Exploring cerebral structural and functional abnormalities in a mouse model of post-traumatic headache induced by mild traumatic brain injury.

Mild traumatic brain injury (mTBI)-induced post-traumatic headache (PTH) is a pressing public health concern and leading cause of disability worldwide. Although PTH is often accompanied by neurological disorders, the exact underlying mechanism remains largely unknown. Identifying potential biomarkers may prompt the diagnosis and development of effective treatments for mTBI-induced PTH. In this study, a mouse model of mTBI-induced PTH was established to investigate its effects on cerebral structure and function during short-term recovery. Results indicated that mice with mTBI-induced PTH exhibited balance deficits during the early post-injury stage. Metabolic kinetics revealed that variations in neurotransmitters were most prominent in the cerebellum, temporal lobe/cortex, and hippocampal regions during the early stages of PTH. Additionally, variations in brain functional activities and connectivity were further detected in the early stage of PTH, particularly in the cerebellum and temporal cortex, suggesting that these regions play central roles in the mechanism underlying PTH. Moreover, our results suggested that GABA and glutamate may serve as potential diagnostic or prognostic biomarkers for PTH. Future studies should explore the specific neural circuits involved in the regulation of PTH by the cerebellum and temporal cortex, with these two regions potentially utilized as targets for non-invasive stimulation in future clinical treatment.

IRE1α: from the function to the potential therapeutic target in atherosclerosis.

Inositol requiring enzyme 1 (IRE1) is generally thought to control the most conserved pathway in the unfolded protein response (UPR). Two isoforms of IRE1, IRE1α and IRE1ß, have been reported in mammals. IRE1α is a ubiquitously expressed protein whose knockout shows marked lethality. In contrast, the expression of IRE1ß is exclusively restricted in the epithelial cells of the respiratory and gastrointestinal tracts, and IRE1ß-knockout mice are phenotypically normal. As research continues to deepen, IRE1α was showed to be tightly linked to inflammation, lipid metabolism regulation, cell death and so on. Growing evidence also suggests an important role for IRE1α in promoting atherosclerosis (AS) progression and acute cardiovascular events through disrupting lipid metabolism balance, facilitating cells apoptosis, accelerating inflammatory responses and promoting foam cell formation. In addition, IRE1α was recognized as novel potential therapeutic target in AS prevention. This review provides some clues about the relationship between IRE1α and AS, hoping to contribute to further understanding roles of IRE1α in atherogenesis and to be helpful for the design of novel efficacious therapeutics agents targeting IRE1α-related pathways.

Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice.

Synapse loss in medial prefrontal cortex (mPFC) has been implicated in stress-related mood disorders, such as depression. However, the exact effect of synapse elimination in the depression and how it is triggered are largely unknown. Through repeated longitudinal imaging of mPFC in the living brain, we found both presynaptic and postsynaptic components were declined, together with the impairment of synapse remodeling and cross-synaptic signal transmission in the mPFC during chronic stress. Meanwhile, chronic stress also induced excessive microglia phagocytosis, leading to engulfment of excitatory synapses. Further investigation revealed that the elevated complement C3 during the stress acted as the tag of synapses to be eliminated by microglia. Besides, chronic stress induced a reduction of the connectivity between the mPFC and neighbor regions. C3 knockout mice displayed significant reduction of synaptic pruning and alleviation of disrupted functional connectivity in mPFC, resulting in more resilience to chronic stress. These results indicate that complement-mediated excessive microglia phagocytosis in adulthood induces synaptic dysfunction and cortical hypo-connectivity, leading to stress-related behavioral abnormality.

Role of Sp1 in atherosclerosis.

Specificity protein (Sp) is a famous family of transcription factors including Sp1, Sp2 and Sp3. Sp1 is the first one of Sp family proteins to be characterized and cloned in mammalian. It has been proposed that Sp1 acts as a modulator of the expression of target gene through interacting with a series of proteins, especially with transcriptional factors, and thereby contributes to the regulation of diverse biological processes. Notably, growing evidence indicates that Sp1 is involved in the main events in the development of atherosclerosis (AS), such as inflammation, lipid metabolism, plaque stability, vascular smooth muscle cells (VSMCs) proliferation and endothelial dysfunction. This review is designed to provide useful clues to further understanding roles of Sp1 in the pathogenesis of AS, and may be helpful for the design of novel efficacious therapeutics agents targeting Sp1.

Retrosplenial Cortex Effects Contextual Fear Formation Relying on Dysgranular Constituent in Rats.

