RESUMEN

Gain-of-function mutations in SCN8A cause developmental and epileptic encephalopathy (DEE), a disorder characterized by early-onset refractory seizures, deficits in motor and intellectual functions, and increased risk of sudden unexpected death in epilepsy. Altered activity of neurons in the corticohippocampal circuit has been reported in mouse models of DEE. We examined the effect of chronic seizures on gene expression in the hippocampus by single-nucleus RNA sequencing in mice expressing the patient mutation SCN8A-p.Asn1768Asp (N1768D). One hundred and eighty four differentially expressed genes were identified in dentate gyrus granule cells, many more than in other cell types. Electrophysiological recording from dentate gyrus granule cells demonstrated an elevated firing rate. Targeted reduction of Scn8a expression in the dentate gyrus by viral delivery of an shRNA resulted in doubling of median survival time from 4 months to 8 months, whereas delivery of shRNA to the CA1 and CA3 regions did not result in lengthened survival. These data indicate that granule cells of the dentate gyrus are a specific locus of pathology in SCN8A-DEE.

Asunto(s)

Giro Dentado , Canal de Sodio Activado por Voltaje NAV1.6 , Neuronas , Animales , Canal de Sodio Activado por Voltaje NAV1.6/genética , Canal de Sodio Activado por Voltaje NAV1.6/metabolismo , Giro Dentado/patología , Giro Dentado/metabolismo , Ratones , Neuronas/metabolismo , Neuronas/patología , Ratones Transgénicos , Masculino , Mutación

RESUMEN

Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and brain injury repair. In the brain, ApoE is produced predominantly by astrocytes, but it is also abundantly expressed in most neurons of the CNS. In this study, we addressed the role of ApoE in the hippocampus in mice, focusing on its role in response to radiation injury. To this aim, 8-week-old, wild-type, and ApoE-deficient (ApoE-/-) female mice were acutely whole-body irradiated with 3 Gy of X-rays (0.89 Gy/min), then sacrificed 150 days post-irradiation. In addition, age-matching ApoE-/- females were chronically whole-body irradiated (20 mGy/d, cumulative dose of 3 Gy) for 150 days at the low dose-rate facility at the Institute of Environmental Sciences (IES), Rokkasho, Japan. To seek for ApoE-dependent modification during lineage progression from neural stem cells to neurons, we have evaluated the cellular composition of the dentate gyrus in unexposed and irradiated mice using stage-specific markers of adult neurogenesis. Our findings indicate that ApoE genetic inactivation markedly perturbs adult hippocampal neurogenesis in unexposed and irradiated mice. The effect of ApoE inactivation on the expression of a panel of miRNAs with an established role in hippocampal neurogenesis, as well as its transcriptional consequences in their target genes regulating neurogenic program, have also been analyzed. Our data show that the absence of ApoE-/- also influences synaptic functionality and integration by interfering with the regulation of mir-34a, mir-29b, and mir-128b, leading to the downregulation of synaptic markers PSD95 and synaptophysin mRNA. Finally, compared to acute irradiation, chronic exposure of ApoE null mice yields fewer consequences except for the increased microglia-mediated neuroinflammation. Exploring the function of ApoE in the hippocampus could have implications for developing therapeutic approaches to alleviate radiation-induced brain injury.

Asunto(s)

Apolipoproteínas E , Hipocampo , MicroARNs , Radiación Ionizante , Animales , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Hipocampo/metabolismo , Hipocampo/efectos de la radiación , Ratones , Femenino , MicroARNs/metabolismo , MicroARNs/genética , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/efectos de la radiación , Neurogénesis/efectos de la radiación , Irradiación Corporal Total , Exposición a la Radiación/efectos adversos , Giro Dentado/metabolismo , Giro Dentado/efectos de la radiación , Giro Dentado/patología

RESUMEN

Depression triggered by harmful stress during adolescence is a common problem that can affect mental health. To date, the mechanisms underlying this type of depression remain unclear. One mechanism for the promotion of depression by chronic stress in adulthood is the loss of hippocampal microglia. Since deleterious stress in adolescence also activates microglia, we investigated the dynamic changes of microglia in the hippocampus in mice exposed to chronic unpredictable stress (CUS) in adolescence. Our results showed that 12 days of CUS stimulation in adolescence induced typical depression-like behaviors in adult mice, which were accompanied by a significant decrease and dystrophy of microglia in the dentate gyrus of the hippocampus. Further analysis showed that this decrease in microglia was mediated by the initial response of microglia to unpredictable stress in the dentate gyrus of the hippocampus and their subsequent apoptosis. Blocking the initial response of microglia to unpredictable stress by pretreatment with minocycline was able to prevent apoptosis and microglial decline as well as the development of depression-like behaviors in adult mice induced by adolescent CUS. Moreover, administration of lipopolysaccharide (LPS) or macrophage-colony stimulatory factor (M-CSF), two drugs that reversed microglia decline in the dentate gyrus, ameliorated the depression-like behaviors induced by CUS stimulation in adolescence. These findings reveal a novel mechanism for the development of depression-like behaviors in animals triggered by deleterious stress in adolescence and suggest that reversing microglial decline in the hippocampus may be a hopeful strategy for the treatment of depression triggered by deleterious stress in adolescence.

Asunto(s)

Apoptosis , Conducta Animal , Depresión , Hipocampo , Microglía , Estrés Psicológico , Animales , Microglía/efectos de los fármacos , Microglía/patología , Estrés Psicológico/complicaciones , Estrés Psicológico/psicología , Apoptosis/efectos de los fármacos , Ratones , Masculino , Hipocampo/efectos de los fármacos , Hipocampo/patología , Conducta Animal/efectos de los fármacos , Minociclina/farmacología , Ratones Endogámicos C57BL , Giro Dentado/efectos de los fármacos , Giro Dentado/patología , Modelos Animales de Enfermedad , Factores de Edad , Lipopolisacáridos/farmacología

RESUMEN

Traumatic brain injury (TBI) can result in long-lasting changes in hippocampal function. The changes induced by TBI on the hippocampus contribute to cognitive deficits. The adult hippocampus harbors neural stem cells (NSCs) that generate neurons (neurogenesis), and astrocytes (astrogliogenesis). While deregulation of hippocampal NSCs and neurogenesis have been observed after TBI, it is not known how TBI may affect hippocampal astrogliogenesis. Using a controlled cortical impact model of TBI in male mice, single cell RNA sequencing and spatial transcriptomics, we assessed how TBI affected hippocampal NSCs and the neuronal and astroglial lineages derived from them. We observe an increase in NSC-derived neuronal cells and a concomitant decrease in NSC-derived astrocytic cells, together with changes in gene expression and cell dysplasia within the dentate gyrus. Here, we show that TBI modifies NSC fate to promote neurogenesis at the cost of astrogliogenesis and identify specific cell populations as possible targets to counteract TBI-induced cellular changes in the adult hippocampus.

Asunto(s)

Astrocitos , Lesiones Traumáticas del Encéfalo , Hipocampo , Células-Madre Neurales , Neurogénesis , Animales , Masculino , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/fisiopatología , Hipocampo/patología , Hipocampo/citología , Astrocitos/metabolismo , Ratones , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Neuronas/metabolismo , Ratones Endogámicos C57BL , Giro Dentado/patología , Modelos Animales de Enfermedad , Diferenciación Celular , Transcriptoma

RESUMEN

OBJECTIVE: The mechanistic target of rapamycin (mTOR) pathway has been implicated in promoting epileptogenesis in animal models of acquired epilepsy, such as posttraumatic epilepsy (PTE) following traumatic brain injury (TBI). However, the specific anatomical regions and neuronal populations mediating mTOR's role in epileptogenesis are not well defined. In this study, we tested the hypothesis that mTOR activation in dentate gyrus granule cells promotes neuronal death, mossy fiber sprouting, and PTE in the controlled cortical impact (CCI) model of TBI. METHODS: An adeno-associated virus (AAV)-Cre viral vector was injected into the hippocampus of Rptorflox/flox (regulatory-associated protein of mTOR) mutant mice to inhibit mTOR activation in dentate gyrus granule cells. Four weeks after AAV-Cre or AAV-vehicle injection, mice underwent CCI injury and were subsequently assessed for mTOR pathway activation by Western blotting, neuronal death, and mossy fiber sprouting by immunopathological analysis, and posttraumatic seizures by video-electroencephalographic monitoring. RESULTS: AAV-Cre injection primarily affected the dentate gyrus and inhibited hippocampal mTOR activation following CCI injury. AAV-Cre-injected mice had reduced neuronal death in dentate gyrus detected by Fluoro-Jade B staining and decreased mossy fiber sprouting by ZnT3 immunostaining. Finally, AAV-Cre-injected mice exhibited a decrease in incidence of PTE. SIGNIFICANCE: mTOR pathway activation in dentate gyrus granule cells may at least partly mediate pathological abnormalities and epileptogenesis in models of TBI and PTE. Targeted modulation of mTOR activity in this hippocampal network may represent a focused therapeutic approach for antiepileptogenesis and prevention of PTE.

Asunto(s)

Giro Dentado , Modelos Animales de Enfermedad , Epilepsia Postraumática , Serina-Treonina Quinasas TOR , Animales , Giro Dentado/metabolismo , Giro Dentado/patología , Ratones , Serina-Treonina Quinasas TOR/metabolismo , Epilepsia Postraumática/etiología , Fibras Musgosas del Hipocampo/efectos de los fármacos , Masculino , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Ratones Endogámicos C57BL , Neuronas/patología , Neuronas/metabolismo , Electroencefalografía , Ratones Transgénicos

RESUMEN

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.

Asunto(s)

Trastorno Depresivo Mayor , Hipocampo , Hipotálamo , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Humanos , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/patología , Masculino , Femenino , Hipotálamo/metabolismo , Hipotálamo/diagnóstico por imagen , Adulto , Hipocampo/metabolismo , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Persona de Mediana Edad , Método Doble Ciego , Tomografía de Emisión de Positrones/métodos , Giro Dentado/metabolismo , Giro Dentado/diagnóstico por imagen , Giro Dentado/patología , Citalopram/uso terapéutico , Sistema Hipotálamo-Hipofisario/metabolismo , Tamaño de los Órganos

RESUMEN

INTRODUCTION: In Alzheimer's disease (AD), early diagnosis facilitates treatment options and leads to beneficial outcomes for patients, their carers and the healthcare system. The neuropsychological battery of the Uniform Data Set (UDSNB3.0) assesses cognition in ageing and dementia, by measuring scores across different cognitive domains such as attention, memory, processing speed, executive function and language. However, its neuroanatomical correlates have not been investigated using 7 Tesla MRI (7T MRI). METHODS: We used 7T MRI to investigate the correlations between hippocampal subfield volumes and the UDSNB3.0 in 24 individuals with Amyloidß-status AD and 18 age-matched controls, with respective age ranges of 60 (42-76) and 62 (52-79) years. AD participants with a Medial Temporal Atrophy scale of higher than 2 on 3T MRI were excluded from the study. RESULTS: A significant difference in the entire hippocampal volume was observed in the AD group compared to healthy controls (HC), primarily influenced by CA1, the largest hippocampal subfield. Notably, no significant difference in whole brain volume between the groups implied that hippocampal volume loss was not merely reflective of overall brain atrophy. UDSNB3.0 cognitive scores showed significant differences between AD and HC, particularly in Memory, Language, and Visuospatial domains. The volume of the Dentate Gyrus (DG) showed a significant association with the Memory and Executive domain scores in AD patients as assessed by the UDSNB3.0.. The data also suggested a non-significant trend for CA1 volume associated with UDSNB3.0 Memory, Executive, and Language domain scores in AD. In a reassessment focusing on hippocampal subfields and MoCA memory subdomains in AD, associations were observed between the DG and Cued, Uncued, and Recognition Memory subscores, whereas CA1 and Tail showed associations only with Cued memory. DISCUSSION: This study reveals differences in the hippocampal volumes measured using 7T MRI, between individuals with early symptomatic AD compared with healthy controls. This highlights the potential of 7T MRI as a valuable tool for early AD diagnosis and the real-time monitoring of AD progression and treatment efficacy. CLINICALTRIALS: GOV: ID NCT04992975 (Clinicaltrial.gov 2023).

Asunto(s)

Enfermedad de Alzheimer , Región CA1 Hipocampal , Giro Dentado , Imagen por Resonancia Magnética , Trastornos de la Memoria , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Masculino , Imagen por Resonancia Magnética/métodos , Femenino , Anciano , Giro Dentado/diagnóstico por imagen , Giro Dentado/patología , Persona de Mediana Edad , Región CA1 Hipocampal/diagnóstico por imagen , Región CA1 Hipocampal/patología , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/patología , Adulto , Péptidos beta-Amiloides/metabolismo

RESUMEN

The hippocampal dentate gyrus, responds to diverse pathological stimuli through neurogenesis. This phenomenon, observed following brain injury or neurodegeneration, is postulated to contribute to neuronal repair and functional recovery, thereby presenting an avenue for endogenous neuronal restoration. This study investigated the extent of regenerative response in hippocampal neurogenesis by leveraging the well-established kainic acid-induced status epilepticus model in vivo. In our study, we observed the activation and proliferation of neuronal progenitors or neural stem cell (NSC) and their subsequent migration to the injury sites following the seizure. At the injury sites, new neurons (Tuj1+BrdU+ and NeuN+BrdU+) have been generated indicating regenerative and reparative roles of the progenitor cells. We further detected whether this transient neurogenic burst, which might be a response towards an attempt to repair the brain, is associated with persistent long-term exhaustion of the dentate progenitor cells and impairment of adult neurogenesis marked by downregulation of Ki67, HoPX, and Sox2 with BrdU+ cell in the later part of life. Our studies suggest that the adult brain has the constitutive endogenous regenerative potential for brain repair to restore the damaged neurons, meanwhile, in the long term, it accelerates the depletion of the finite NSC pool in the hippocampal neurogenic niche by changing its proliferative and neurogenic capacity. A thorough understanding of the impact of modulating adult neurogenesis will eventually be required to design novel therapeutics to stimulate or assist brain repair while simultaneously preventing the adverse effects of early robust neurogenesis on the proliferative potential of endogenous neuronal progenitors.

Asunto(s)

Hipocampo , Células-Madre Neurales , Neurogénesis , Animales , Células-Madre Neurales/metabolismo , Hipocampo/patología , Hipocampo/metabolismo , Proliferación Celular , Masculino , Nicho de Células Madre , Giro Dentado/patología , Giro Dentado/fisiopatología , Neuronas/metabolismo , Neuronas/patología , Ácido Kaínico/toxicidad , Estado Epiléptico/inducido químicamente , Estado Epiléptico/patología , Estado Epiléptico/metabolismo , Regeneración Nerviosa , Modelos Animales de Enfermedad , Ratones , Movimiento Celular

RESUMEN

BACKGROUND: Influenced by the global aging population, the incidence of Alzheimer's disease (AD) has increased sharply. In addition to increasing ß-amyloid plaque deposition and tau tangle formation, neurogenesis dysfunction has recently been observed in AD. Therefore, promoting regeneration to improve neurogenesis and cognitive dysfunction can play an effective role in AD treatment. Acupuncture and moxibustion have been widely used in the clinical treatment of neurodegenerative diseases because of their outstanding advantages such as early, functional, and benign two-way adjustment. It is urgent to clarify the effectiveness, greenness, and safety of acupuncture and moxibustion in promoting neurogenesis in AD treatment. METHODS: Senescence-accelerated mouse prone 8 (SAMP8) mice at various ages were used as experimental models to simulate the pathology and behaviors of AD mice. Behavioral experiments, immunohistochemistry, Western blot, and immunofluorescence experiments were used for comparison between different groups. RESULTS: Acupuncture and moxibustion could increase the number of PCNA+ DCX+ cells, Nissl bodies, and mature neurons in the hippocampal Dentate gyrus (DG) of SAMP8 mice, restore the hippocampal neurogenesis, delay the AD-related pathological presentation, and improve the learning and memory abilities of SAMP8 mice. CONCLUSION: The pathological process underlying AD and cognitive impairment were changed positively by improving the dysfunction of neurogenesis. This indicates the promising role of acupuncture and moxibustion in the prevention and treatment of AD.

Asunto(s)

Terapia por Acupuntura , Enfermedad de Alzheimer , Moxibustión , Ratones , Animales , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/patología , Hipocampo/patología , Neurogénesis/fisiología , Giro Dentado/patología , Modelos Animales de Enfermedad

RESUMEN

Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.

Asunto(s)

Acetilcisteína , Sobrecarga de Hierro , Oligopéptidos , Animales , Masculino , Ratas , Acetilcisteína/farmacología , Acetilcisteína/metabolismo , Caspasas/metabolismo , Claudinas/genética , Giro Dentado/metabolismo , Giro Dentado/patología , Dextranos/metabolismo , Dextranos/farmacología , Regulación hacia Abajo , Glutatión/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Hierro/metabolismo , Hierro/farmacología , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/tratamiento farmacológico , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/farmacología , Nestina/genética , Nestina/metabolismo , Nestina/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/farmacología , Regulación hacia Arriba , Oligopéptidos/farmacología , Hemo-Oxigenasa 1/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo

RESUMEN

Bright light exposure (BL) induces neurogenesis in the rat hippocampal dentate gyrus (DG). We had previously conducted a randomized controlled trial (RCT) in which a 4-week period of BL in healthy participants resulted in increased volume of the left DG-head. This study aimed to investigate the effects of BL on the DG in patients with mood disorders. A 4-week RCT was conducted in which patients with mood disorders were randomly assigned to either a BL group (10,000 lx) or dim light exposure group (DL group; 50 lx). All patients underwent clinical assessment and magnetic resonance imaging at baseline and after the intervention. The study registration number is UMIN000019220. Our final sample included 24 patients (BL group, n = 12; DL group, n = 12). A significant effect of time and group was detected in the volumes of the left DG-head (F (1, 22) = 11.6, partial η2 = 0.35, p = 0.003) and left DG-total (left DG-total = left DG-head + left DG-body; [F (1, 22) = 6.5, partial η2 = 0.23, p = 0.02]). Additionally, the BL group demonstrated a significant increase in the volume of the left DG-head (95% CI: -5.4 to -1.6, d = 1.2, p = 0.002) and left DG-total (95% CI: -6.3 to -1.5, d = 1.06, p = 0.005) as well as a positive correlation between the percentage change in the volume of the left DG-total and the percentage change in the scores of the mood visual analog scale (r = 0.58, p = 0.04). In conclusion, our study results suggest that compared to DL, BL leads to a significantly greater increase in the left DG volume in patients with mood disorders. This increase in the left DG volume may be associated with mood improvement in the patients.

Asunto(s)

Giro Dentado , Hipocampo , Humanos , Cognición , Giro Dentado/diagnóstico por imagen , Giro Dentado/patología , Hipocampo/patología , Imagen por Resonancia Magnética , Trastornos del Humor/diagnóstico por imagen , Trastornos del Humor/patología , Proyectos de Investigación

RESUMEN

Epileptogenesis is a complex process involving a multitude of changes at the molecular, cellular and network level. Previous studies have identified several key alterations contributing to epileptogenesis and the development of hyper-excitability in different animal models, but only a few have focused on the early stages of this process. For post status epilepticus (SE) temporal lobe epilepsy in particular, understanding network dynamics during the early phases might be crucial for developing accurate preventive treatments to block the development of chronic spontaneous seizures. In this study, we used a viral vector mediated approach to examine activity of neurons in the dentate gyrus of the hippocampus during early epileptogenesis. We find that while granule cells are active 8 h after SE and then gradually decrease their activity, Calretinin-positive mossy cells and Neuropeptide Y-positive GABAergic interneurons in the hilus show a delayed activation pattern starting at 24 and peaking at 48 h after SE. These data suggest that indirect inhibition of granule cells by mossy cells through recruitment of local GABAergic interneurons could be an important mechanisms of excitability control during early epileptogenesis, and contribute to our understanding of the complex role of these cells in normal and pathological conditions.

Asunto(s)

Epilepsia del Lóbulo Temporal , Estado Epiléptico , Animales , Neuronas/patología , Hipocampo/patología , Convulsiones/patología , Interneuronas , Epilepsia del Lóbulo Temporal/patología , Estado Epiléptico/patología , Giro Dentado/química , Giro Dentado/patología , Modelos Animales de Enfermedad

RESUMEN

The hippocampal formation plays a central role in the development of temporal lobe epilepsy (TLE), a disease characterized by recurrent, unprovoked epileptic discharges. TLE is a neurologic disorder characterized by acute long-lasting seizures (i.e., abnormal electrical activity in the brain) or seizures that occur in close proximity without recovery, typically after a brain injury or status epilepticus. After status epilepticus, epileptogenic hyperexcitability develops gradually over the following months to years, resulting in the emergence of chronic, recurrent seizures. Acting as a filter or gate, the hippocampal dentate gyrus (DG) normally prevents excessive excitation from propagating through the hippocampus, and is considered a critical region in the progression of epileptogenesis in pathological conditions. Importantly, lipid-derived endogenous cannabinoids (endocannabinoids), which are produced on demand as retrograde messengers, are central regulators of neuronal activity in the DG circuit. In this review, we summarize recent findings concerning the role of the DG in controlling hyperexcitability and propose how DG regulation by cannabinoids (CBs) could provide avenues for therapeutic interventions. We also highlight possible pathways and manipulations that could be relevant for the control of hyperexcitation. The use of CB compounds to treat epilepsies is controversial, as anecdotal evidence is not always validated by clinical trials. Recent publications shed light on the importance of the DG as a region regulating incoming hippocampal excitability during epileptogenesis. We review recent findings concerning the modulation of the hippocampal DG circuitry by CBs and discuss putative underlying pathways. A better understanding of the mechanisms by which CBs exert their action during seizures may be useful to improve therapies.

Asunto(s)

Cannabinoides , Epilepsia del Lóbulo Temporal , Epilepsia , Estado Epiléptico , Humanos , Animales , Hipocampo/patología , Convulsiones/patología , Epilepsia/etiología , Epilepsia/patología , Epilepsia del Lóbulo Temporal/patología , Neuronas/patología , Estado Epiléptico/patología , Giro Dentado/patología , Modelos Animales de Enfermedad

RESUMEN

Although hippocampal pathologies of multiple system atrophy (MSA) and their association with dementia have been reported, no studies have reported clinicopathological differences among MSA patients with and without neuronal cytoplasmic inclusions (NCIs) in the dentate gyrus (dntNCIs). We investigated hippocampal NCI pathology in 18 MSA patient autopsies, focusing on phosphorylated α-synuclein (pAS)- and phosphorylated tau (pT)-positive dntNCIs. There were 8 MSA patients without and 10 with dntNCIs. The latter group was subclassified by immunophenotype: those with pAS-positive dntNCIs (pAS-dntNCI subtype), those with pT-positive dntNCIs (pT-dntNCI subtype), and those with both types of dntNCIs. MSA patients with dntNCIs survived longer with prolonged tracheostomy and had dementia more frequently than those without dntNCIs. The brain weights of patients with dntNCIs were lower than those without dntNCIs. The presence of dementia was similar among the dntNCI subtypes. The pAS-dntNCI subtype was associated with longer survival and smaller brain weights; the pT-dntNCI subtype exhibited more frequent tau pathologies than the pAS-dntNCI subtype. Thus, MSA with dntNCIs is a possible pathological subtype of longer survivors that correlates with longer disease duration, prolonged tracheostomy, and high frequency of dementia. Understanding clinicopathological differences in MSA patients with and without dntNCIs may lead to improved personalized management strategies.

Asunto(s)

Demencia , Atrofia de Múltiples Sistemas , Humanos , Atrofia de Múltiples Sistemas/patología , alfa-Sinucleína/metabolismo , Cuerpos de Inclusión/patología , Hipocampo/patología , Demencia/patología , Giro Dentado/patología , Encéfalo/patología

RESUMEN

BACKGROUND: The dentate gyrus (DG) has been implicated in the pathophysiology of depression. Many studies have revealed the cellular types, neural circuits, and morphological changes of the DG involved in the development of depression. However, the molecular regulating its intrinsic activity in depression is unknown. METHODS: Utilizing the mode of depression induced by lipopolysaccharide (LPS), we investigate the involvement of the sodium leak channel (NALCN) in inflammation-induced depressive-like behaviors of male mice. The expression of NALCN was detected by immunohistochemistry and real-time polymerase chain reaction. DG microinjection of the adeno-associated virus or lentivirus was carried out using a stereotaxic instrument and followed by behavioral tests. Neuronal excitability and NALCN conductance were recorded by whole-cell patch-clamp techniques. RESULTS: The expression and function of NALCN were reduced in both the dorsal and ventral DG in LPS-treated mice; whereas, only knocking down NALCN in the ventral pole produced depressive-like behaviors and this effect of NALCN was specific to ventral glutamatergic neurons. The excitability of ventral glutamatergic neurons was impaired by both the knockdown of NALCN and/or the treatment of LPS. Then, the overexpression of NALCN in the ventral glutamatergic neurons decreased the susceptibility of mice to inflammation-induced depression, and the intracranial injection of substance P (non-selective NALCN activator) into the ventral DG rapidly ameliorated inflammation-induced depression-like behaviors in an NALCN-dependent manner. CONCLUSIONS: NALCN, which drives the neuronal activity of the ventral DG glutamatergic neurons, uniquely regulates depressive-like behaviors and susceptibility to depression. Therefore, the NALCN of glutamatergic neurons in the ventral DG may present a molecular target for rapid antidepressant drugs.

Asunto(s)

Giro Dentado , Depresión , Canales Iónicos , Lipopolisacáridos , Animales , Masculino , Ratones , Giro Dentado/metabolismo , Giro Dentado/patología , Depresión/genética , Depresión/metabolismo , Ácido Glutámico/metabolismo , Inflamación/complicaciones , Canales Iónicos/metabolismo , Lipopolisacáridos/farmacología , Proteínas de la Membrana/metabolismo , Neuronas/metabolismo , Sodio/metabolismo

RESUMEN

The dentate gyrus (DG) is an integral portion of the hippocampal formation, and it is composed of three layers. Quantitative magnetic resonance (MR) imaging has the capability to map brain tissue microstructural properties which can be exploited to investigate neurodegeneration in Alzheimer's disease (AD). However, assessing subtle pathological changes within layers requires high resolution imaging and histological validation. In this study, we utilized a 16.4 Tesla scanner to acquire ex vivo multi-parameter quantitative MRI measures in human specimens across the layers of the DG. Using quantitative diffusion tensor imaging (DTI) and multi-parameter MR measurements acquired from AD (N = 4) and cognitively normal control (N = 6) tissues, we performed correlation analyses with histological measurements. Here, we found that quantitative MRI measures were significantly correlated with neurofilament and phosphorylated Tau density, suggesting sensitivity to layer-specific changes in the DG of AD tissues.

Asunto(s)

Enfermedad de Alzheimer , Imagen de Difusión Tensora , Humanos , Imagen de Difusión Tensora/métodos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Imagen por Resonancia Magnética/métodos , Encéfalo/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Giro Dentado/diagnóstico por imagen , Giro Dentado/patología

RESUMEN

Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia.

Asunto(s)

Giro Dentado , Oligodendroglía , Esquizofrenia , Humanos , Astrocitos/patología , Neuronas/patología , Oligodendroglía/patología , Esquizofrenia/patología , Giro Dentado/patología

RESUMEN

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents1,2 and are dysregulated in multiple human neurological disorders3-5. Little is known about the molecular characteristics of adult human hippocampal imGCs, and even their existence is under debate1,6-8. Here we performed single-nucleus RNA sequencing aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus at different stages across the lifespan. We identified common molecular hallmarks of human imGCs across the lifespan and observed age-dependent transcriptional dynamics in human imGCs that suggest changes in cellular functionality, niche interactions and disease relevance, that differ from those in mice9. We also found a decreased number of imGCs with altered gene expression in Alzheimer's disease. Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a substantial number of imGCs in the adult human hippocampus via low-frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in Alzheimer's disease.

Asunto(s)

Envejecimiento , Hipocampo , