH by China Scholarship Council (No. 201806240005), to ES by National Health and Medical Research Council (GNT1147498) and National Breast Cancer Foundation (IIRS-20 to 025), and to AW by the National Breast Cancer Foundation (PF-15 to 014). The researchers were independent of the funding agencies. The funding bodies have no role in the design of the study or collection, analysis, and interpretation of data or in writing the manuscript. Open access funding provided by Karolinska Institute.

Signaling through β-adrenergic receptors drives cancer progression and β-blockers are being evaluated as a novel therapeutic strategy to prevent metastasis. Orthotopic mouse models of breast cancer show that β-adrenergic signaling induced by chronic stress accelerates metastasis, and that β2-adrenergic receptors on tumor cells are critical for this. Endogenous catecholamines are released during chronic stress: norepinephrine from the adrenal medulla and sympathetic nerves, and epinephrine from the adrenal medulla. β2-adrenergic receptors are much more sensitive to epinephrine than to norepinephrine. To determine if epinephrine is necessary in the effects of stress on cancer progression, we used a denervation strategy to eliminate circulating epinephrine, and quantified the effect on metastasis. Using both human xenograft and immune-intact murine models of breast cancer, we show that circulating epinephrine is dispensable for the effects of chronic stress on cancer progression. Measured levels of circulating norepinephrine were sufficiently low that they were unlikely to influence β2-adrenergic signaling, suggesting a possible role for norepinephrine release from sympathetic nerve terminals.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, ‘rNLS’, mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS mice. Finally, riluzole treatment beginning after disease onset in rNLS mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in rNLS mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways directly related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.Significance StatementAccumulation of cytoplasmic TDP-43 protein is the hallmark pathology of ALS. Riluzole is the most widely used drug for ALS treatment, but provides only a short extension of lifespan. We demonstrate here in the rNLS mouse model, which mimics TDP-43 pathology, that riluzole does not ameliorate progressive alterations in motor strength and coordination, muscle atrophy, glutamate receptor levels, or TDP-43 protein levels and solubility, and does not prolong animal survival. Riluzole similarly did not affect decreased levels of glutamate receptor subunits GluA2/GluA3 in rNLS mice. The inability of riluzole to rescue pathological or phenotypic changes in this TDP-43 model provides further impetus for the discovery of improved therapies targeting the key drivers of ALS pathogenesis.

Cancer patients with non-central nervous system tumors often suffer from cognitive impairment. While chemotherapy has long been attributed as the cause of these memory, learning and concentration difficulties, we recently observed cognitive impairment in cancer patients prior to treatment. This suggests the cancer alone may be sufficient to induce cognitive impairment, however the mechanisms are unknown. Here, we show that we can experimentally replicate the clinical phenomenon of cancer-associated cognitive impairment and we identify inflammation as a causal mechanism. We demonstrate that a peripheral tumor is sufficient to induce memory loss. Using an othotopic mouse model of breast cancer, we found that mice with 4T1.2 or EO771 mammary tumors had significantly poorer memory than mice without tumors. Memory impairment was independent of cancer-induced sickness behavior, which was only observed during the later stage of cancer progression in mice with high metastatic burden. Tumor-secreted factors were sufficient to induce memory impairment and pro-inflammatory cytokines were elevated in the plasma of tumor-bearing mice. Oral treatment with low-dose aspirin completely blocked tumor-induced memory impairment without affecting tumor-induced sickness or tumor growth, demonstrating a causal role for inflammation in cognitive impairment. These findings suggest that anti-inflammatories may be a safe and readily translatable strategy that could be used to prevent cancer-associated cognitive impairment in patients.

