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Welcome to OXION, Universities of Oxford, Cambridge, London and MRC Harwell
An orexin-sensitive subpopulation of layer 6 neurons regulates cortical excitability and anxiety behaviour.
Cortical layer 6 neurons are the only projection neuron population in the cortical mantle known to electrophysiologically respond to orexin-a neuropeptide involved in cortical arousal and emotive behaviour. These neurons exhibit extensive intercortical and thalamic projections, yet the exact mechanisms underlying these responses are not fully understood. We hypothesize that cortical circuits activated by orexin sensitive L6 neurons in the medial prefrontal cortex (mPFC) are responsible for detecting salient features of sensory stimuli and are therefore involved in regulating emotional states. Here, we show that Drd1a-Cre+ neurons in the mPFC are selectively sensitive to orexin and gate the activation of the prefrontal network in vivo. Moreover, we demonstrated that chronically "silencing" this subpopulation of L6 neurons (Drd1a-Cre+/+:Snap25fl/fl) across the cortical mantle from birth abolishes the orexin-induced prefrontal activation. Consequently, the chronic silencing of these neurons had strong anxiolytic effects on several anxiety-related behavioural paradigms, indicating that orexin-responsive L6 neurons modulate emotional states and may be a substrate for anxiety regulation.
Association of cholesterol and glycemic state biomarkers with phenotypic variation and Parkinson's disease progression: The Oxford Discovery cohort.
BackgroundParkinson's disease (PD) has marked phenotypic variability. Increased lipids have been suggested as being neuroprotective whilst hyperglycemia may increase α-synuclein aggregation.ObjectiveWe have tested whether high total cholesterol and high-density lipoprotein cholesterol (HDL-C) and low levels of fructosamine are associated with better PD phenotypes and predict less rapid progressionMethodsNon-fasting serum HDL-C, total cholesterol, and fructosamine were measured at baseline in 866 patients with early PD (median duration, 0.96; IQR, 0.43-1.98 years) from the Oxford Discovery cohort. These biomarkers were compared against our data-derived PD subtypes using multinomial logistic regression. We used multilevel models to predict longitudinal motor and non-motor outcomes (e.g., cognition, mood).ResultsHDL-C and total cholesterol differed across baseline PD phenotype clusters, with reduced levels associated with the most severe motor and non-motor phenotypes (psychological well-being, cognitive impairment, REM sleep behavior disorder, and daytime sleepiness). Higher HDL-C and total cholesterol, although the latter was attenuated after adjustment for statin use, were associated with better baseline activities of daily living (e.g., UPDRS-II score with 1 SD increase in HDL-C -0.74, 95%CI -1.22 to -0.26, p = 0.002) and non-motor features. Neither predicted the rate of motor or non-motor progression. Fructosamine levels were not associated with phenotypic variability or rate of disease progression.ConclusionsHypercholesterolemia was associated with a better motor/non-motor disease subtype and daily living impairment at presentation, but did not predict longitudinal change. Future research needs to determine if these associations are causally related or secondary to disease onset by examining prodromal subjects.
Heritable maintenance of chromatin modifications confers transcriptional memory of interferon-γ signaling.
Interferon-γ (IFNγ) transiently activates genes related to inflammation and innate immunity. A subset of targets retain a mitotically heritable memory of prior IFNγ exposure, resulting in hyperactivation upon re-exposure through poorly understood mechanisms. Here, we discover that the transcriptionally permissive chromatin marks H3K4me1, H3K14ac and H4K16ac are established during IFNγ priming and are selectively maintained on a cluster of guanylate-binding protein (GBP) genes in dividing human cells in the absence of transcription. The histone acetyltransferase KAT7 is required for H3K14ac deposition at GBP genes and for accelerated GBP reactivation upon re-exposure to IFNγ. In naive cells, the GBP cluster is maintained in a low-level repressive chromatin state, marked by H3K27me3, limiting priming through a PRC2-dependent mechanism. Unexpectedly, IFNγ priming results in transient accumulation of this repressive mark despite active gene expression. However, during the memory phase, H3K27 methylation is selectively depleted from primed GBP genes, facilitating hyperactivation. Furthermore, we identified a cis-regulatory element that forms transient, long-range contacts across the GBP cluster and acts as a repressor, curbing hyperactivation of previously IFNγ-primed cells. Our results provide insight into the chromatin basis for the long-term transcriptional memory of IFNγ signaling, which might contribute to enhanced innate immunity.
