Differential perivascular microglial activation in the deep white matter in vascular dementia developed post-stroke.

With the hypothesis that perivascular microglia are involved as neuroinflammatory components of the gliovascular unit contributing to white matter hyperintensities on MRI and pathophysiology, we assessed their status in stroke survivors who develop dementia. Immunohistochemical and immunofluorescent methods were used to assess the distribution and quantification of total and perivascular microglial cell densities in 68 brains focusing on the frontal lobe WM and overlying neocortex in post-stroke dementia (PSD), post-stroke non-dementia (PSND) and similar age control subjects. We primarily used CD68 as a marker of phagocytic microglia, as well as other markers of microglia including Iba-1 and TMEM119, and the myeloid cell marker TREM2 to assess dementia-specific changes. We first noted greater total densities of CD68+ and TREM2+ cells per mm2 in the frontal WM compared to the overlying cortex across the stroke cases and controls (p = 0.001). PSD subjects showed increased percentage of activated perivascular CD68+ cells distinct from ramified or primed microglia in the WM (p < 0.05). However, there was no apparent change in perivascular TREM2+ cells. Total densities of TREM2+ cells were only ~10% of CD68+ cells but there was high degree of overlap (>70%) between them in both the WM and the cortex. CD68 and Iba-1 or CD68 and TMEM119 markers were colocalised by ~55%. Within the deep WM, ~30% of CD68+ cells were co-localised with fragments of degraded myelin basic protein. Among fragmented CD68+ cells in adjacent WM of PSD subjects, >80% of the cells expressed cleaved caspase-3. Our observations suggest although the overall repertoire of perivascular microglial cells is not changed in the parenchyma, PSD subjects accrue more perivascular-activated CD68+ microglia rather than TREM2+ cells. This implies there is a subset of CD68+ cells, which are responsible for the differential response in perivascular inflammation within the gliovascular unit of the deep WM.

Sex differences regulate immune responses in experimental autoimmune encephalomyelitis and multiple sclerosis.

MS is an autoimmune disease of the CNS that afflicts over 2.5 million people worldwide. There are striking sex differences in the susceptibility to and progression of this disease in humans. Females are twice as likely to develop MS than males, whereas disease progression and disability is more rapid in males compared with females; however, the latter is still controversial. There is growing evidence, mainly from animal models, that innate and adaptive immune responses are different in males and females, and that this can influence the outcome of a range of diseases including infection, cancer, and autoimmunity. Since MS is an immune-mediated disease, sex differences in pathogenic immune responses may account for some of the differences in susceptibility to and progression seen in men versus women. Indeed, data from the mouse model of MS, EAE, have already provided some evidence that female mice have earlier disease onset associated with stronger Th17 responses. This review will discuss the possible immunological basis of sex differences in susceptibility and disease outcome in EAE and MS and how a better understanding of sex differences in the responses to disease-modifying therapies may lead to improved patient treatment.

Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age.

Double stranded RNA is generated during viral replication. The synthetic analogue poly I:C is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disorders including schizophrenia, autism, Parkinson's disease and Alzheimer's disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly I:C preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly I:C (1-6 kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF-α responses than poly I:C of < 500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFNß nor brain transcription of Irf7 were significantly induced by LMW poly I:C, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFNß binding of IFNAR1. In aged animals, poly I:C induced exaggerated IL-6, IL-1ß and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length-, IFNAR1- and age-dependent effects on anti-viral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.

Double stranded RNA drives innate immune responses, sickness behavior and cognitive impairment dependent on dsRNA length, IFNAR1 expression and age.

Double stranded RNA is generated during viral replication. The synthetic analog poly I:C is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disease including autism, schizophrenia, Parkinsons disease and Alzheimers disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly I:C preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly I:C (1 to 6 kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF alpha responses than poly I:C of less than 500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFN beta nor brain transcription of Irf7 were significantly induced by LMW poly I:C, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFN beta binding of IFNAR1. In aged animals, poly I:C induced exaggerated IL-6, IL-1beta and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length, IFNAR1 and age-dependent effects on antiviral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.

Competing native and invasive Anolis lizards exhibit thermal preference plasticity in opposite directions.

