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Diabetes, Obesity & Metabolism Mar 2024To characterize the comparative contributions of different glycaemic indicators to cognitive dysfunction, and further investigate the associations between the most...
AIMS
To characterize the comparative contributions of different glycaemic indicators to cognitive dysfunction, and further investigate the associations between the most significant indicator and cognitive function, along with related cerebral alterations.
MATERIALS AND METHODS
We performed a cross-sectional study in 449 subjects with type 2 diabetes who completed continuous glucose monitoring and cognitive assessments. Of these, 139 underwent functional magnetic resonance imaging to evaluate cerebral structure and olfactory neural circuit alterations. Relative weight and Sobol's sensitivity analyses were employed to characterize the comparative contributions of different glycaemic indicators to cognitive dysfunction.
RESULTS
Complexity of glucose time series index (CGI) was found to have a more pronounced association with mild cognitive impairment (MCI) compared to glycated haemoglobin, time in range, and standard deviation. The proportion and multivariable-adjusted odds ratios (ORs) for MCI increased with descending CGI tertile (Tertile 1: reference group [≥4.0]; Tertile 2 [3.6-4.0] OR 1.23, 95% confidence interval [CI] 0.68-2.24; Tertile 3 [<3.6] OR 2.27, 95% CI 1.29-4.00). Decreased CGI was associated with cognitive decline in executive function and attention. Furthermore, individuals with decreased CGI displayed reduced olfactory activation in the left orbitofrontal cortex (OFC) and disrupted functional connectivity between the left OFC and right posterior cingulate gyrus. Mediation analysis demonstrated that the left OFC activation partially mediated the associations between CGI and executive function.
CONCLUSION
Decreased glucose complexity closely relates to cognitive dysfunction and olfactory brain activation abnormalities in diabetes.
Topics: Adult; Humans; Diabetes Mellitus, Type 2; Glucose; Time Factors; Cross-Sectional Studies; Blood Glucose Self-Monitoring; Blood Glucose; Cognition; Cognitive Dysfunction; Magnetic Resonance Imaging; Brain
PubMed: 37994378
DOI: 10.1111/dom.15376 -
Glia Jan 2024The postnatal neural stem cell (NSC) pool hosts quiescent and activated radial glia-like NSCs contributing to neurogenesis throughout adulthood. However, the underlying...
The postnatal neural stem cell (NSC) pool hosts quiescent and activated radial glia-like NSCs contributing to neurogenesis throughout adulthood. However, the underlying regulatory mechanism during the transition from quiescent NSCs to activated NSCs in the postnatal NSC niche is not fully understood. Lipid metabolism and lipid composition play important roles in regulating NSC fate determination. Biological lipid membranes define the individual cellular shape and help maintain cellular organization and are highly heterogeneous in structure and there exist diverse microdomains (also known as lipid rafts), which are enriched with sugar molecules, such as glycosphingolipids. An often overlooked but key aspect is that the functional activities of proteins and genes are highly dependent on their molecular environments. We previously reported that ganglioside GD3 is the predominant species in NSCs and that the reduced postnatal NSC pools are observed in global GD3-synthase knockout (GD3S-KO) mouse brains. The specific roles of GD3 in determining the stage and cell-lineage determination of NSCs remain unclear, since global GD3S-KO mice cannot distinguish if GD3 regulates postnatal neurogenesis or developmental impacts. Here, we show that inducible GD3 deletion in postnatal radial glia-like NSCs promotes NSC activation, resulting in the loss of the long-term maintenance of the adult NSC pools. The reduced neurogenesis in the subventricular zone (SVZ) and the dentate gyrus (DG) of GD3S-conditional-knockout mice led to the impaired olfactory and memory functions. Thus, our results provide convincing evidence that postnatal GD3 maintains the quiescent state of radial glia-like NSCs in the adult NSC niche.
Topics: Mice; Animals; Neural Stem Cells; Neurogenesis; Gangliosides; Cell Differentiation; Mice, Knockout
PubMed: 37667994
DOI: 10.1002/glia.24468 -
Frontiers in Aging Neuroscience 2023To determine changes in protein expression related to brain aging and imaging features in mice after chronic hypoxia exposure at high altitude.
OBJECTIVE
To determine changes in protein expression related to brain aging and imaging features in mice after chronic hypoxia exposure at high altitude.