Pneumonia represents a leading cause of death. Recently, a novel treatment strategy for pneumonia has involved enhancing the host pulmonary innate immune response by pre-exposure to aerosolized toll-like receptor (TLR)9 and TLR2/6 agonists, known as O/P. O/P inhalation in mice has been demonstrated to prime the lung inflammatory response, and thus increase survival against subsequent pneumonia infection while producing barely detectable increases in systemic cytokines. Here, we examined the safety of O/P treatment when used in mice that are inflamed systemically. Swiss-Webster mice were treated with two doses of aerosolized O/P (1x or 8x) vs phosphate buffered saline (PBS) either immediately before intraperitoneal injection of 0.1 mg/kg lipopolysaccharide (LPS) or PBS (equivolume) or 2 hours after. Sickness responses (reduced body weight, food intake, activity and social interaction) were examined at 2 and 5.5 h post-treatment. Immediately following behavioral testing, mice were euthanized, perfused with PBS, and brains, spleens, livers and lungs snap frozen for assessment of pro-inflammatory cytokine mRNAs. While O/P treatment alone increased lung IL-1β, IFNγ and TNF-α, no such effects were observed in the brain, spleen or liver. Furthermore, there was no evidence that O/P treatment administered before or after LPS had any synergizing effect to potentiate the cytokine response to LPS in any compartment measured. Supportive of these findings were the measures of sickness behaviors that did not show any increased sickness response in O/P-treated mice exposed to LPS, suggestive that the cytokine signal produced in the lungs from O/P inhalation did not propagate to the brain and synergize with LPS-induced neuroinflammation. These findings support the safety of the use of O/P inhalation as a preventative measure against pneumonia and demonstrate a unique ability of the lungs to compartmentalize pulmonary inflammation and limit propagation of the cytokine signal to the brain.

Comorbid depression and chronic pain are highly prevalent in individuals suffering from physical illness. Here, we critically examine the possibility that inflammation is the common mediator of this comorbidity, and we explore the implications of this hypothesis. Inflammation signals the brain to induce sickness responses that include increased pain and negative affect. This is a typical and adaptive response to acute inflammation. However, chronic inflammation induces a transition from these typical sickness behaviors into depression and chronic pain. Several mechanisms can account for the high comorbidity of pain and depression that stem from the precipitating inflammation in physically ill patients. These mechanisms include direct effects of cytokines on the neuronal environment or indirect effects via downregulation of G protein–coupled receptor kinase 2, activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase that generates neurotropic kynurenine metabolites, increased brain extracellular glutamate, and the switch of GABAergic neurotransmission from inhibition to excitation. Despite the existence of many neuroimmune candidate mechanisms for the co-occurrence of depression and chronic pain, little work has been devoted so far to critically assess their mediating role in these comorbid symptoms. Understanding neuroimmune mechanisms that underlie depression and pain comorbidity may yield effective pharmaceutical targets that can treat both conditions simultaneously beyond traditional antidepressants and analgesics.

Neonatal lipopolysaccharide (LPS) exposure increases anxiety-like behaviour in adulthood. Our current aim was to examine whether neonatal LPS exposure is associated with changes in microglial activation, and whether these alterations correspond with alterations in behaviour. In adulthood, LPS-treated animals exhibited significantly increased anxiety-like behaviour and hippocampal microglial activation. The efficacy of the LPS challenge was confirmed by increased neonatal plasma corticosterone and tyrosine hydroxylase (TH) phosphorylation in the adrenal medulla. These findings suggest a neuroimmune pathway which may underpin the long-term behavioural and neuroendocrine changes following neonatal infection.

