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Translational Psychiatry Mar 2021Early detection of patients with late-life depression (LLD) with a high risk of developing dementia contributes to early intervention. Odor identification (OI)...
Early detection of patients with late-life depression (LLD) with a high risk of developing dementia contributes to early intervention. Odor identification (OI) dysfunction serves as a marker for predicting dementia, but whether OI dysfunction increases the risk of dementia in LLD patients remains unclear. The present study aimed to explore the interactive effect of LLD and OI dysfunction on the risk of dementia and its underlying neuroimaging changes. One hundred and fifty-seven LLD patients and 101 normal controls were recruited, and data on their OI, cognition, activity of daily living (ADL), and resting-state functional magnetic resonance imaging were collected. Two × two factorial analyses were used to analyze the interactive effects of LLD and OI dysfunction on neuropsychological and neuroimaging abnormalities. Mediation analyses were used to explore whether abnormalities detected by neuroimaging mediated the the associations between OI and cognition/ADL. The results suggested that LLD and OI dysfunction exhibited additive effects on reduced ADL, global cognition and memory scores, as well as neuroimaging variables including (i) increased fractional amplitude of low-frequency fluctuation (fALFF) in the right orbitofrontal cortex and right precentral cortex, and (ii) increased regional homogeneity (ReHo) in the left hippocampus/fusiform gyrus, etc. In addition, these increased fALFF and ReHo values were associated with reduced neuropsychological scores (ADL, global cognition, memory, and language). Moreover, ReHo of the left hippocampus/fusiform gyrus completely mediated the relationship between OI and ADL, and partially mediated the relationship between OI and global cognition. Overall, mediated by the hypersynchronization of the left hippocampus/fusiform gyrus, OI dysfunction may increase the risk of dementia in LLD patients.
Topics: Brain; Dementia; Depression; Hippocampus; Humans; Magnetic Resonance Imaging; Olfaction Disorders; Temporal Lobe
PubMed: 33731679
DOI: 10.1038/s41398-021-01291-0 -
Experimental Neurology Jun 2010While a massive and progressive neuronal loss in specific areas such as the hippocampus and cortex unequivocally underlies cognitive deterioration and memory loss in... (Review)
Review
While a massive and progressive neuronal loss in specific areas such as the hippocampus and cortex unequivocally underlies cognitive deterioration and memory loss in Alzheimer's disease, noteworthy alterations take place in the neurogenic microenvironments, namely, the subgranule layer of the dentate gyrus and the subventricular zone. Compromised neurogenesis presumably takes place earlier than onset of hallmark lesions or neuronal loss, and may play a role in the initiation and progression of neuropathology in Alzheimer's disease. Neurogenesis in the adult brain is thought to play a role in numerous forms and aspects of learning and memory and contribute to the plasticity of the hippocampus and olfactory system. Misregulated or impaired neurogenesis on the other hand, may compromise plasticity and neuronal function in these areas and exacerbate neuronal vulnerability. Interestingly, increasing evidence suggests that molecular players in Alzheimer's disease, including PS1, APP and its metabolites, play a role in adult neurogenesis. In addition, recent studies suggest that alterations in tau phosphorylation are pronounced in neurogenic areas, and may interfere with the potential central role of tau proteins in neuronal maturation and differentiation. On the other hand, numerous neurogenic players, such as Notch-1, ErbB4 and L1 are substrates of alpha- beta- and gamma- secretase that play a major role in Alzheimer's disease. This review will discuss current knowledge concerning alterations of neurogenesis in Alzheimer's disease with specific emphasis on the cross-talk between signaling molecules involved in both processes, and the ways by which familial Alzheimer's disease-linked dysfunction of these signaling molecules affect neurogenesis in the adult brain.
Topics: Alzheimer Disease; Brain; Humans; Neurogenesis
PubMed: 19699201
DOI: 10.1016/j.expneurol.2009.08.009 -
Brain : a Journal of Neurology Aug 2019Generalized convulsive status epilepticus is a life-threatening emergency, because recurrent convulsions can cause death or injury. A common form of generalized...