Connectivity related to major brain functions in Alzheimer disease progression: microstructural properties of the cingulum bundle and its subdivision using diffusion-weighted MRI.
BACKGROUND: The cingulum bundle is a brain white matter fasciculus associated with the cingulate gyrus. It connects areas from the temporal to the frontal lobe. It is composed of fibers with different terminations, lengths, and structural properties, related to specific brain functions. We aimed to automatically reconstruct this fasciculus in patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) and to assess whether trajectories have different microstructural properties in relation to dementia progression. METHODS: Multi-shell high angular resolution diffusion imaging-HARDI image datasets from the "Alzheimer's Disease Neuroimaging Initiative"-ADNI repository of 10 AD, 18 MCI, and 21 cognitive normal (CN) subjects were used to reconstruct three subdivisions of the cingulum bundle, using a probabilistic approach, combined with measurements of diffusion tensor and neurite orientation dispersion and density imaging metrics in each subdivision. RESULTS: The subdivisions exhibit different pathways, terminations, and structural characteristics. We found differences in almost all the diffusivity metrics among the subdivisions (p
Auditory training alters the cortical representation of complex sounds.
Auditory learning is supported by long-term changes in the neural processing of sound. We examined these task-depend changes in auditory cortex by mapping neural sensitivity to timbre, pitch and location cues in cues in trained (n = 5), and untrained control female ferrets (n = 5). Trained animals either identified vowels in a two-alternative forced choice task (n = 3) or discriminated when a repeating vowel changed in identity or pitch (n = 2). Neural responses were recorded under anesthesia in two primary auditory cortical fields and two tonotopically organized non-primary fields. In trained animals, the overall sensitivity to sound timbre was reduced across three cortical fields compared to control animals, but maintained in a non-primary field (the posterior pseudosylvian field). While training did not increase sensitivity to timbre across auditory cortex, it did change the way in which neurons integrated spectral information with neural responses in trained animals increasing their sensitivity to first and second formant frequencies, whereas in control animals' cortical sensitivity to spectral timbre depends mostly on the second formant. Animals trained on timbre identification were required to generalize across pitch when discriminating timbre and their neurons became less modulated by fundamental frequency relative to control animals. Finally, both trained groups showed increased spatial sensitivity and an enhanced response to sound source locations close to the midline, where the loudspeaker was located in the training chamber. These results demonstrate that training elicited widespread alterations in the cortical representation of complex sounds.Significance Statement Learning a task can elicit widespread changes in the brain. Here, we trained animals to discriminate sound timbre using synthetic vowel sounds. Somewhat surprisingly we observed that in 3 out of 4 of the brain regions studied, neural responses became less sensitive to timbre, while in the 4th area sensitivity was maintained. This suggests that training does not simply rewire more neurons to represent learned stimuli. Neurons also changed the way in which they processed stimuli becoming more sensitive to the formant cues that determine vowel identity and tuned preferentially for the region of space in which sounds were presented during training. Together, these results suggest that learning results in complex changes in how and whether neurons represent learned sounds.
The release of GLP-1 from gut L cells is inhibited by low extracellular pH.
