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Frontiers in Neuroscience 2023
PubMed: 38249580
DOI: 10.3389/fnins.2023.1307844 -
Scientific Reports May 2024Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus-pituitary-adrenal... (Randomized Controlled Trial)
Randomized Controlled Trial
Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus-pituitary-adrenal (HPA) axis. To examine this in humans, hippocampal volume and hypothalamus (HPA axis) metabolism was quantified in participants with MDD before and after antidepressant treatment. 65 participants (n = 24 males, n = 41 females) with MDD were treated in a double-blind, randomized clinical trial of escitalopram. Participants received simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) before and after treatment. Linear mixed models examined the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism. Chi-squared tests and multivariable logistic regression examined the association between hippocampus/dentate gyrus volume change direction and hypothalamus activity change direction with treatment. Multiple linear regression compared these changes between remitter and non-remitter groups. Covariates included age, sex, and treatment type. No significant linear association was found between hippocampus/dentate gyrus volume and hypothalamus metabolism. 62% (38 of 61) of participants experienced a decrease in hypothalamus metabolism, 43% (27 of 63) of participants demonstrated an increase in hippocampus size (51% [32 of 63] for the dentate gyrus) following treatment. No significant association was found between change in hypothalamus activity and change in hippocampus/dentate gyrus volume, and this association did not vary by sex, medication, or remission status. As this multimodal study, in a cohort of participants on standardized treatment, did not find an association between hypothalamus metabolism and hippocampal volume, it supports a more complex pathway between hippocampus neurogenesis and hypothalamus metabolism changes in response to treatment.
Topics: Humans; Depressive Disorder, Major; Male; Female; Hypothalamus; Adult; Hippocampus; Magnetic Resonance Imaging; Middle Aged; Double-Blind Method; Positron-Emission Tomography; Dentate Gyrus; Citalopram; Hypothalamo-Hypophyseal System; Organ Size
PubMed: 38724691
DOI: 10.1038/s41598-024-61519-z -
Neurology Feb 2024Many physicians and researchers are familiar with the tragic phenomenon known as sudden infant death syndrome (SIDS), the leading cause of postneonatal mortality in...
Many physicians and researchers are familiar with the tragic phenomenon known as sudden infant death syndrome (SIDS), the leading cause of postneonatal mortality in high-resource countries. A less familiar category of unexplained deaths is the problem of sudden unexplained death in childhood (SUDC), a more rare and unusual presentation of sudden death in children who are no longer infants and whose reasons for death defy explanation. A substantial body of research in SUDC now supports the possibility of an overlap with epilepsy and associated sudden death in that context (SUDEP). Stemming from the first contemporary reports of SUDC, we have learned that a disproportionate number of these children have personal and/or family histories of febrile seizures, in many cases, inherited in an autosomal dominant manner. Their febrile seizures can be associated with abnormalities in their temporal lobes, including bilamination of the dentate gyrus and other findings conventionally associated with temporal lobe epilepsy, implicating potential epilepsy-related mechanisms. Further evaluation of this emerging epilepsy-related phenotype has led to the identification of genetic variants in and other epilepsy-associated genes, moving SUDC away from being considered an unexplained phenomenon to one where the working hypothesis includes a role for genetic predisposition and epilepsy-like mechanisms in the deaths, even without an established history of epilepsy. Nonetheless, because the terminal events of these seemingly healthy children are unexpected and unobserved, the clinical manifestations of whatever underlying vulnerabilities exist-generally discovered posthumously-remain a matter of speculation.
Topics: Child; Humans; Infant; Death, Sudden; Epilepsy; Seizures, Febrile; Sudden Unexpected Death in Epilepsy; Temporal Lobe
PubMed: 38175993
DOI: 10.1212/WNL.0000000000208119 -
Progress in Neuro-psychopharmacology &... Jun 2024Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating...
Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.
Topics: Animals; Mice; Dentate Gyrus; Depressive Disorder, Major; Hippocampus; Cognition; Neuronal Plasticity; Neurogenesis; Receptors, G-Protein-Coupled
PubMed: 38514038
DOI: 10.1016/j.pnpbp.2024.110995 -
Brain, Behavior, and Immunity Jan 2024Mental disorders may be involved in neuroinflammatory processes that are triggered by gut microbiota. How gut microbiota influence microglia-mediated sensitivity to...
BACKGROUND
Mental disorders may be involved in neuroinflammatory processes that are triggered by gut microbiota. How gut microbiota influence microglia-mediated sensitivity to stress remains unclear. Here we explored in an animal model of depression whether disruption of the gut microbiome primes hippocampal microglia, thereby impairing neurogenesis and sensitizing to stress.
METHODS
Male C57BL/6J mice were exposed to chronic unpredictable mild stress (CUMS) for 4 weeks, and effects on gut microbiota were assessed using 16S rRNA sequencing. Fecal microbiota was transplanted from control or CUMS mice into naïve animals. The depression-like behaviors of recipients were evaluated in a forced swimming test and sucrose preference test. The morphology and phenotype of microglia in the hippocampus of recipients were examined using immunohistochemistry, quantitative PCR, and enzyme-linked immunosorbent assays. The recipients were treated with lipopolysaccharide or chronic stress exposure, and effects were evaluated on behavior, microglial responses and hippocampal neurogenesis. Finally, we explored the ability of minocycline to reverse the effects of CUMS on hippocampal neurogenesis and stress sensitivity in recipients.
RESULTS
CUMS altered the gut microbiome, leading to higher relative abundance of some bacteria (Helicobacter, Bacteroides, and Desulfovibrio) and lower relative abundance of some bacteria (Lactobacillus, Bifidobacterium, and Akkermansia). Fecal microbiota transplantation from CUMS mice to naïve animals induced microglial priming in the dentate gyrus of recipients. This microglia showed hyper-ramified morphology, and became more sensitive to LPS challenge or chronic stress, which characterized by more significant morphological changes and inflammatory responses, as well as impaired hippocampal neurogenesis and increased depressive-like behaviors. Giving minocycline to recipients reversed these effects of fecal transplantation.
CONCLUSIONS
These findings suggest that gut microbiota from stressed animals can induce microglial priming in the dentate gyrus, which is associated with a hyper-immune response to stress and impaired hippocampal neurogenesis. Remodeling the gut microbiome or inhibiting microglial priming may be strategies to reduce sensitivity to stress.
Topics: Humans; Mice; Male; Animals; Depression; Gastrointestinal Microbiome; Microglia; Minocycline; RNA, Ribosomal, 16S; Mice, Inbred C57BL; Hippocampus; Neurogenesis; Stress, Psychological
PubMed: 37914097
DOI: 10.1016/j.bbi.2023.10.031 -
Glia Jul 2023Astrocytes are integral components of brain circuits, where they sense, process, and respond to surrounding activity, maintaining homeostasis and regulating synaptic...
Astrocytes are integral components of brain circuits, where they sense, process, and respond to surrounding activity, maintaining homeostasis and regulating synaptic transmission, the sum of which results in behavior modulation. These interactions are possible due to their complex morphology, composed of a tree-like structure of processes to cover defined territories ramifying in a mesh-like system of fine leaflets unresolved by conventional optic microscopy. While recent reports devoted more attention to leaflets and their dynamic interactions with synapses, our knowledge about the tree-like "backbone" structure in physiological conditions is incomplete. Recent transcriptomic studies described astrocyte molecular diversity, suggesting structural heterogeneity in regions such as the hippocampus, which is crucial for cognitive and emotional behaviors. In this study, we carried out the structural analysis of astrocytes across the hippocampal subfields of Cornu Ammonis area 1 (CA1) and dentate gyrus in the dorsoventral axis. We found that astrocytes display heterogeneity across the hippocampal subfields, which is conserved along the dorsoventral axis. We further found that astrocytes appear to contribute in an exocytosis-dependent manner to a signaling loop that maintains the backbone structure. These findings reveal astrocyte heterogeneity in the hippocampus, which appears to follow layer-specific cues and depend on the neuro-glial environment.
