Highlights •LSD reduces firing rate and directionality of hippocampal place cells •LSD reduces hippocampal-cortical interactions in active/immobile behavior •LSD promotes a cortical state similar to wakefulness-to-sleep transition •Reactivation within hippocampus but not across hippocampus and cortex under LSD Summary Lysergic acid diethylamide (LSD) produces hallucinations, which are perceptions uncoupled from the external environment. How LSD alters neuronal activities in vivo that underlie abnormal perceptions is unknown. Here, we show that when rats run along a familiar track, hippocampal place cells under LSD reduce their firing rates, their directionality, and their interaction with visual cortical neurons. However, both hippocampal and visual cortical neurons temporarily increase firing rates during head-twitching, a behavioral signature of a hallucination-like state in rodents. When rats are immobile on the track, LSD enhances cortical firing synchrony in a state similar to the wakefulness-to-sleep transition, during which the hippocampal-cortical interaction remains dampened while hippocampal awake reactivation is maintained. Our results suggest that LSD suppresses hippocampal-cortical interactions during active behavior and during immobility, leading to internal hippocampal representations that are degraded and isolated from external sensory input. These effects may contribute to LSD-produced abnormal perceptions.
Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer’s disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([11C]PBR28), amyloid-β (Aβ) ([18F]AZD4694) and tau ([18F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [11C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of Aβ, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aβ and activated microglia sets the pace for tau spread across Braak stages.
Many but not all cognitive abilities decline during ageing. Some even improve due to lifelong experience. The critical capacities of attention and executive functions have been widely posited to decline. However, these capacities are composed of multiple components, so multifaceted ageing outcomes might be expected. Indeed, prior findings suggest that whereas certain attention/executive functions clearly decline, others do not, with hints that some might even improve. We tested ageing effects on the alerting, orienting and executive (inhibitory) networks posited by Posner and Petersen’s influential theory of attention, in a cross-sectional study of a large sample (N = 702) of participants aged 58–98. Linear and nonlinear analyses revealed that whereas the efficiency of the alerting network decreased with age, orienting and executive inhibitory efficiency increased, at least until the mid-to-late 70s. Sensitivity analyses indicated that the patterns were robust. The results suggest variability in age-related changes across attention/executive functions, with some declining while others improve.
Decision-making and representations of arousal are intimately linked. Behavioral investigations have classically shown that either too little or too much bodily arousal is detrimental to decision-making, indicating that there is an inverted “U” relationship between bodily arousal and performance. How these processes interact at the level of single neurons as well as the neural circuits involved are unclear. Here we recorded neural activity from orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) of macaque monkeys while they made reward-guided decisions. Heart rate (HR) was also recorded and used as a proxy for bodily arousal. Recordings were made both before and after subjects received excitotoxic lesions of the bilateral amygdala. In intact monkeys, higher HR facilitated reaction times (RTs). Concurrently, a set of neurons in OFC and dACC selectively encoded trial-by-trial variations in HR independent of reward value. After amygdala lesions, HR increased, and the relationship between HR and RTs was altered. Concurrent with this change, there was an increase in the proportion of dACC neurons encoding HR. Applying a population-coding analysis, we show that after bilateral amygdala lesions, the balance of encoding in dACC is skewed away from signaling either reward value or choice direction toward HR coding around the time that choices are made. Taken together, the present results provide insight into how bodily arousal and decision-making are signaled in frontal cortex.
The pathology of familial Alzheimer’s disease, which is caused by dominant mutations in the gene that encodes amyloid-beta precursor protein (APP) and in those that encode presenilin 1 and presenilin 2, is characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles in multiple brain regions. Here we show that the brain-wide selective disruption of a mutated APP allele in transgenic mouse models carrying the human APP Swedish mutation alleviates amyloid-beta-associated pathologies for at least six months after a single intrahippocampal administration of an adeno-associated virus that encodes both Cas9 and a single-guide RNA that targets the mutation. We also show that the deposition of amyloid-beta, as well as microgliosis, neurite dystrophy and the impairment of cognitive performance, can all be ameliorated when the CRISPR–Cas9 construct is delivered intravenously via a modified adeno-associated virus that can cross the blood–brain barrier. Brain-wide disease-modifying genome editing could represent a viable strategy for the treatment of familial Alzheimer’s disease and other monogenic diseases that affect multiple brain regions.
Highlights •Microbiota, immune, and neurophysiological profile of 60 extremely premature infants •Pro-inflammatory T cell response correlates with suppressed electrocortical maturation •γδ T cells have central implications for the pathogenesis of brain injury •Klebsiella overgrowth in the gastrointestinal tract is predictive for brain damage Summary Premature infants are at substantial risk for suffering from perinatal white matter injury. Though the gut microbiota has been implicated in early-life development, a detailed understanding of the gut-microbiota-immune-brain axis in premature neonates is lacking. Here, we profiled the gut microbiota, immunological, and neurophysiological development of 60 extremely premature infants, which received standard hospital care including antibiotics and probiotics. We found that maturation of electrocortical activity is suppressed in infants with severe brain damage. This is accompanied by elevated γδ T cell levels and increased T cell secretion of vascular endothelial growth factor and reduced secretion of neuroprotectants. Notably, Klebsiella overgrowth in the gut is highly predictive for brain damage and is associated with a pro-inflammatory immunological tone. These results suggest that aberrant development of the gut-microbiota-immune-brain axis may drive or exacerbate brain injury in extremely premature neonates and represents a promising target for novel intervention strategies.