METHOD
A total of 24 healthy 4-week-old mice were randomly divided into high altitude hypoxia (HH) and plain control (PC) groups ( = 8 per group). HH mice were transported from Xi'an (450 m above sea level) to Maduo (4,300 m above sea level) while PC mice were raised in Xi'an. After 6 months, 7.0T magnetic resonance imaging (MRI) was performed. All mice completed T2-weighted imaging (T2WI), diffusion tensor imaging (DTI), resting-state functional MRI (rs-fMRI), arterial spin labeling (ASL), and magnetic resonance angiography (MRA) examinations. Next, brain slices were prepared and Nissl staining was used to observe morphological changes in neurons. Ultrastructural changes in neurons were observed by transmission electron microscopy. Expression changes of Caspase-3, klotho, P16, P21, and P53 at the gene and protein levels were detected by real-time PCR (RT-PCR) and Western blot.
RESULTS
The number of neuronal Nissl bodies in the hippocampus and frontal cortex was significantly decreased in the HH group compared to the PC group. Some hippocampal and frontal cortical neurons were apoptotic, the nuclei were wrinkled, chromatin was aggregated, and most mitochondria were mildly swollen (crista lysis, fracture). Compared with the PC group, the HH group showed elevated expression of caspase-3 mRNA, P16 mRNA, P21 mRNA, and P53 mRNA in the hippocampus and frontal cortex. Expression of Klotho mRNA in the frontal cortex was also significantly decreased. Western blot results showed that caspase-3 protein expression in the hippocampus and frontal cortex of the HH group was increased compared with the PC group. Moreover, there was decreased Klotho protein expression and significantly increased P-P53 protein expression. Compared with the PC group, expression of P16 protein in the frontal cortex of the HH group was increased and the gray matter (GM) volume in the left visceral area, left caudate nucleus, and left piriform cortex was decreased. Furthermore, the amplitude of low frequency fluctuation was decreased in the left posterior nongranular insular lobe, right small cell reticular nucleus, left flocculus, left accessory flocculus, and left primary auditory area, but increased in the GM layer of the left superior colliculus. Regional homogeneity was decreased in the left and right olfactory regions, but increased in the left bed nucleus. After exposure to high altitude, functional connectivity (FC) between the bilateral caudate nucleus and thalamus, corpus callosum, cingulate gyrus, anterior limbic cortex, globus pallidus, and hippocampus was weakened. FC between the right caudate nucleus and hypothalamus and entorhinal cortex was also weakened. The fractional anisotropy value of the left hippocampus was decreased in the HH group. Compared with the PC group, the HH group showed significantly increased inner diameters of the bilateral common carotid artery and left internal carotid artery. The cerebral blood flow values of the bilateral cortex and bilateral hippocampus in the HH group did not change significantly.
CONCLUSION
Taken together, our findings show that chronic hypoxia exposure at high altitude may promote neuronal apoptosis and abnormal expression of related proteins, changing the structure and function of brain. These changes may contribute to brain aging.
PubMed: 37849650
DOI: 10.3389/fnagi.2023.1268230 -
The Journal of Neuroscience : the... Nov 2023It is known that humans and rodents are capable of transmitting stress to their naive partners via social interaction. However, a comprehensive understanding of...
It is known that humans and rodents are capable of transmitting stress to their naive partners via social interaction. However, a comprehensive understanding of transmitted stress, which may differ from authentic stress, thus revealing unique neural mechanisms of social interaction resulting from transmitted stress and the associated anxiety, is missing. We used, in the present study, maternal separation (MS) as a stress model to investigate whether MS causes abnormal behavior in adolescence. A key concern in the analysis of stress transmission is whether the littermates of MS mice who only witness MS stress ("Partners") exhibit behavioral abnormalities similar to those of MS mice themselves. Of special interest is the establishment of the neural mechanisms underlying transmitted stress and authentic stress. The results show that Partners, similar to MS mice, exhibit anxiety-like behavior and hyperalgesia after witnessing littermates being subjected to early-life repetitive MS. Electrophysiological analysis revealed that mice subjected to MS demonstrate a reduction in both the excitatory and inhibitory synaptic activities of parvalbumin interneurons (PVINs) in the anterior cingulate cortex (ACC). However, Partners differed from MS mice in showing an increase in the number and excitability of GABAergic PVINs in the ACC and in the ability of chemogenetic PVIN inactivation to eliminate abnormal behavior. Furthermore, the social transfer of anxiety-like behavior required intact olfactory, but not visual, perception. This study suggests a functional involvement of ACC PVINs in mediating the distinct neural basis of transmitted anxiety. The anterior cingulate cortex (ACC) is a critical brain area in physical and social pain and contributes to the exhibition of abnormal behavior. ACC glutamatergic neurons have been shown to encode transmitted stress, but it remains unclear whether inhibitory ACC neurons also play a role. We evaluate, in this study, ACC neuronal, synaptic and network activities and uncover a critical role of parvalbumin interneurons (PVINs) in the expression of transmitted stress in adolescent mice who had witnessed MS of littermates in infancy. Furthermore, inactivation of ACC PVINs blocks transmitted stress. The results suggest that emotional contagion has a severe effect on brain function, and identify a potential target for the treatment of transmitted anxiety.
Topics: Humans; Mice; Animals; Gyrus Cinguli; Parvalbumins; Maternal Deprivation; Neurons; Anxiety
PubMed: 37845036
DOI: 10.1523/JNEUROSCI.0558-23.2023 -
Journal of Neuroradiology = Journal de... Sep 2023Voxel-based morphometry (VBM) and surfaced-based morphometry (SBM) investigate the characteristics of gray matter (GM) in various diseases such as post-traumatic anosmia...
PURPOSE AND BACKGROUND
Voxel-based morphometry (VBM) and surfaced-based morphometry (SBM) investigate the characteristics of gray matter (GM) in various diseases such as post-traumatic anosmia (PTA). This study uses SBM and VBM to examine neuroanatomical measurements of GM and its functional correlates in patients with PTA.
METHODS
MRI images and olfactory test results were collected from 39 PTA patients and 39 healthy controls. Sniffin' Sticks test was used to assess olfactory function. GM structure was analyzed using CAT12 and FreeSurfer, and olfactory bulb (OB) volume and olfactory sulcus (OS) depth were calculated using 3D-Slicer.
RESULTS
Anosmic patients showed lower scores in the Sniffin' Sticks olfactory test, as well as reduction of OB volume and OS depth compared to control subjects. In these patients, overlapping changes were found between the VBM and SBM findings in the areas with significant effects, in particular, orbitofrontal cortex, superior and middle frontal gyrus, superior and middle temporal gyrus, anterior cingulate cortex, and insular cortex. Using SBM, decreased cortical thickness clusters were located in inferior and superior parietal gyrus. Further analysis in the region of interest demonstrated correlations between the orbitofrontal cortex and odor threshold score as well as the middle frontal gyrus and smell loss duration.
CONCLUSION
These findings show that the morphological alterations in the OB, OS, and the central olfactory pathways might contribute to the pathogenic mechanism of olfactory dysfunction after head injury.
Topics: Humans; Anosmia; Olfaction Disorders; Brain; Gray Matter; Gyrus Cinguli; Magnetic Resonance Imaging
PubMed: 36610937
DOI: 10.1016/j.neurad.2022.11.005 -
Clinical Radiology Feb 2024To investigate peripheral and central olfactory pathways using cranial magnetic resonance imaging (MRI) in human immunodeficiency virus (HIV)-infected patients.
AIM
To investigate peripheral and central olfactory pathways using cranial magnetic resonance imaging (MRI) in human immunodeficiency virus (HIV)-infected patients.
MATERIALS AND METHODS
The cranial MRI images of 37 HIV-infected adult patients and 37 adults without HIV infection having normal cranial MRI results were included in the study. In both groups, olfactory bulb (OB) volume and olfactory sulcus (OS) depth; and insular gyrus and corpus amygdala areas were measured using cranial MRI. In the HIV group, disease duration, HIV RNA, and CD4 lymphocyte count and levels as a percentage were also recorded.
RESULTS
The HIV group had significantly lower bilateral OB volumes, insular gyrus and corpus amygdala areas compared to the control group. The HIV group showed positive correlations between OB volumes, OS depths, insular gyrus, and corpus amygdala areas bilaterally. Increases in OB volumes and OS depths were associated with an increase in the insular gyrus area. The corpus amygdala and insular gyrus areas increased similarly. There was no significant correlation between age, gender, disease duration, CD4 lymphocyte count and per cent, HIV RNA values, and the measurement values of the central and peripheral olfactory regions.
