Background: CAIDE Dementia Risk Score is the first validated tool for estimating dementia risk based on a midlife risk profile. Objectives: This observational study investigated longitudinal associations of CAIDE Dementia Risk Score with brain MRI, amyloid burden evaluated with PIB-PET, and detailed cognition measures. Methods: FINGER participants were at-risk elderly without dementia. CAIDE Risk Score was calculated using data from previous national surveys (mean age 52.4 years). In connection to baseline FINGER visit (on average 17.6 years later, mean age 70.1 years), 132 participants underwent MRI scans, and 48 underwent PIB-PET scans. All 1,260 participants were cognitively assessed (Neuropsychological Test Battery, NTB). Neuroimaging assessments included brain cortical thickness and volumes (Freesurfer 5.0.3), visually rated medial temporal atrophy (MTA), white matter lesions (WML), and amyloid accumulation. Results: Higher CAIDE Dementia Risk Score was related to more pronounced deep WML (OR 1.22, 95% CI 1.05-1.43), lower total gray matter (beta- coefficient -0.29, p = 0.001) and hippocampal volume (beta- coefficient -0.28, p = 0.003), lower cortical thickness (beta-coefficient -0.19, p = 0.042), and poorer cognition (beta-coefficients -0.31 for total NTB score, -0.25 for executive functioning, -0.33 for processing speed, and -0.20 for memory, all p <0.001). Higher CAIDE Dementia Risk Score including APOE genotype was additionally related to more pronounced MTA (OR 1.15,95% CI 1.00-1.30). No associations were found with periventricular WML or amyloid accumulation. Conclusions: The CAIDE Dementia Risk Score was related to indicators of cerebrovascular changes and neurodegeneration on MRI, and cognition. The lack of association with brain amyloid accumulation needs to be verified in studies with larger sample sizes.

Exposure to early life stress (ELS) is associated with a variety of detrimental psychological and neurodevelopmental effects. Importantly, ELS has been associated with regional alterations and aberrant connectivity in the structure and functioning of brain regions involved in emotion processing and self-regulation, creating vulnerability to mental health problems. However, longitudinal research regarding the impact of ELS on functional connectivity between brain regions in the default mode network (DMN) and fronto-limbic network (FLN), both implicated in emotion-related processes, is relatively scarce. Neuroimaging research on ELS has mostly focused on single nodes or bi-nodal connectivity instead of functional networks. We examined how ELS is associated with connectivity patterns within the DMN and FLN during rest in early adulthood. The participants (n = 86; 47 females) in the current functional magnetic resonance imaging (fMRI) study were young adults (18-21 years old) whose families had participated in a longitudinal study since pregnancy. ELS was assessed both prospectively (parental reports of family relationship problems and mental health problems during pregnancy and infancy) and retrospectively (self-reported adverse childhood experiences). Inter-subject representational similarity analysis (IS-RSA) and multivariate distance matrix regression (MDMR) were used to analyze the association between ELS and the chosen networks. The IS-RSA results suggested that prospective ELS was associated with complex alterations within the DMN, and that retrospective ELS was associated with alterations in the FLN. MDMR results, in turn, suggested that that retrospective ELS was associated with DMN connectivity. Mean connectivity of the DMN was also associated with retrospective ELS. Analyses further showed that ELS-related alterations in the FLN were associated with increased connectivity between the prefrontal and limbic regions, and between different prefrontal regions. These results suggest that exposure to ELS in infancy might have long-lasting influences on functional brain connectivity that persist until early adulthood. Our results also speak for the importance of differentiating prospective and retrospective assessment methods to understand the specific neurodevelopmental effects of ELS.

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3 beta (GSK3 beta). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.

Objective: Birth asphyxia is a major cause of hypoxic-ischemic encephalopathy (HIE) in neonates and often associated with mortality, neonatal seizures, brain damage, and later life motor, cognitive, and behavioral impairments and epilepsy. Preclinical studies on rodent models are needed to develop more effective therapies for preventing HIE and its consequences. Thus far, the most popular rodent models have used either exposure of intact animals to hypoxia-only, or a combination of hypoxia and carotid occlusion, for the induction of neonatal seizures and adverse outcomes. However, such models lack systemic hypercapnia, which is a fundamental constituent of birth asphyxia with major effects on neuronal excitability. Here, we use a recently developed noninvasive rat model of birth asphyxia with subsequent neonatal seizures to study later life adverse outcome. Methods: Intermittent asphyxia was induced for 30 min by exposing male and female postnatal day 11 rat pups to three 7 + 3-min cycles of 9% and 5% O-2 at constant 20% CO2. All pups exhibited convulsive seizures after asphyxia. A set of behavioral tests were performed systematically over 14 months following asphyxia, that is, a large part of the rat's life span. Video-electroencephalographic (EEG) monitoring was used to determine whether asphyxia led to the development of epilepsy. Finally, structural brain alterations were examined. Results: The animals showed impaired spatial learning and memory and increased anxiety when tested at an age of 3-14 months. Video-EEG at similar to 10 months showed an abundance of spontaneous seizures, which was paralleled by neurodegeneration in the hippocampus and thalamus, and by aberrant mossy fiber sprouting. Significance: The present model of birth asphyxia recapitulates several of the later life consequences associated with human HIE. This model thus allows evaluation of the efficacy of novel therapies designed to prevent HIE and seizures following asphyxia, and of how such therapies might alleviate long-term adverse consequences.