"Perinatal programming" is a phenomenon describing how early life environmental conditions can produce long-term physiological alterations that either enhance or inhibit adaptive functioning. Previously, we have demonstrated that neonatal exposure to lipopolysaccharide (LPS) predisposes to anxiety-like behaviour in later life, which was associated with changes to the neuroendocrine response to stress. Given the known interactions between the neuroendocrine and neuroimmune systems, here we investigated whether neonatal exposure to a bacterial mimetic alters neuroimmune responses to acute stress in adulthood. Male and female Wistar rats were administered LPS (0.05 mg/kg, i.p.), or saline vehicle (equivolume) on days 3 and 5 post-partum. One group of rats was euthanised following early life treatment to assess immediate hypothalamic-pituitary-adrenal axis and central cytokine responses to treatment. A second group was assessed in adulthood (85 days) following exposure to either a "stress" (30-min restraint) or "no stress" condition. Blood was collected from all rats at baseline, 30, 60 and 90 min after "stress", "no stress" treatment to assess peripheral corticosterone responses, and brains were collected 180 min following baseline to assess hippocampal content of interleukin-1β (IL-1β), tumour necrosis factor-α (TNFα) and IL-6 protein. Radioimmunoassay revealed that neonatal LPS treatment resulted in a prolonged corticosterone response to stress in adulthood compared to controls (p 0.05). Enzyme-linked-immunosorbent assays revealed no group differences in hippocampal IL-6 content. However, brain IL-1β and TNFα protein concentrations were significantly greater in rats neonatally exposed to LPS and then exposed to stress in adulthood when compared to all other groups (p 0.05). These findings suggest that early life bacterial toxin exposure results in a prolonged neuroendocrine response to acute stress in adulthood, which may be a consequence of increased release of IL-1β and TNFα in the brain.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article has been retracted at the request of the authors.The authors became aware of an issue with incorrect loading control images being presented and are now retracting the article in the interests of maintaining their publication standards and those of the journal. The authors maintain that these presentational errors do not impact the underlying scientific findings of the article, some of which have been verified in other laboratories.Figure 4 contains incorrect loading control images of SOD1G93A mouse. The b-actin images blots presented are SOD1G93A rat b-actin bands that were accidentally used when compiling the image for publication. Similarly, in Figure 1 the samples were run in two separate experiments with the controls split across the two blots. The b-actin for one set of controls was accidentally used for the second controls. The authors state that quantifications were performed using the correct b-actin bands.In figure 1, concerns were raised that each of the panels had 13 lanes except for the ATF panel which appeared to have only twelve lanes. The authors state that the ATF6 panel has 13 lanes, but last two control lanes of the gel have no signal, making it difficult to accurately align the end part of the gel correctly for display in the figure.

While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms) of chemotherapy include (i) cognitive deficiencies such as problems with attention, memory and executive functioning; (ii) fatigue and motivational deficit; and (iii) neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence, neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs) activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

Chronic pain frequently co-occurs with major depressive disorder but the mechanisms are poorly understood. We investigated the contribution of indoleamine 2,3-dioxygenase-1 (IDO1), a rate-limiting enzyme in the conversion of tryptophan to neurotoxic metabolites, to this comorbidity using the spared nerve injury (SNI) model of neuropathic pain in mice. SNI resulted in unilateral mechanical allodynia, reduced social interaction, and increased immobility in the forced swim test without changes in locomotor activity. These findings indicate SNI-induced pain and comorbid depression-like behavior. These behavioral responses were accompanied by increases in plasma kynurenine/tryptophan ratios and increased expression of Ido1 and Il1b mRNA in the liver. Interestingly, SNI did not induce detectable changes in spinal cord or brain Ido1 mRNA levels. SNI was associated with spinal cord inflammatory activity as evidenced by increased Il1b mRNA expression. The SNI-induced increase of liver Ido1 and Il1b mRNA was abrogated by intrathecal administration of the IL-1 inhibitor IL-1RA. Intrathecal IL-1RA also inhibited both mechanical allodynia and depression-like behavior. We also show that Ido1 is required for the development of depression-like behavior because Ido1 −/− mice do not develop increased immobility in the forced swim test or decreased social exploration in response to SNI. Mechanical allodynia was similar in WT and Ido1 −/− mice. In conclusion, our findings show for the first time that neuropathic pain is associated with an increase of Ido1 in liver, but not brain, downstream of spinal cord IL-1β signaling and that Ido1 mediates comorbid depression. Moreover, comorbidity of neuropathic pain and depression are only partially mediated by a common mechanism because mechanical hyperalgesia develops independently of Ido1 .

Sleep is promoted by numerous pathways in the central nervous system, including factors involved in brain metabolism (e.g., adenosine) and factors involved in immune function (e.g., cytokines). Current mathematical models of sleep regulation do not include any (neuro) immune-related factors and therefore cannot be used to explain or predict effects of inflammation or normal cytokine function on sleep. We have previously developed a receptor-ligand model of the adenosine system, which accurately predicts human sleep patterns, daily changes in extracellular adenosine concentrations in the central nervous system, and cognitive performance under normal or sleep-deprived conditions. Here, we develop an extended mathematical model that includes cytokines that are known to be actively involved in regulating human sleep: IL-1, IL-6, and TNF-alpha. We fit the new model to published data from three conditions: (i) Normal daily variations in cytokine concentrations in healthy individuals. (ii) Changes in cytokine concentrations during and following sleep deprivation in healthy individuals. (iii) Changes in sleep duration and cytokine concentrations during infection. After fitting, the model is used to predict how sleep and cognitive performance would be expected to vary under conditions of sleep restriction and recovery during an active infection. This model provides a novel quantitative framework for studying links between sleep regulation, cognition, and immune function.

Inflammation may contribute to the adverse effects of chemotherapy on cognition and affect, (chemobrain). Here, we tested the hypothesis that the chemoagent paclitaxel induces sustained changes in cognitive and affective-like behavior that correspond with increased inflammation in mice. We treated BALB/c mice with paclitaxel (10 mg/kg i.p.) or vehicle every second day over two weeks. We conducted a battery of tests to examine memory, sickness and affect at 24 h and 14 days after treatment. Paclitaxel significantly reduced memory and increased depression-like behavior as measured by novel object recognition and sucrose preference at both timepoints. These effects were independent of sickness. Analysis of inflammation by ELISA showed no evidence of inflammation at 24 h, suggesting that inflammation may not be responsible. Cytotoxic effects on the brain may be responsible for these immediate behavioral changes. We confirmed that paclitaxel crosses the blood-brain barrier by HPLC, and are performing untargeted metabolomics analyses on brain tissue to examine widespread functional changes in brain metabolism and neurochemistry. Inflammation was apparent at 2 weeks, and we are confirming that inflammation is also elevated in the brain at this timepoint. These findings suggest that inflammation may be responsible for the later paclitaxel-induced cognitive and affective symptoms but cannot be responsible for the immediate effects of paclitaxel on cognition and depression-like behavior.

We have previously discovered a synergistically therapeutic combination of two Toll-like receptor ligands, an oligodeoxynucleotide (ODN) and Pam2CSK4. Aerosolization of these ligands stimulates innate immunity within the lungs to prevent pneumonia from bacterial and viral pathogens. Here we examined the safety and tolerability of this treatment in mice, and characterized the expression of biomarkers of innate immune activation. We found that neutrophils appeared in lung lavage fluid 4 h after treatment, reached a peak at 48 h, and resolved by 7 days. The peak of neutrophil influx was accompanied by a small increase in lung permeability. Despite the abundance of neutrophils in lung lavage fluid, only rare neutrophils were visible histopathologically in the interstitium surrounding bronchi and veins and none were visible in alveolar airspaces. The cytokines interleukin 6 (IL-6), tumour necrosis factor, and Chemokine (C-X-C motif) ligand 2 rose several hundred-fold in lung lavage fluid 4 h after treatment in a dose-dependent and synergistic manner, providing useful biomarkers of lung activation. IL-6 rose fivefold in serum with delayed kinetics compared to its rise in lavage fluid, and might serve as a systemic biomarker of immune activation of the lungs. The dose–response relationship of lavage fluid cytokines was preserved in mice that underwent myeloablative treatment with cytosine arabinoside to model the treatment of hematologic malignancy. There were no overt signs of distress in mice treated with ODN/Pam2CSK4 in doses up to eightfold the therapeutic dose, and no changes in temperature, respiratory rate, or behavioral signs of sickness including sugar water preference, food disappearance, cage exploration or social interaction, though there was a small degree of transient weight loss. We conclude that treatment with aerosolized ODN/Pam2CSK4 is well tolerated in mice, and that innate immune activation of the lungs can be monitored by the measurement of inflammatory cytokines in lung lavage fluid and serum.