CONCLUSION
A decrease in olfactory regions of OB, insular gyrus, and corpus amygdala in HIV-infected patients shows that HIV infection may cause olfactory impairment. There is no correlation between disease duration and olfactory impairment. It may be related to neuroinflammation, HIV-related brain atrophy, acquired immunodeficiency syndrome (AIDS) dementia complex, or neurocognitive impairment, which are the other explanations for the olfactory impairment in HIV. The possible toxicity from antiretroviral therapy (ART) may be another cause that should be investigated further.
Topics: Adult; Humans; HIV; Olfactory Pathways; HIV Infections; Magnetic Resonance Imaging; Olfaction Disorders; RNA
PubMed: 38030506
DOI: 10.1016/j.crad.2023.10.035 -
Neurological Sciences : Official... Jan 2024Our study aimed to explore the functional connectivity alterations between cortical nodes of resting-state networks in Parkinson's disease (PD) patients with wearing-off...
OBJECTIVE
Our study aimed to explore the functional connectivity alterations between cortical nodes of resting-state networks in Parkinson's disease (PD) patients with wearing-off (WO) at different levels.
METHODS
Resting-state functional magnetic resonance imaging was performed on 36 PD patients without wearing-off (PD-nWO), 30 PD patients with wearing-off (PD-WO), and 35 healthy controls (HCs) to extract functional networks. Integrity, network, and edge levels were calculated for comparison between groups. UPDRS-III, MMSE, MOCA, HAMA, and HAMD scores were collected for further regression analysis.
RESULTS
We observed significantly reduced connectivity strength in the dorsal attention network and limbic network in the PD-WO group compared with the HC group. The PD-WO group showed a decreased degree of functional connectivity at 12 nodes, including the bilateral orbital part of the superior frontal gyrus, right olfactory cortex, left medial orbital part of the superior frontal gyrus, bilateral gyrus rectus, right parahippocampal gyrus, right thalamus, left Heschl's gyrus, right superior temporal gyrus part of the temporal pole, left middle temporal gyrus part of the temporal pole, and right inferior temporal gyrus. Furthermore, the PD-WO group showed a significantly lower degree of functional connectivity in the left orbital part of the superior frontal gyrus and right gyrus rectus than the PD-nWO group. Internetwork analysis indicated reduced functional connectivity in five pairs of resting-state networks.
CONCLUSION
Our results demonstrated altered intra- and internetwork connections in PD patients with WO. These findings will facilitate a better understanding of the distinction between the network changes in PD pathophysiology.
Topics: Humans; Brain Mapping; Magnetic Resonance Imaging; Parkinson Disease; Prefrontal Cortex; Temporal Lobe
PubMed: 37578631
DOI: 10.1007/s10072-023-07005-2 -
Neuroendocrinology 2024Brain insulin reactivity has been reported in connection with systematic energy metabolism, enhancement in cognition, olfactory sensitivity, and neuroendocrine circuits.... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Brain insulin reactivity has been reported in connection with systematic energy metabolism, enhancement in cognition, olfactory sensitivity, and neuroendocrine circuits. High receptor densities exist in regions important for sensory processing. The main aim of the study was to examine whether intranasal insulin would modulate the activity of areas in charge of olfactory-visual integration.
METHODS
As approach, a placebo-controlled double-blind within crossover design was chosen. The experiments were conducted in a research unit of a university hospital. On separate mornings, twenty-six healthy normal-weight males aged between 19 and 31 years received either 40 IU intranasal insulin or placebo vehicle. Subsequently, they underwent 65 min of functional magnetic resonance imaging whilst performing an odor identification task. Functional brain activations of olfactory, visual, and multisensory integration as well as insulin versus placebo were assessed. Regarding the odor identification task, reaction time, accuracy, pleasantness, and intensity measurements were taken to examine the role of integration and treatment. Blood samples were drawn to control for peripheral hormone concentrations.
RESULTS
Intranasal insulin administration during olfactory-visual stimulation revealed strong bilateral engagement of frontoinsular cortices, anterior cingulate, prefrontal cortex, mediodorsal thalamus, striatal, and hippocampal regions (p ≤ 0.001 familywise error [FWE] corrected). In addition, the integration contrast showed increased activity in left intraparietal sulcus, left inferior frontal gyrus, left superior frontal gyrus, and left middle frontal gyrus (p ≤ 0.013 FWE corrected).
CONCLUSIONS
Intranasal insulin application in lean men led to enhanced activation in multisensory olfactory-visual integration sites and salience hubs which indicates stimuli valuation modulation. This effect can serve as a basis for understanding the connection of intracerebral insulin and olfactory-visual processing.
Topics: Male; Humans; Young Adult; Adult; Brain; Visual Perception; Cerebral Cortex; Brain Mapping; Insulin; Magnetic Resonance Imaging
PubMed: 37634508
DOI: 10.1159/000533663 -
Pharmacological Research Mar 2024Neuronal death is one of the key pathologies in Alzheimer's disease (AD). How neuronal death begins in AD is far from clear, so clarifying this process may help develop...
Neuronal death is one of the key pathologies in Alzheimer's disease (AD). How neuronal death begins in AD is far from clear, so clarifying this process may help develop effective therapies. This study collected single-cell RNA sequencing data of 85 AD samples and 83 control samples, covering the prefrontal cortex, internal olfactory cortex, superior parietal lobe, superior frontal gyrus, caudal internal olfactory cortex, somatosensory cortex, hippocampus, superior frontal cortex and peripheral blood mononuclear cells. Additionally, spatial transcriptomic data of coronal sections from 6 App AD mice and 6 control C57Bl/6 J mice were acquired. The main single-cell and spatial transcriptomics results were experimentally validated in wild type and 5 × FAD mice. We found that the microglia subpopulation Mic_PTPRG can communicate with specific types of neurons (especially excitatory ExNeu_PRKN_VIRMA and inhibitory InNeu_PRKN_VIRMA neuronal subpopulations) and cause them to express PTPRG during AD progression. Within neurons, PTPRG binds and upregulates the mA methyltransferase VIRMA, thus inhibiting translation of PRKN mRNA to prevent the clearance of damaged mitochondria in neurons through suppressing mitophagy. As the disease progresses, the energy and nutrient metabolic pathways in neurons are reprogrammed, leading to their death. Consistently, we determined that PTPTRG can physically interact with VIRMA in mouse brains and PRKN is significantly upregulated in 5 × FAD mouse brain. Altogether, our findings demonstrate that PTPRG activates the mA methyltransferase VIRMA to block mitophagy-mediated neuronal death in AD, which is a potential pathway, through which microglia and neuronal PTPRG modify neuronal connections in the brain during AD progression.
Topics: Animals; Mice; Alzheimer Disease; Leukocytes, Mononuclear; Mitophagy; Gene Expression Profiling; Methyltransferases; Mice, Inbred C57BL
PubMed: 38325728
DOI: 10.1016/j.phrs.2024.107098 -
Neurochemistry International May 2024Impaired olfactory function may be associated with the development of psychiatric disorders such as depression and anxiety; however, knowledge on the mechanisms...
Impaired olfactory function may be associated with the development of psychiatric disorders such as depression and anxiety; however, knowledge on the mechanisms underlying psychiatric disorders is incomplete. A reversible model of olfactory dysfunction, zinc sulfate (ZnSO) nasal-treated mice, exhibit depression-like behavior accompanying olfactory dysfunction. Therefore, we investigated olfactory function and depression-like behaviors in ZnSO-treated mice using the buried food finding test and tail suspension test, respectively; investigated the changes in the hippocampal microglial activity and neurogenesis in the dentate gyrus by immunohistochemistry; and evaluated the inflammation and microglial polarity related-proteins in the hippocampus using western blot study. On day 14 after treatment, ZnSO-treated mice showed depression-like behavior in the tail suspension test and recovery of the olfactory function in the buried food finding test. In the hippocampus of ZnSO-treated mice, expression levels of ionized calcium-binding adapter molecule 1 (Iba1), cluster of differentiation 40, inducible nitric oxide synthase, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, cleaved caspase-3, as well as the number of Iba1-positive cells and cell body size increased, and arginase-1 expression and neurogenesis decreased. Except for the increased IL-6, these changes were prevented by a microglia activation inhibitor, minocycline. The findings suggest that neuroinflammation due to polarization of M1-type hippocampal microglia is involved in depression accompanied with olfactory dysfunction.
Topics: Humans; Mice; Animals; Depression; Microglia; Interleukin-6; Hippocampus; Olfaction Disorders
PubMed: 38490486
DOI: 10.1016/j.neuint.2024.105723