Generalized convulsive status epilepticus is a life-threatening emergency, because recurrent convulsions can cause death or injury. A common form of generalized convulsive status epilepticus is of focal onset. The neuronal circuits activated during seizure spread from the hippocampus, a frequent site of seizure origin, to the bilateral motor cortex, which mediates convulsive seizures, have not been delineated. Status epilepticus was initiated by electrical stimulation of the hippocampus. Neurons transiently activated during seizures were labelled with tdTomato and then imaged following brain slice clearing. Hippocampus was active throughout the episode of status epilepticus. Neuronal activation was observed in hippocampus parahippocampal structures: subiculum, entorhinal cortex and perirhinal cortex, septum, and olfactory system in the initial phase status epilepticus. The tdTomato-labelled neurons occupied larger volumes of the brain as seizures progressed and at the peak of status epilepticus, motor and somatosensory cortex, retrosplenial cortex, and insular cortex also contained tdTomato-labelled neurons. In addition, motor thalamic nuclei such as anterior and ventromedial, midline, reticular, and posterior thalamic nuclei were also activated. Furthermore, circuits proposed to be crucial for systems consolidation of memory: entorhinal cortex, retrosplenial cortex, cingulate gyrus, midline thalamic nuclei and prefrontal cortex were intensely active during periods of generalized tonic-clonic seizures. As the episode of status epilepticus waned, smaller volume of brain was activated. These studies suggested that seizure spread could have occurred via canonical thalamocortical pathway and many cortical structures involved in memory consolidation. These studies may help explain retrograde amnesia following seizures.
Topics: Amnesia, Retrograde; Animals; Brain; Brain Mapping; Cerebral Cortex; Electroshock; Genes, Reporter; Hippocampus; Memory Consolidation; Mice; Neural Pathways; Neurons; Olfactory Bulb; Seizures; Single-Blind Method; Status Epilepticus; Thalamic Nuclei
PubMed: 31237945
DOI: 10.1093/brain/awz170 -
BioRxiv : the Preprint Server For... Sep 2023Schizophrenia is marked by poor social functioning that can have a severe impact on quality of life and independence, but the underlying neural circuity is not well...
Schizophrenia is marked by poor social functioning that can have a severe impact on quality of life and independence, but the underlying neural circuity is not well understood. Here we used a translational model of subanesthetic ketamine in mice to delineate neural pathways in the brain linked to social deficits in schizophrenia. Mice treated with chronic ketamine (30 mg/kg/day for 10 days) exhibit profound social and sensorimotor deficits as previously reported. Using three- dimensional c-Fos immunolabeling and volume imaging (iDISCO), we show that ketamine treatment resulted in hypoactivation of the lateral septum (LS) in response to social stimuli. Chemogenetic activation of the LS rescued social deficits after ketamine treatment, while chemogenetic inhibition of previously active populations in the LS (i.e. social engram neurons) recapitulated social deficits in ketamine-naïve mice. We then examined the translatome of LS social engram neurons and found that ketamine treatment dysregulated genes implicated in neuronal excitability and apoptosis, which may contribute to LS hypoactivation. We also identified 38 differentially expressed genes (DEGs) in common with human schizophrenia, including those involved in mitochondrial function, apoptosis, and neuroinflammatory pathways. Chemogenetic activation of LS social engram neurons induced downstream activity in the ventral part of the basolateral amygdala, subparafascicular nucleus of the thalamus, intercalated amygdalar nucleus, olfactory areas, and dentate gyrus, and it also reduces connectivity of the LS with the piriform cortex and caudate-putamen. In sum, schizophrenia-like social deficits may emerge via changes in the intrinsic excitability of a discrete subpopulation of LS neurons that serve as a central hub to coordinate social behavior via downstream projections to reward, fear extinction, motor and sensory processing regions of the brain.
PubMed: 37609170
DOI: 10.1101/2023.08.08.552372 -
Journal of Neurochemistry Dec 2018In the adult mammalian brain, neural stem cells (NSCs) reside in two neurogenic regions, the walls of the lateral ventricles, and the subgranular zone of the... (Review)
Review
In the adult mammalian brain, neural stem cells (NSCs) reside in two neurogenic regions, the walls of the lateral ventricles, and the subgranular zone of the hippocampus, which generate new neurons for the olfactory bulb and dentate gyrus, respectively. These adult NSCs retain their self-renewal ability and capacity to differentiate into neurons and glia as demonstrated by in vitro studies. However, their contribution to tissue repair in disease and injury is limited, lending credence to the claim by prominent neuropathologist Ramón y Cajal that 'once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably'. However, recent progress toward understanding the fundamental biology of adult NSCs and their role in pathological conditions has provided new insight into the potential therapeutic utility of endogenous NSCs. In this short review, we highlight two topics: the altered behavior of NSCs after brain damage and the dysfunction of NSCs and oligodendrocyte precursor cells, another type of undifferentiated cell in the adult brain, in mood affective disorders.
Topics: Brain; Brain Injuries; Humans; Mental Disorders; Mood Disorders; Neural Stem Cells; Neurogenesis; Oligodendroglia
PubMed: 30028510
DOI: 10.1111/jnc.14557 -
Brain and Behavior Apr 2023In patients with mild cognitive impairment, pathological changes begin in the amygdala (AMG) and hippocampus (HI), especially in the parahippocampal gyrus and entorhinal...
INTRODUCTION
In patients with mild cognitive impairment, pathological changes begin in the amygdala (AMG) and hippocampus (HI), especially in the parahippocampal gyrus and entorhinal cortex (ENT). These areas play an important role in olfactory detection and recognition. It is important to understand how subtle signs of olfactory disability relate to the functions of the above-mentioned regions, as well as the orbitofrontal cortex (OFC). In this study, we evaluated brain activation using functional magnetic resonance imaging (fMRI), performed during the presentation of olfactory stimuli (classified as "normal odors" not inducing memory retrieval), and investigated the relationships of the blood oxygen level-dependent (BOLD) signal with olfactory detection and recognition abilities in healthy elderly subjects.
METHODS
Twenty-four healthy elderly subjects underwent fMRI during olfaction, and raw mean BOLD signals were extracted from regions of interest, including bilateral regions (AMG, HI, parahippocampus, and ENT) and orbitofrontal subregions (frontal inferior OFC, frontal medial OFC, frontal middle OFC, and frontal superior OFC). Multiple regression and path analyses were conducted to understand the roles of these areas in olfactory detection and recognition.
RESULTS
Activation of the left AMG had the greatest impact on olfactory detection and recognition, while the ENT, parahippocampus, and HI acted as a support system for AMG activation. Less activation of the right frontal medial OFC was associated with good olfactory recognition. These findings improve our understanding of the roles of limbic and prefrontal regions in olfactory awareness and identification in elderly individuals.
CONCLUSION
Functional decline of the ENT and parahippocampus crucially impacts olfactory recognition. However, AMG function may compensate for deficits through connections with frontal regions.
Topics: Humans; Aged; Odorants; Amygdala; Brain; Smell; Recognition, Psychology; Magnetic Resonance Imaging
PubMed: 36897168
DOI: 10.1002/brb3.2956 -
Acta Radiologica (Stockholm, Sweden :... Sep 2022Coronaviruses may lead to invasion of the central nervous system.
BACKGROUND
Coronaviruses may lead to invasion of the central nervous system.
PURPOSE
To investigate the effects of COVID-19 infection on smell using cranial magnetic resonance imaging (MRI).
MATERIAL AND METHODS
Cranial MRI scans of 23 patients with COVID-19 (patient group [PG]) and 23 healthy controls (HCs) were evaluated. Peripheric (olfactory bulb [OB] volume and olfactory sulcus [OS] depth) and central (insular gyrus and corpus amygdala areas) smell regions were measured.
RESULTS
Smell loss was present in nine patients (39.1%) in the PG. The means of the disease duration and antiviral treatment were 3.00 ± 2.35 and 5.65 ± 1.72 days, respectively. OB volumes of the PG were significantly lower than those of the HCs bilaterally. However, no significant differences were observed between the OS depth, insular gyrus, and corpus amygdala areas of both groups. The left corpus amygdala areas were both increased with the increased disease ( = 0.035, r = 0.442) and treatment durations ( = 0.037, r = 0.438). In the PG, longer treatment duration, increase in C-reactive protein (CRP), lymphocyte count decrease, and positive thoracic computed tomography (CT) involvement were related to OS depth decrease. Right corpus amygdala areas increased in patients with COVID-19 with increased D-dimer values, and thoracic CT involvement was detected.
CONCLUSION
COVID-19 disease affects the peripheric smell region of OBs and does not affect the central smell regions of the insular gyrus and corpus amygdala areas. The importance of our study is to detect MRI findings in patients with COVID-19 leading to odor disorders. These findings may help in diagnosing the disease at an early stage.
Topics: COVID-19; Humans; Magnetic Resonance Imaging; Olfaction Disorders; Olfactory Bulb; Smell
PubMed: 34282630
DOI: 10.1177/02841851211034043 -
European Journal of Nuclear Medicine... Aug 2021In the context of the worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), some patients report functional complaints after apparent...
PURPOSE
In the context of the worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), some patients report functional complaints after apparent recovery from COVID-19. This clinical presentation has been referred as "long COVID." We here present a retrospective analysis of F-FDG brain PET of long COVID patients from the same center with a biologically confirmed diagnosis of SARS-CoV-2 infection and persistent functional complaints at least 3 weeks after the initial infection.
METHODS
PET scans of 35 patients with long COVID were compared using whole-brain voxel-based analysis to a local database of 44 healthy subjects controlled for age and sex to characterize cerebral hypometabolism. The individual relevance of this metabolic profile was evaluated to classify patients and healthy subjects. Finally, the PET abnormalities were exploratory compared with the patients' characteristics and functional complaints.
RESULTS
In comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected). These metabolic clusters were highly discriminant to distinguish patients and healthy subjects (100% correct classification). These clusters of hypometabolism were significantly associated with more numerous functional complaints (brainstem and cerebellar clusters), and all associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia) (p < 0.05). In a more preliminary analysis, the metabolism of the frontal cluster which included the olfactory gyrus was worse in the 7 patients treated by ACE drugs for high blood pressure (p = 0.032), and better in the 3 patients that had used nasal decongestant spray at the infectious stage (p < 0.001).
CONCLUSION
This study demonstrates a profile of brain PET hypometabolism in long COVID patients with biologically confirmed SARS-CoV-2 and persistent functional complaints more than 3 weeks after the initial infection symptoms, involving the olfactory gyrus and connected limbic/paralimbic regions, extended to the brainstem and the cerebellum. These hypometabolisms are associated with patients' symptoms, with a biomarker value to identify and potentially follow these patients. The hypometabolism of the frontal cluster, which included the olfactory gyrus, seems to be linked to ACE drugs in patients with high blood pressure, with also a better metabolism of this olfactory region in patients using nasal decongestant spray, suggesting a possible role of ACE receptors as an olfactory gateway for this neurotropism.
Topics: Brain; COVID-19; Fluorodeoxyglucose F18; Humans; Positron-Emission Tomography; Retrospective Studies; SARS-CoV-2; Post-Acute COVID-19 Syndrome
PubMed: 33501506
DOI: 10.1007/s00259-021-05215-4 -
Frontiers in Neuroscience 2023Experiencing chronic stress significantly increases the risk for depression. Depression is a complex disorder with varied symptoms across patients. However, feeling of...
Experiencing chronic stress significantly increases the risk for depression. Depression is a complex disorder with varied symptoms across patients. However, feeling of sadness and decreased motivation, and diminished feeling of pleasure (anhedonia) appear to be core to most depressive pathology. Odorants are potent signals that serve a critical role in social interactions, avoiding danger, and consummatory behaviors. Diminished quality of olfactory function is associated with negative effects on quality of life leading to and aggravating the symptoms of depression. Odor hedonic value (I like or I dislike this smell) is a dominant feature of olfaction and guides approach or avoidance behavior of the odor source. The neural representation of the hedonic value of odorants is carried by the granule cells in the olfactory bulb, which functions to modulate the cortical relay of olfactory information. The granule cells of the olfactory bulb and those of the dentate gyrus are the two major populations of cells in the adult brain with continued neurogenesis into adulthood. In hippocampus, decreased neurogenesis has been linked to development or maintenance of depression symptoms. Here, we hypothesize that chronic mild stress can alter olfactory hedonics through effects on the olfactory bulb neurogenesis, contributing to the broader anhedonia phenotype in stress-associated depression. To test this, mice were subjected to chronic unpredictable mild stress and then tested on measures of depressive-like behaviors, odor hedonics, and measures of olfactory neurogenesis. Chronic unpredictable mild stress led to a selective effect on odor hedonics, diminishing attraction to pleasant but not unpleasant odorants, an effect that was accompanied by a specific decrease in adult neurogenesis and of the percentage of adult-born cells responding to pleasant odorants in the olfactory bulb.
PubMed: 37600017
DOI: 10.3389/fnins.2023.1224941 -
Frontiers in Cellular Neuroscience 2020Neuronal migration is a fundamental brain development process that allows cells to move from their birthplaces to their sites of integration. Although neuronal migration... (Review)
Review
Neuronal migration is a fundamental brain development process that allows cells to move from their birthplaces to their sites of integration. Although neuronal migration largely ceases during embryonic and early postnatal development, neuroblasts continue to be produced and to migrate to a few regions of the adult brain such as the dentate gyrus and the subventricular zone (SVZ). In the SVZ, a large number of neuroblasts migrate into the olfactory bulb (OB) along the rostral migratory stream (RMS). Neuroblasts migrate in chains in a tightly organized micro-environment composed of astrocytes that ensheath the chains of neuroblasts and regulate their migration; the blood vessels that are used by neuroblasts as a physical scaffold and a source of molecular factors; and axons that modulate neuronal migration. In addition to diverse sets of extrinsic micro-environmental cues, long-distance neuronal migration involves a number of intrinsic mechanisms, including membrane and cytoskeleton remodeling, Ca signaling, mitochondria dynamics, energy consumption, and autophagy. All these mechanisms are required to cope with the different micro-environment signals and maintain cellular homeostasis in order to sustain the proper dynamics of migrating neuroblasts and their faithful arrival in the target regions. Neuroblasts in the postnatal brain not only migrate into the OB but may also deviate from their normal path to migrate to a site of injury induced by a stroke or by certain neurodegenerative disorders. In this review, we will focus on the intrinsic mechanisms that regulate long-distance neuroblast migration in the adult brain and on how these pathways may be modulated to control the recruitment of neuroblasts to damaged/diseased brain areas.
PubMed: 33519385
DOI: 10.3389/fncel.2020.620379