Perineuronal nets (PNNs) have an important physiological role in the retention of learning by restricting cognitive flexibility. Their deposition peaks after developmental periods of intensive learning, usually in late childhood, and they help in long-term preservation of newly acquired skills and information. Modulation of PNN function by various techniques enhances plasticity and regulates the retention of memories, which may be beneficial when memory persistence entails negative symptoms such as post-traumatic stress disorder (PTSD). In this study, we investigated the role of PTP sigma [receptor-type tyrosine-protein phosphatase S, a phosphatase that is activated by binding of chondroitin sulfate proteoglycans (CSPGs) from PNNs] in retention of memories using Novel Object Recognition and Fear Conditioning models. We observed that mice haploinsufficient for PTPRS gene (PTP sigma(+/-)), although having improved short-term object recognition memory, display impaired long-term memory in both Novel Object Recognition and Fear Conditioning paradigm, as compared to WT littermates. However, PTP sigma(+/-) mice did not show any differences in behavioral tests that do not heavily rely on cognitive flexibility, such as Elevated Plus Maze, Open Field, Marble Burying, and Forced Swimming Test. Since PTP sigma has been shown to interact with and dephosphorylate TRKB, we investigated activation of this receptor and its downstream pathways in limbic areas known to be associated with memory. We found that phosphorylation of TRKB and PLC gamma are increased in the hippocampus, prefrontal cortex, and amygdaloid complex of PTP sigma(+/-) mice, but other TRKB-mediated signaling pathways are not affected. Our data suggest that PTP sigma downregulation promotes TRKB phosphorylation in different brain areas, improves short-term memory performance but disrupts long-term memory retention in the tested animal models. Inhibition of PTP sigma or disruption of PNN-PTP sigma-TRKB complex might be a potential target for disorders where negative modulation of the acquired memories can be beneficial.

Diffusion tensor imaging (DTI) reveals microstructural features of grey and white matter non-invasively. The contrast produced by DTI, however, is not fully understood and requires further validation. We used serial block-face scanning electron microscopy (SBEM) to acquire tissue metrics, i.e., anisotropy and orientation, using three-dimensional Fourier transform-based (3D-FT) analysis, to correlate with fractional anisotropy and orientation in DTI. SBEM produces high-resolution 3D data at the mesoscopic scale with good contrast of cellular membranes. We analysed selected samples from cingulum, corpus callosum, and perilesional cortex of sham-operated and traumatic brain injury (TBI) rats. Principal orientations produced by DTI and 3D-FT in all samples were in good agreement. Anisotropy values showed similar patterns of change in corresponding DTI and 3D-FT parameters in sham-operated and TBI rats. While DTI and 3D-FT anisotropy values were similar in grey matter, 3D-FT anisotropy values were consistently lower than fractional anisotropy values from DTI in white matter. We also evaluated the effect of resolution in 3D-FT analysis. Despite small angular differences in grey matter samples, lower resolution datasets provided reliable results, allowing for analysis of larger fields of view. Overall, 3D SBEM allows for more sophisticated validation studies of diffusion imaging contrast from a tissue microstructural perspective.

Poor health is a risk factor for damaging behaviors, but the mechanisms behind this link are unknown. Injection of pigs with lipopolysaccharide (LPS) can be used to model aspects of poor health. Recent studies have shown that LPS-injected pigs perform more tail- and ear-directed behavior compared to saline-injected pigs and suggest that pro-inflammatory cytokines may play a role in these behaviors. The aims of this study were to test the effect of LPS on the social behavior of pigs and the neurotransmitters and modulators in their brains and to test the effect of a nonsteroidal anti-inflammatory drug on the effects of LPS. Fifty-two female pigs (11-12 weeks) were allocated to four treatments comprising two injections: saline-saline (SS), saline-LPS (SL), ketoprofen-saline (KS), and ketoprofen-LPS (KL). Activity was scan-sampled every 5 min for 6 h after the last injection in the pen. Social behavior was observed continuously in 10 x 15-min bouts between 8 a.m. and 5 p.m. 1 day before (baseline) and 1 and 2 days after the injection. Saliva was analyzed for cortisol and plasma for tryptophan and kynurenine. The frontal cortex, hippocampus, hypothalamus, and brain stem were sampled 72 h after the injection and analyzed for cytokines and monoamines. LPS activated the HPA axis and decreased the activity within 6 h after the injection. Ketoprofen lowered the effect of LPS on cortisol release and attenuated the behavioral signs of sickness in challenged pigs. SL pigs manipulated the ears of their pen mates significantly longer than SS pigs 2 days after the injection. LPS had no observed effect on IFN-gamma, TNF-alpha, and IL-18. At 72 h after the injection, plasma tryptophan was depleted in SL pigs, and tryptophan and kynurenine concentrations in the frontal cortex and brain stem of SL pigs were significantly lower compared to those in SS pigs. Dopamine concentrations in the hypothalamus of SL pigs were significantly lower compared to those in SS pigs. Serotonin concentrations in the hypothalamus and noradrenaline concentrations in the hippocampus of SL pigs were significantly lower compared to those in KL pigs. In conclusion, LPS influenced the different neurotransmitters and modulators in the brain that are hypothesized to play an important role in the regulation of mood and behavior.