Invasive species have emerged as a significant problem in the age of anthropogenic change. Behavior can be key to invasive species success and is strongly affected by temperature. Therefore, knowledge of the temperature dependence of behavior is likely critical to understand invasive species dynamics and their interactions with native species. In this study, we tested for differences in thermal preference plasticity and temperature-dependent activity levels in a pair of congeneric lizards found in the United States: the invasive Anolis sagrei and the native A. carolinensis. We predicted that A. sagrei would demonstrate greater thermal preference plasticity and would utilize a higher and/or wider range of activity temperatures than A. carolinensis. Both would point to plasticity allowing A. sagrei to behaviorally exploiting thermal conditions that A. carolinensis cannot. We found that both species exhibited plasticity in thermal preference, but in opposite directions: preferred temperatures of A. carolinensis increased with acclimation temperature, while those of A. sagrei decreased. As a result, which species had a higher thermal preference changed with acclimation conditions. We saw no difference in overall field activity rates between the species, but that A. sagrei did tend to be active over a broader range of body temperatures. In sum, we found little evidence that differences in thermal preference plasticity between the species allow A. sagrei to remain active at a higher or broader temperature range than A. carolinensis. Nonetheless, the thermal preference data suggest complementary thermal preferences between the species that could promote microclimatic partitioning, though more work is required to test this idea.

Acute neuroinflammation, sickness behavior and working memory responses to acute systemic LPS challenge following noradrenergic lesion in mice.

Locus coeruleus (LC)-derived noradrenaline is important in cognition and decreases with age, but the impact of prior noradrenaline deficiency on vulnerability to inflammation-induced acute cognitive dysfunction is unclear. Here we assessed whether noradrenergic depletion, in female mice, impacted upon inflammation, locomotor activity and working memory directly after acute systemic immune challenge with bacterial lipopolysaccharide (LPS), a paradigm we have previously used to capture delirium-like acute cognitive deficits. Mice received 2 doses of the LC-selective noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg i.p.) and were challenged, 2 weeks later, with LPS (100 µg/kg i.p.). DSP-4 dramatically reduced noradrenaline concentrations and tyrosine hydroxylase-positive afferents in the frontal cortex and hippocampus. This did not significantly alter numbers of Pu.1-positive microglia, Iba1-positive microglial morphology or mRNA expression of microglia-associated gene transcripts (Tyrobp, Sall1, Cd68, Sra2, Clec7a) in the hippocampus or frontal cortex and produced modest reductions in Cx3cr1 and P2ry12. LPS induced blood and brain cytokine levels, cFOS activation and locomotor responses that were highly similar in DSP-4- and vehicle-treated mice, although LPS-induced plasma TNF-α was significantly reduced in those treated with DSP-4. Importantly, prior noradrenergic depletion did not predispose to LPS-induced T-maze working memory deficits. The data demonstrate that significant depletion of noradrenaline in the hippocampus and frontal cortex does not prompt acutely exaggerated neuroinflammation or leave the brain vulnerable to acute, transient working memory deficits upon low dose LPS challenge. These findings have implications for our understanding of the impact of systemic inflammation on the aging and vulnerable brain during septic encephalopathy and delirium.

Acute kidney injury (AKI) associated with intravenous aciclovir in adults: Incidence and risk factors in clinical practice.

OBJECTIVES: This study sought to identify the incidence of, and risk factors for, acute kidney injury (AKI) in adults treated with parenteral aciclovir. METHODS: A single-centre retrospective cohort study of prospectively acquired electronic clinical, pharmacy and laboratory data was performed with approval of the Caldicott guardian. AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria, prior to analysis of baseline patient and treatment-related risk factors. RESULTS: 269 aciclovir treatment episodes were identified in 268 patients. Overall incidence of AKI was 13%. Half of AKI episodes were KDIGO grade 2/3. In univariate analysis, AKI occurred more frequently in patients with pre-existing chronic kidney disease (CKD), diabetes, and in patients treated with higher daily doses of aciclovir. There was also a trend to increased age in patients with AKI. In a binomial logistic regression model only CKD and daily dose remained significant independent factors. CONCLUSIONS: AKI is an important side effect of parenteral aciclovir, the incidence of which is comparable to established nephrotoxic drugs such as aminoglycosides. Patients with pre-existing chronic kidney disease or receiving higher total doses are at greatest risk, reinforcing the clinical importance of appropriate dose adjustment for ideal body weight and baseline renal function.