Animal contextual fear conditioning (CFC) models are the most-studied forms used to explore the neural substances of posttraumatic stress disorder (PTSD). In addition to the well-recognized hippocampal-amygdalar system, the retrosplenial cortex (RSC) is getting more and more attention due to substantial involvement in CFC, but with a poor understanding of the specific roles of its two major constituents-dysgranular (RSCd) and granular (RSCg). The current study sought to identify their roles and underlying brain network mechanisms during the encoding processing of the rat CFC model. Rats with pharmacologically inactivated RSCd, RSCg, and corresponding controls underwent contextual fear conditioning. [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scanning was performed for each animal. The 5-h and 24-h retrieval were followed to test the formation of contextual memory. Graph theoretic tools were used to identify the brain metabolic network involved in encoding phase, and changes of nodal (brain region) properties linked, respectively, to disturbed RSCd and RSCg were analyzed. Impaired retrieval occurred in disturbed RSCd animals, not in RSCg ones. The RSC, hippocampus (Hip), amygdala (Amy), piriform cortex (Pir), and visual cortex (VC) are hub nodes of the brain-wide network for contextual fear memory encoding in rats. Nodal degree and efficiency of hippocampus and its connectivity with amygdala, Pir, and VC were decreased in rats with disturbed RSCd, while not in those with suppressed RSCg. The RSC plays its role in contextual fear memory encoding mainly relying on its RSCd part, whose condition would influence the activity of the hippocampal-amygdalar system.

Hypothermia selectively protects the anterior forebrain mesocircuit during global cerebral ischemia.

Hypothermia is an important protective strategy against global cerebral ischemia following cardiac arrest. However, the mechanisms of hypothermia underlying the changes in different regions and connections of the brain have not been fully elucidated. This study aims to identify the metabolic nodes and connection integrity of specific brain regions in rats with global cerebral ischemia that are most affected by hypothermia treatment. 18F-fluorodeoxyglucose positron emission tomography was used to quantitatively determine glucose metabolism in different brain regions in a rat model of global cerebral ischemia established at 31-33°C. Diffusion tensor imaging was also used to reconstruct and explore the brain connections involved. The results showed that, compared with the model rats established at 37-37.5°C, the rat models of global cerebral ischemia established at 31-33°C had smaller hypometabolic regions in the thalamus and primary sensory areas and sustained no obvious thalamic injury. Hypothermia selectively preserved the integrity of the anterior forebrain mesocircuit, exhibiting protective effects on the brain during the global cerebral ischemia. The study was approved by the Institutional Animal Care and Use Committee at Capital Medical University (approval No. XW-AD318-97-019) on December 15, 2019.

Induction of core symptoms of autism spectrum disorder by in vivo CRISPR/Cas9-based gene editing in the brain of adolescent rhesus monkeys.

Although CRISPR/Cas9-mediated gene editing is widely applied to mimic human disorders, whether acute manipulation of disease-causing genes in the brain leads to behavioral abnormalities in non-human primates remains to be determined. Here we induced genetic mutations in MECP2, a critical gene linked to Rett syndrome (RTT) and autism spectrum disorders (ASD), in the hippocampus (DG and CA1-4) of adolescent rhesus monkeys (Macaca mulatta) in vivo via adeno-associated virus (AAV)-delivered Staphylococcus aureus Cas9 with small guide RNAs (sgRNAs) targeting MECP2. In comparison to monkeys injected with AAV-SaCas9 alone (n = 4), numerous autistic-like behavioral abnormalities were identified in the AAV-SaCas9-sgMECP2-injected monkeys (n = 7), including social interaction deficits, abnormal sleep patterns, insensitivity to aversive stimuli, abnormal hand motions, and defective social reward behaviors. Furthermore, some aspects of ASD and RTT, such as stereotypic behaviors, did not appear in the MECP2 gene-edited monkeys, suggesting that different brain areas likely contribute to distinct ASD symptoms. This study showed that acute manipulation of disease-causing genes via in vivo gene editing directly led to behavioral changes in adolescent primates, paving the way for the rapid generation of genetically engineered non-human primate models for neurobiological studies and therapeutic development.

Alterations of regional homogeneity in Parkinson's disease with mild cognitive impairment: a preliminary resting-state fMRI study.