Topics: Animals; Mice; Astrocytes; Hippocampus; CA1 Region, Hippocampal; Neuroglia; Synaptic Transmission
PubMed: 36949723
DOI: 10.1002/glia.24362 -
Biological Research Dec 2023Impaired pattern separation occurs in the early stage of Alzheimer's disease (AD), and hippocampal dentate gyrus (DG) neurogenesis participates in pattern separation....
BACKGROUND
Impaired pattern separation occurs in the early stage of Alzheimer's disease (AD), and hippocampal dentate gyrus (DG) neurogenesis participates in pattern separation. Here, we investigated whether spatial memory discrimination impairment can be improved by promoting the hippocampal DG granule cell neogenesis-mediated pattern separation in the early stage of AD by electroacupuncture (EA).
METHODS
Five familial AD mutations (5 × FAD) mice received EA treatment at Baihui and Shenting points for 4 weeks. During EA, mice were intraperitoneally injected with BrdU (50 mg/kg) twice a day. rAAV containing Wnt5a shRNA was injected into the bilateral DG region, and the viral efficiency was evaluated by detecting Wnt5a mRNA levels. Cognitive behavior tests were conducted to assess the impact of EA treatment on cognitive function. The hippocampal DG area Aβ deposition level was detected by immunohistochemistry after the intervention; The number of BrdU/CaR cells and the gene expression level of calretinin (CaR) and prospero homeobox 1(Prox1) in the DG area of the hippocampus was detected to assess neurogenesis by immunofluorescence and western blotting after the intervention; The gene expression levels of FZD2, Wnt5a, DVL2, p-DVL2, CaMKII, and p-CaMKII in the Wnt signaling pathway were detected by Western blotting after the intervention.
RESULTS
Cognitive behavioral tests showed that 5 × FAD mice had impaired pattern separation (P < 0.001), which could be improved by EA (P < 0.01). Immunofluorescence and Western blot showed that the expression of Wnt5a in the hippocampus was decreased (P < 0.001), and the neurogenesis in the DG was impaired (P < 0.001) in 5 × FAD mice. EA could increase the expression level of Wnt5a (P < 0.05) and promote the neurogenesis of immature granule cells (P < 0.05) and the development of neuronal dendritic spines (P < 0.05). Interference of Wnt5a expression aggravated the damage of neurogenesis (P < 0.05), weakened the memory discrimination ability (P < 0.05), and inhibited the beneficial effect of EA (P < 0.05) in AD mice. The expression level of Wnt pathway related proteins such as FZD2, DVL2, p-DVL2, CAMKII, p-CAMKII increased after EA, but the effect of EA was inhibited after Wnt5a was knocked down. In addition, EA could reduce the deposition of Aβ plaques in the DG without any impact on Wnt5a.
CONCLUSION
EA can promote hippocampal DG immature granule cell neogenesis-mediated pattern separation to improve spatial memory discrimination impairment by regulating Wnt5a in 5 × FAD mice.
Topics: Mice; Animals; Alzheimer Disease; Electroacupuncture; Bromodeoxyuridine; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Hippocampus; Disease Models, Animal; Neurogenesis; Dentate Gyrus
PubMed: 38041203
DOI: 10.1186/s40659-023-00472-z -
Neuron Oct 2023Heterozygous mutations in the dual-specificity tyrosine phosphorylation-regulated kinase 1a (Dyrk1a) gene define a syndromic form of autism spectrum disorder. The...
Heterozygous mutations in the dual-specificity tyrosine phosphorylation-regulated kinase 1a (Dyrk1a) gene define a syndromic form of autism spectrum disorder. The synaptic and circuit mechanisms mediating DYRK1A functions in social cognition are unclear. Here, we identify a social experience-sensitive mechanism in hippocampal mossy fiber-parvalbumin interneuron (PV IN) synapses by which DYRK1A recruits feedforward inhibition of CA3 and CA2 to promote social recognition. We employ genetic epistasis logic to identify a cytoskeletal protein, ABLIM3, as a synaptic substrate of DYRK1A. We demonstrate that Ablim3 downregulation in dentate granule cells of adult heterozygous Dyrk1a mice is sufficient to restore PV IN-mediated inhibition of CA3 and CA2 and social recognition. Acute chemogenetic activation of PV INs in CA3/CA2 of adult heterozygous Dyrk1a mice also rescued social recognition. Together, these findings illustrate how targeting DYRK1A synaptic and circuit substrates as "enhancers of DYRK1A function" harbors the potential to reverse Dyrk1a haploinsufficiency-associated circuit and cognition impairments.