Background and Objectives: Observational research has shown that a substantial proportion of all dementia cases worldwide is attributable to modifiable risk factors. Dementia risk scores might be useful to identify high-risk individuals and monitor treatment adherence. The objective of this study was to investigate whether a dementia risk score, the LIfestyle for BRAin health (LIBRA) index, is associated with MRI markers and cognitive functioning/impairment in the general population. Methods: Cross-sectional data was used from the observational population-based cohort of The Maastricht Study.. The weighted compound score of LIBRA (including twelve dementia risk and protective factors, e.g. hypertension, physical inactivity) was calculated, with higher scores indicating higher dementia risk. Standardized volumes of white matter, grey matter, CSF (as proxy for general brain atrophy), white matter hyperintensities, and presence of cerebral small vessel disease were derived from 3T MRI. Cognitive functioning was tested in three domains: memory, information processing speed, and executive function and attention. Values ≤1.5 SD below the average were defined as cognitive impairment. Multiple regression analyses and structural equation modelling were used, adjusted for age, sex, education, intracranial volume and type-2 diabetes. Results: Participants (n=4,164; mean age 59y; 49.7% men) with higher LIBRA scores (mean=1.19, range=-2.7 to +9.2), denoting higher dementia risk, had higher volumes of white matter hyperintensities (β=0.051, p=.002), and lower scores on information processing speed (β=-0.067, p=.001) and executive function and attention (β=-0.065, p=.004). Only in men, associations between LIBRA and volumes of grey matter (β=-0.093, p
Background The high prevalence of office stress and its detrimental health consequences are of concern to individuals, employers and society at large. Laboratory studies investigating office stress have mostly relied on data from participants that were tested individually on abstract tasks. In this study, we examined the effect of psychosocial office stress and work interruptions on the psychobiological stress response in a realistic but controlled group office environment. We also explored the role of cognitive stress appraisal as an underlying mechanism mediating the relationship between work stressors and the stress response. Methods and Materials Ninety participants (44 female; mean age 23.11 ± 3.80) were randomly assigned to either a control condition or one of two experimental conditions in which they were exposed to psychosocial stress with or without prior work interruptions in a realistic multi-participant laboratory setting. To induce psychosocial stress, we adapted the Trier Social Stress Test for Groups to an office environment. Throughout the experiment, we continuously monitored heart rate and heart rate variability. Participants repeatedly reported on their current mood, calmness, wakefulness and perceived stress and gave saliva samples to assess changes in salivary cortisol and salivary alpha-amylase. Additionally, cognitive appraisal of the psychosocial stress test was evaluated. Results Our analyses revealed significant group differences for most outcomes during or immediately after the stress test (i.e., mood, calmness, perceived stress, salivary cortisol, heart rate, heart rate variability) and during recovery (i.e., salivary cortisol and heart rate). Interestingly, the condition that experienced work interruptions showed a higher increase of cortisol levels but appraised the stress test as less threatening than individuals that experienced only psychosocial stress. Exploratory mediation analyses revealed a blunted response in subjective measures of stress, which was partially explained by the differences in threat appraisal. Discussion The results showed that experimentally induced work stress led to significant responses of subjective measures of stress, the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. However, there appears to be a discrepancy between the psychological and biological responses to preceding work interruptions. Appraising psychosocial stress as less threatening but still as challenging could be an adaptive way of coping and reflect a state of engagement and eustress.
Wireless, battery-free, and fully subdermally implantable optogenetic tools are poised to transform neurobiological research in freely moving animals. Current-generation wireless devices are sufficiently small, thin, and light for subdermal implantation, offering some advantages over tethered methods for naturalistic behavior. Yet current devices using wireless power delivery require invasive stimulus delivery, penetrating the skull and disrupting the blood–brain barrier. This can cause tissue displacement, neuronal damage, and scarring. Power delivery constraints also sharply curtail operational arena size. Here, we implement highly miniaturized, capacitive power storage on the platform of wireless subdermal implants. With approaches to digitally manage power delivery to optoelectronic components, we enable two classes of applications: transcranial optogenetic activation millimeters into the brain (validated using motor cortex stimulation to induce turning behaviors) and wireless optogenetics in arenas of more than 1 m 2 in size. This methodology allows for previously impossible behavioral experiments leveraging the modern optogenetic toolkit.
Abstract Background Neurologic manifestations are well-recognized features of coronavirus disease 2019 (COVID-19). However, the longitudinal association of biomarkers reflecting CNS impact and neurological symptoms is not known. We sought to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID-19. Methods Patients with confirmed acute COVID-19 were studied prospectively. Neurological symptoms were recorded during the acute phase of the disease and at six months follow-up, and blood samples were collected longitudinally. Healthy age-matched individuals were included as controls. We analysed plasma concentrations of neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF-15). Findings One hundred patients with mild ( n = 24), moderate ( n = 28), and severe ( n = 48) COVID-19 were followed for a median (IQR) of 225 (187–262) days. In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all p