As cancer-related symptoms are similar to those of sickness associated with inflammation, it has been proposed that they are also mediated by increased inflammatory cytokines in the brain. However, there is still limited evidence for this relationship. The current study evaluated the alternative possibility that cancer-related symptoms are associated with changes in gene expression indicative of hypoxia signaling and mitochondrial abnormalities using PCR Arrays. Mice were injected or not with heterotopic tonsil epithelial cells transfected with Ras, E6/E7 of HPV16 and were exposed or not to 3 rounds of cisplatin (5.28 mg/kg) and radiotherapy (8 Gy). Tumor-bearing mice showed increased brain and liver inflammatory cytokine mRNA expression that was associated with decreased burrowing. Chemoradiation in non-tumor-bearing mice decreased burrowing but did not induce liver or brain inflammatory cytokine expression. Chemoradiation in tumor-bearing mice reduced burrowing and attenuated liver and brain inflammation, presumably by reducing tumor volume. Both the tumor and its treatment were associated gene expression changes indicative of mitochondrial dysfunction and HIF-1 α activation in liver and brain, with evidence of an additive effect of tumor and chemoradiation on brain mitochondrial dysfunction. Although correlative at this stage, these findings indicate that targeting mitochondrial dysfunction following cancer and cancer therapy may be a strategy for prevention of cancer-related symptoms. Ongoing work is exploring whether this can be achieved without interfering with the tumor response to chemoradiation.

Depression is a common comorbid condition in substance abuse disorders. In particular, comorbidity between alcoholism and depression occurs with extremely high prevalence in the general population. Early studies investigating this dual diagnosis issue reported alcohol abuse to occur in almost a quarter of patients with affective disorders [1, 2]. Prevalence rises as high as 32 % if other substance abuse disorders are included [2]. These findings made it clear that enormous challenges lie ahead in tracing the individual etiology of substance abuse and depression, let alone their interaction. Clearly, this dilemma was to produce further difficulties in providing adequate and appropriate treatment for sufferers.

Infections during pregnancy and adolescent cannabis use have both been identified as environmental risk factors for schizophrenia. We combined these factors in an animal model and looked at their effects, alone and in combination, on serotonin 5HT1A receptor binding (5HT1AR) binding longitudinally from late adolescence to adulthood. Pregnant rats were exposed to the viral mimic poly I:C on embryonic day 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Hippocampal and cortical 5HT1AR binding was quantified autoradiographically using [3H]8-OH-DPAT, in late adolescent (PND 55), young adult (PND 65) and adult (PND 90) rats. Descendants of poly I:C treated rats showed significant increases of 15–18% in 5HT1AR in the hippocampus (CA1) compared to controls at all developmental ages. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited even greater elevations in 5HT1AR (with increases of 44, 29, and 39% at PNDs 55, 65, and 90). No effect of HU210 alone was observed. Our results suggest a synergistic effect of prenatal infection and adolescent cannabinoid exposure on the integrity of the serotoninergic system in the hippocampus that may provide the neurochemical substrate for abnormal hippocampal-related functions relevant to schizophrenia.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterised by the progressive loss of motor neurons, leading to paralysis and death within several years of onset. Although protein misfolding is a key feature of ALS, the upstream triggers of disease remain elusive. Recently, endoplasmic reticulum (ER) stress was identified as an early and central feature in ALS disease models as well as in human patient tissues, indicating that ER stress could be an important process in disease pathogenesis. One important chaperone induced by ER stress is protein disulphide isomerase (PDI), which is both upregulated and posttranslationally inhibited by S-nitrosylation in ALS. In this paper, we present evidence from studies of genetics, model organisms, and patient tissues which indicate an active role for PDI and ER stress in ALS disease processes.

The health status of an individual in adulthood is proposed to be determined by events occurring in the prenatal and early postnatal period. A common early life event proven to have long lasting effects on the developing fetus is stress, including pain. Exposure of fetal and neonatal infants to repetitive psychological (e.g., maternal stress) or physiological (e.g., pain, infection, and noise) stress during this period is proposed to alter mechanisms involved in the regulation of stress, immunological maturation, pain perception, and cognition. Such changes, which persist into adulthood, may occur via alterations in the development of the hypothalamic-pituitary-adrenal (HPA) axis. This process is typically referred to as ‘perinatal programming’. Ontogenic alterations in the development of the HPA-axis have been related to a number of adult pathologies such as cardiovascular disease, type 2 diabetes, asthma, as well as psychopathologies such as anxiety and depression. Objective: In this review, the effectiveness of complementary and alternative medicine (CAM), such as music, dietary supplements, massage and aromatherapy, in reducing perinatal stress in mothers and infants is examined. An emphasis is placed on these therapies as preventative measures which may be of value to individuals at risk of developing disease profiles associated with the consequences of adverse perinatal programming. The widening interest in perinatal programming and CAM suggests the potential for CAM to become a valuable tool in offsetting negative adult health outcomes resulting from perinatal programming associated with adverse gestational early life environments.

The RNA/DNA-binding protein, TDP-43, is the key component of ubiquitinated inclusions characteristic of amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) referred to collectively as TDP-43 proteinopathies. To further elucidate mechanisms of pathological TDP-43 processing and identify TDP-43 epitopes that could be useful as potential biomarkers of TDP-43 proteinopathies, we developed a panel of novel monoclonal antibodies (MAbs) directed at regions extending across the length of TDP-43. Here, we confirm previous observations that there is no or minimal accumulation of TDP-43 N-terminal domains in neocortical inclusions in human TDP-43 proteinopathy tissues and we identify a subset of these MAbs that are specific for human versus mouse TDP-43. Notably, one of these MAbs recognized an epitope that preferentially detected pathological TDP-43 inclusions with negligible reactivity for normal nuclear TDP-43 resembling anti-phospho-TDP-43 specific antibodies that only bind pathological TDP-43. Hence, we infer that this new MAb recognizes a phosphorylation independent but disease-specific pathologic conformation in abnormal TDP-43. These data suggest that the novel MAbs reported here will be useful for patient-oriented research as well as for studies of animal and cell-based models of TDP-43 proteinopathies including ALS and FTLD-TDP.

Ketamine, an NMDA receptor antagonist, has been shown to rapidly treat depressive-like behavior in clinical and pre-clinical studies. To date, its efficacy in treating inflammation-induced depression has not been reported. Here we demonstrate that peripheral administration of ketamine (6 mg/kg, i.p.) immediately prior to peripheral administration of lipopolysaccharide (LPS) (0.83 mg/kg, i.p.) in C57Bl/6J mice abrogates LPS-induced depressive-like behavior. LPS induced a reduction in sucrose preference and increase in immobility in the forced swim test (p NIH R01 MH079829 to R.D. and NIH R01 AG-029573 to K.W.K.

11. Postnatal exposure to a bacterial mimetic increases microglial activation and histone H3 acetylation in rats L. Sominsky , A.K. Walker , L.K. Ong , F.R. Walker , D.M. Hodgson a a Laboratory of Neuroimmunology, School of Psychology, Faculty of Science and IT, The University of Newcastle, Callaghan, NSW 2308, Australia b School of Biomedical Sciences & Pharmacy, The University of Newcastle, Australia c Priority Research Centre for Brain and Mental Health Research, University of Newcastle, Australia Hunter Medical Research Institute, Newcastle, Australia