Topics: Animals; Mice; Autism Spectrum Disorder; Brain; Mossy Fibers, Hippocampal; Parvalbumins; Recognition, Psychology; Synapses; Dyrk Kinases
PubMed: 37797581
DOI: 10.1016/j.neuron.2023.09.009 -
Nature Communications Oct 2023The hippocampus plays major roles in learning and memory, and its formation requires precise coordination of patterning, cell proliferation, differentiation, and...
The hippocampus plays major roles in learning and memory, and its formation requires precise coordination of patterning, cell proliferation, differentiation, and migration. Here we removed the chromatin-association capability of KDM2B in the progenitors of developing dorsal telencephalon (Kdm2b) to discover that Kdm2b hippocampus, particularly the dentate gyrus, became drastically smaller with disorganized cellular components and structure. Kdm2b mice display prominent defects in spatial memory, motor learning and fear conditioning, resembling patients with KDM2B mutations. The migration and differentiation of neural progenitor cells is greatly impeded in the developing Kdm2b hippocampus. Mechanism studies reveal that Wnt signaling genes in developing Kdm2b hippocampi are de-repressed due to reduced enrichment of repressive histone marks by polycomb repressive complexes. Activating the Wnt signaling disturbs hippocampal neurogenesis, recapitulating the effect of KDM2B loss. Together, we unveil a previously unappreciated gene repressive program mediated by KDM2B that controls progressive fate specifications and cell migration, hence morphogenesis of the hippocampus.
Topics: Animals; Humans; Mice; Cell Differentiation; Hippocampus; Neurogenesis; Polycomb-Group Proteins; Wnt Signaling Pathway
PubMed: 37838801
DOI: 10.1038/s41467-023-42322-2 -
Journal of Neuroimaging : Official... 2024The hippocampus is a complex structure located in the mesial temporal lobe that plays a critical role in cognitive and memory-related processes. The hippocampal... (Review)
Review
The hippocampus is a complex structure located in the mesial temporal lobe that plays a critical role in cognitive and memory-related processes. The hippocampal formation consists of the dentate gyrus, hippocampus proper, and subiculum, and its importance in the neural circuitry makes it a key anatomic structure to evaluate in neuroimaging studies. Advancements in imaging techniques now allow detailed assessment of hippocampus internal architecture and signal features that has improved identification and characterization of hippocampal abnormalities. This review aims to summarize the neuroimaging features of the hippocampus and its common pathologies. It provides an overview of the hippocampal anatomy on magnetic resonance imaging and discusses how various imaging techniques can be used to assess the hippocampus. The review explores neuroimaging findings related to hippocampal variants (incomplete hippocampal inversion, sulcal remnant and choroidal fissure cysts), and pathologies of neoplastic (astrocytoma and glioma, ganglioglioma, dysembryoplastic neuroepithelial tumor, multinodular and vacuolating neuronal tumor, and metastasis), epileptic (mesial temporal sclerosis and focal cortical dysplasia), neurodegenerative (Alzheimer's disease, progressive primary aphasia, and frontotemporal dementia), infectious (Herpes simplex virus and limbic encephalitis), vascular (ischemic stroke, arteriovenous malformation, and cerebral cavernous malformations), and toxic-metabolic (transient global amnesia and opioid-associated amnestic syndrome) etiologies.
Topics: Humans; Child; Hippocampus; Epilepsy; Temporal Lobe; Magnetic Resonance Imaging; Alzheimer Disease; Glioma; Epilepsy, Temporal Lobe
PubMed: 37872430
DOI: 10.1111/jon.13165