OBJECTIVE: The intestinal luminal pH profile varies from stomach to rectum and becomes disrupted in diseases. However, little is known about the pH dependence of incretin hormone secretion, with most in vitro studies having failed to consider this modulatory factor or having used nonphysiological buffer systems. Here, we report the extracellular pH (pHe) dependence of glucagon-like peptide-1 (GLP-1) exocytosis from L cells. METHODS: The pHe dependence of GLP-1 release from GLUTag cells and murine ex vivo primary gut cultures was detected by ELISA. GLP-1 release was measured over a range of pHe under a physiological (CO2/HCO3 -) buffering regime and in its absence (HEPES buffer). The relationship between intracellular pH (pHi) and pHe was mapped given that at least some component of pH sensitivity is likely to be intracellular. RESULTS: GLP-1 secretion from L cells was pHe-dependent and stimulated under alkaline conditions. In the absence of glucose or extracellular calcium, secretion remained at a pHe-insensitive baseline. pHi followed changes in pHe, but the relationship was offset to more alkaline levels in the absence of CO2/HCO3 - buffer and became shallower if [Cl-] changes that normally accompany [HCO3 -] changes were compensated iso-osmotically with gluconate. CONCLUSIONS: GLP-1 secretion is sensitive to pHe and the buffer present. Exploiting this mechanism therapeutically may benefit patients with obesity.
LRRK2-associated parkinsonism with and without in vivo evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization
Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years of follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates. Data were from the Parkinson's Progression Markers Initiative, a multicentre prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient-reported outcome assessments were administered. Biomarkers included dopamine transporter scan, CSF amyloid-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels and serum neurofilament light chain. Linear mixed-effects (LMMs) models examined differences in trajectory in CSF-negative and CSF-positive groups. A total of 148 LRRK2 parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay, were included. At baseline, the negative group was older than the positive group [median (inter-quartile range) 69.1 (65.2-72.3) versus 61.5 (55.6-66.9) years, P < 0.001] and a greater proportion were female [28 (61%) versus 43 (42%), P = 0.035]. Despite being older, the negative group had similar duration since diagnosis and similar motor rating scale [16 (11-23) versus 16 (10-22), P = 0.480] though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared with 75 (77%) of the positive group. The negative group, compared with the positive group, had higher per cent-expected putamenal dopamine transporter binding for their age and sex [0.36 (0.29-0.45) versus 0.26 (0.22-0.37), P < 0.001]. Serum neurofilament light chain was higher in the negative group compared with the positive group [17.10 (13.60-22.10) versus 10.50 (8.43-14.70) pg/mL; age-adjusted P-value = 0.013]. In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (P = 0.037), but no other differences in trajectory were found. Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline. The underlying biology in LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.
Clinical neurocardiology: defining the value of neuroscience-based cardiovascular therapeutics - 2024 update.
The intricate role of the autonomic nervous system (ANS) in regulating cardiac physiology has long been recognized. Aberrant function of the ANS is central to the pathophysiology of cardiovascular diseases. It stands to reason, therefore, that neuroscience-based cardiovascular therapeutics hold great promise in the treatment of cardiovascular diseases in humans. A decade after the inaugural edition, this White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology and pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.
Stereoscopic Vision
The fundamental geometry underlying binocular stereoscopic depth perception was first appreciated in the mid-nineteenth century. Progress in understanding how brain mechanisms enable stereoscopic vision began about 50 years ago and has moved forward steadily since that time. The present view is that different areas of the extrastriate cortex have important and distinct roles in the elaboration of the stereoscopic visual percept.
Cortical evoked activity is modulated by the sleep state in a ferret model of tinnitus. A cross-case study.
Subjective tinnitus is a phantom auditory perception in the absence of an actual acoustic stimulus that affects 15% of the global population. In humans, tinnitus is often associated with disturbed sleep and, interestingly, there is an overlap between the brain areas involved in tinnitus and regulation of NREM sleep. We used eight adult ferrets exposed to mild noise trauma as an animal model of tinnitus. We assessed the phantom percept using two operant paradigms sensitive to tinnitus, silent gap detection and silence detection, before and, in a subset of animals, up to six months after the mild acoustic trauma. The integrity of the auditory brainstem was assessed over the same period using auditory brainstem response recordings. Following noise overexposure, ferrets developed lasting, frequency-specific impairments in operant behaviour and evoked brainstem activity. To explore the interaction between sleep and tinnitus, in addition to tracking the behavioural markers of noise-induced tinnitus and hearing impairment after noise overexposure, we evaluated sleep-wake architecture and spontaneous and auditory-evoked EEG activity across vigilance states. Behavioural performance and auditory-evoked activity measurements after noise overexposure suggested distinct degrees of tinnitus and hearing impairment between individuals. Animals that developed signs of tinnitus consistently developed sleep impairments, suggesting a link between the emergence of noise-induced hearing loss and/or tinnitus and sleep disruption. However, neural markers of tinnitus were reduced during sleep, suggesting that sleep may transiently mitigate tinnitus. These results reveal the importance of sleep-wake states in tinnitus and suggest that understanding the neurophysiological link between sleep and tinnitus may provide a new angle for research into the causes of phantom percepts and inform future treatments.
CTPS cytoophidia in Drosophila: distribution, regulation, and physiological roles
Intracellular compartmentalization plays a critical role in maintaining cellular homeostasis and regulating metabolic processes. A growing body of evidence suggests that various metabolic enzymes, including CTP synthase (CTPS), can dynamically assemble into membraneless filamentous structures. The formation of these membraneless organelles is precisely regulated by the cellular metabolic state. CTPS, a rate-limiting enzyme in the de novo biosynthesis of CTP, has been shown to assemble into filamentous structures known as cytoophidium. First identified in 2010 by three independent research groups, cytoophidia are evolutionarily conserved across diverse organisms, including bacteria, archaea, yeast, mammals, and plants, suggesting a fundamental biological function. Given the well-established advantages of Drosophila melanogaster as a genetic model, this organism provides a powerful system for investigating the physiological roles of cytoophidia. This review synthesizes current findings on CTPS cytoophidia in Drosophila, with a particular focus on their spatiotemporal distribution in tissues and their regulatory roles in three key biological processes: intestinal homeostasis, lipid metabolism, and reproductive physiology. Furthermore, we discuss the challenges and future directions in cytoophidia research, offering insights into their broader implications in cellular metabolism and physiology.
Sleep-wake-related changes in intracellular chloride regulate plasticity at glutamatergic cortical synapses.
Wakefulness and sleep affect the brain's ability to exhibit plastic changes.1,2 For instance, the potentiation of cortical excitatory synaptic connections is associated with the active period, when animals are mainly awake.3,4,5,6,7 It is unclear, however, how changes in neuronal physiology that are associated with sleep-wake history, affect the mechanisms responsible for synaptic plasticity. Recently, it has been shown that sleep-wake history alters transmembrane chloride (Cl-) gradients in cortical pyramidal neurons via Cl- cotransporter activity, which shifts the reversal potential for gamma-aminobutyric acid (GABA) type A receptors (EGABAA) when assessed in vivo and in vitro.8,9 Hyperpolarizing EGABAA values are associated with recent sleep, whereas depolarizing EGABAA values are associated with recent waking. Here, we demonstrate that sleep-wake-history-related changes in EGABAA affect membrane potential dynamics and glutamatergic long-term potentiation (LTP) elicited by spiking activity in pyramidal neurons of the mouse cortex. Reducing the depolarized shift in EGABAA during the active period reduces the potentiation of cortical excitatory synapses onto layer 5 (L5) pyramidal neurons. Depolarized EGABAA values facilitate LTP induction by promoting residual membrane depolarization during synaptically evoked spiking. Changes in LTP induction associated with sleep-wake history can be reversed by switching the EGABAA-dependent effects, either by using direct current injection to counteract the effects upon residual membrane potential depolarization or by modulating cotransporters that regulate EGABAA. We conclude that EGABAA dynamics provide a functional link between changes in a neuron's physiology that are associated with sleep-wake history and the mechanisms responsible for the induction of glutamatergic synaptic plasticity.