PURPOSE: Mild cognitive impairment (MCI) is commonly observed in Parkinson's disease (PD), even in the early stages. However, the neural substrates of cognitive impairment in PD remain unclear. The aim of the current study was to investigate the change of local brain function in PD patients with MCI. METHODS: Fifty patients with PD, including 25 PD patients with MCI (PD-MCI) and 25 PD patients with normal cognition (PD-NC), and 25 age- and sex-matched healthy controls (HC) were enrolled. Conventional magnetic resonance imaging (MRI), 3D structural images, and resting state-functional MRI (rs-fMRI) were performed in all subjects. Regional homogeneity (ReHo) was measured based on the rs-fMRI images to investigate the altered local brain functions. RESULTS: Brain regions with decreased ReHo were located in the left posterior cerebellar lobe in PD sub-groups compared to the HC group, and the brain regions with increased ReHo were located in the limbic lobe (right precuneus/bilateral middle cingulate cortex) in PD-MCI compared with HC group. PD-MCI presented with increased ReHo in the bilateral precuneus/left superior parietal lobe and decreased ReHo in the left insula compared to PD-NC. ReHo values for the left precuneus were negatively related to neuropsychological scores, and ReHo values for the left insula were positively related to neuropsychological scores in PD subjects. CONCLUSION: The present study demonstrated abnormal spontaneous synchrony in the left insula and left precuneus in patients with PD-MCI compared to PD-NC, which might provide a novel insight into the diagnosis and clinical treatment of cognitive impairment in PD.

The specific absorption rate in different brain regions of rats exposed to electromagnetic plane waves.

Accurate dosimetry of a specific brain region in rats exposed to an electromagnetic field (EMF) is essential for studies focusing on dose-effect relationship of the region. However, only dosimetry of whole brain or whole body were evaluated in most of previous studies. In this study, a numerical voxel rat model with 10 segmented brain regions was constructed. Then, the effects of frequency, incidence direction, and E-polarization direction of plane wave EMF on brain region averaged specific absorption rate (BRSAR) of rats were investigated. At last, the reliability of using whole-body averaged SAR (WBDSAR) and whole-brain averaged SAR (WBRSAR) as estimations of BRSAR were also evaluated. Our results demonstrated that the BRSAR depended on the frequency, incidence direction, and E-polarization direction of the EMF. Besides, the largest deviation could be up to 13.1 dB between BRSAR and WBDSAR and 9.59 dB between BRSAR and WBRSAR. The results suggested that to establish an accurate dose-effect relationship, the variance of the BRSAR induced by alteration of frequency, incidence direction, and E-polarization direction of EMF should be avoided or carefully evaluated. Furthermore, the use of WBDSAR and WBRSAR as estimations of BRSAR should be restricted to certain conditions such that the deviations are not too large.

Voxel-based morphology analysis of STZ-induced type 1 diabetes mellitus rats with and without cognitive impairment.

Incidence of diabetes has increased dramatically. Consequently, diabetes-induced cognitive impairment has attracted increasing attention. This study aimed to explore the changes in brain structure in the diabetic rats with and without cognitive impairment. Morris water maze method was used for screening the diabetic rats with/without cognitive impairment. These diabetic rats and controls were imaged using magnetic resonance imaging that segmented into gray and white matter, which was further analyzed using voxel-based morphology (VBM) and regions of interest (ROI) based image retrieval. The ROI results showed that the whole brain volume decreased in diabetic rats with/without cognitive impairment as compared to the control (P < 0.05). The VBM results showed differences in the caudate putamen and prefrontal cortex in the diabetic rats with/without cognitive impairment. The change in the brain of rats with cognitive impairment occurred primarily in the area associated with cognition, such as caudate putamen and hippocampus, and the bi-directional change occurred in the different area of hippocampus. The current results provided important imaging information for early diagnosis and timely treatment of diabetic cognitive impairment.

Spatial learning and memory impairments are associated with increased neuronal activity in 5XFAD mouse as measured by manganese-enhanced magnetic resonance imaging.

Dysfunction of neuronal activity is a major and early contributor to cognitive impairment in Alzheimer's disease (AD). To investigate neuronal activity alterations at early stage of AD, we encompassed behavioral testing and in vivo manganese-enhanced magnetic resonance imaging (MEMRI) in 5XFAD mice at early ages (1-, 2-, 3- and 5-month). The 5XFAD model over-express human amyloid precursor protein (APP) and presenilin 1 (PS1) harboring five familial AD mutations, which have a high APP expression correlating with a high burden and an accelerated accumulation of the 42 amino acid species of amyloid-ß. In the Morris water maze, 5XFAD mice showed longer escape latency and poorer memory retention. In the MEMRI, 5XFAD mice showed increased signal intensity in the brain regions involved in spatial cognition, including the entorhinal cortex, the hippocampus, the retrosplenial cortex and the caudate putamen. Of note, the observed alterations in spatial cognition were associated with increased MEMRI signal intensity. These findings indicate that aberrant increased basal neuronal activity may contribute to the spatial cognitive function impairment at early stage of AD, and may further suggest the potential use of MEMRI to predict cognitive impairments. Early intervention that targets aberrant neuronal activity may be crucial to prevent cognitive impairment.

Blood oxygen level-dependent signals via fMRI in the mood-regulating circuit using two animal models of depression are reversed by chronic escitalopram treatment.

BACKGROUND: People exposed to stressful experience are at increased risk of the development of depression. A number of functional imaging studies have found disturbances in the mood-regulating circuit of the stress-exposed depressed patients, although few animal imaging studies have been undertaken addressing the brain functional changes of depression. METHODS: Two rat models of depression: maternal separation (MS) and chronic unpredictable mild stress (CUMS), imitating early life stress and adult stress respectively, were administered with escitalopram. The differences in functional brain changes were determined by blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). RESULTS: Increased BOLD activation was observed in some brain regions of MS and CUMS animals, such as the bilateral hypothalamus, limbic system, hippocampus and frontal lobe, which were parts of mood-regulating circuit. Furthermore, the MS- and CUMS-induced increases in BOLD activation were partially attenuated by chronic escitalopram treatment. CONCLUSIONS: These results suggested hyperactivation of mood-regulating circuit at baseline in the depressed animals exposed to stressful experience, and escitalopram can at least partially reverse these effects.

Specific Correlation between the Hegu Point (LI4) and the Orofacial Part: Evidence from an fMRI Study.

Acupoint specificity is a foundational concept in acupuncture theory. It is closely related to the function of the acupoint. In this study, we sought to probe the central mechanisms of the specific correlation between LI4 and orofacial part in Bell's palsy patients. In total, 36 patients with left Bell's palsy were divided into three groups in random order, and each group received transcutaneous electrical acupoint stimulation (TEAS) at only one of three acupoints (LI4, ST6, and a sham point). A single-block fMRI design paradigm was applied to separately detect neural activity related to different stages of TEAS (prestimulation resting state, stimulation, and poststimulation resting state). Functional magnetic resonance imaging data were acquired during TEAS. There were extensive neuronal activities in the LI4 and ST6 groups and significant differences between stimulation at real and sham points. Brain regions were activated more by real acupoint TEAS than by sham point TEAS. Brain regions that were activated with LI4 and ST6 were broadly overlapping and adjacent. Our results provide supplementary neuroimaging evidence for the existence of acupoint specificity. These results may confirm the central mechanisms of the specific correlation between the Hegu point and the orofacial part.

Dynamic metabolic changes after permanent cerebral ischemia in rats with/without post-stroke exercise: a positron emission tomography (PET) study.

OBJECTIVES: Recent studies have suggested that rehabilitation therapy can accelerate functional recovery after a stroke. Although often overlooked, the cortical hemisphere contralateral to an infarction plays an important role. This study investigates alterations in metabolism of both the damaged ('ipsilateral') as well as the undamaged ('contralateral') hemisphere using (18)F-fluorodeoxyglucose (FDG)-micro-positron emission tomography (PET) in a rat permanent stroke model (with or without post-injury exercise) in order to elucidate the relative importance of either hemisphere to the recovery process following stroke. METHODS: Thirty-six adult, male Sprague-Dawley rats were divided into four groups before subsequent surgery: sham controls with or without exercise, and ischemic ('stroke') groups with or without exercise. Fluorodeoxyglucose micro-PET imaging was performed at 7, 14, and 21 days after the designated procedure according to group assignment. The imaging data was analyzed by ANOVA using SPMratIHEP software. RESULTS: Both exercise and ischemia have measurable effects on the motor cortex as well as on the striatum, the effects of which notably include the contralateral hemisphere. To that end, regions of the contralateral motor cortex and striatum have been found to be in a hypermetabolic state following exercise. We further observed that exercise reversed the hypometabolism caused by ischemia back to control levels from day 7 through day 21 on the ipsilateral side. Its effect on the contralateral hemisphere, notably, bolsters an already vigorous response observed after ischemic insult. Thus, the beneficial effect of exercise, as inferred by an increase in metabolic activity, is evident in both hemispheres. DISCUSSION: These findings suggest that the contralateral hemisphere can compensate for the damaged cortex by remodeling neuronal activity. Thus, clinical treatments specifically targeted to the 'intact' hemisphere following stroke may provide a complimentary strategy for promoting recovery of functional deficits and for improving quality of life in stroke patients.

FMRI evidence of acupoints specificity in two adjacent acupoints.

Objectives. Acupoint specificity is the foundation of acupuncture treatment. The aim of this study is to investigate whether the acupoint specificity exists in two adjacent acupoints. Design and Setting. Two adjacent real acupoints, LR3 (Taichong) and ST44 (Neiting), and a nearby nonacupoint were selected. Thirty-three health volunteers were divided into three groups in random order, and each group only received acupuncture at one of the three points. While they received acupuncture, fMRI scan was performed. Results. The common cerebral activated areas responding to LR3 and ST44 included the contralateral primary somatosensory area (SI) and ipsilateral cerebellum. Acupuncture at LR3 specifically activated contralateral middle occipital gyrus, ipsilateral medial frontal gyrus, superior parietal lobe, middle temporal gyrus, rostral anterior cingulate cortex (rACC), lentiform nucleus, insula, and contralateral thalamus. Stimulation at ST44 selectively activated ipsilateral secondary somatosensory area (SII), contralateral middle frontal gyrus, inferior frontal gyrus, lingual gyrus, lentiform nucleus, and bilateral posterior cingulate cortex (PCC). Conclusions. Acupuncture at adjacent acupoints elicits distinct cerebral activation patterns, and those specific patterns might be involved in the mechanism of the specific therapeutic effects of different acupoints.

MRI assessment of amplitude of low-frequency fluctuation in rat brains with acute cerebral ischemic stroke.

To investigate fluctuations in the amplitude of low-frequency blood oxygenation level-dependent (BOLD) fMRI during acute brain ischemia, and to evaluate the use of amplitude of low-frequency fluctuations (ALFFs) in resting state fMRI for assessing super-acute focal cerebral ischemic stroke. A super-acute stroke model with middle cerebral artery occlusion (MCAO) in the rat was employed. Spontaneous fluctuations were recorded using a series of gradient echo-planar imaging (EPI) images before and 30 min, 60 min, 2 h, 6 h, 12 h, and 24 h after MCAO. After preprocessing, serial fMRI data were obtained by fast Fourier transformation to calculate the ALFFs. Statistical parametric mapping software was used for the statistical analysis of ALFFs. T2-weighted images and diffusion weighted images (DWI) were also performed to detect the ischemic lesion. The signal intensities of abnormal ALFFs increased and migrated from the core of the ischemic lesion areas to the edge of lesion following MCAO. The dynamic changes in the ALFF maps demonstrated that the sizes of the ALFF regions exceeded beyond the borderline of the DWI lesions during the super-acute ischemic stroke stage. There was a significant difference in the ALFFs maps between the ischemic stroke group and the control group (P<0.005; cluster size>10 voxels), which mainly occurred in the periphery of the ischemic region in the cortex. These data suggest that ALFF maps provide hemodynamic BOLD information on neural activity, and have potential for predicting survival and prognosis of acute ischemic brain tissues.

Hippocampal neurochemistry is involved in the behavioural effects of neonatal maternal separation and their reversal by post-weaning environmental enrichment: a magnetic resonance study.

Exposure to early life stress results in behavioural changes, and these dysfunctions may persist throughout adulthood. In this study, we investigated whether hippocampus volume and neurochemical changes were involved in the appearance of these effects in the maternal separation (MS) animal model using the noninvasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Sprague-Dawley rats exposed to MS for 180 min from postnatal days (PND) 2-14 demonstrated decreased sucrose preference, increased immobility in the forced swimming test (FST), and impaired memory in the Morris water maze in adulthood. Environmental enrichment (EE) (PND 21-60) could ameliorate the effects of MS on sucrose preference and learning and memory but not on immobility in the FST. In addition, EE significantly increased N-acetylaspartate (NAA) of MS animals. However, we did not find an effect of MS or EE on hippocampal volume. These results indicate the involvement of hippocampal neurochemistry in the behavioural changes that result from early stressful life events and their modification by post-weaning EE. Thus changes in NAA, as a measure of neuronal integrity, appear to be a sensitive correlate of these behavioural effects.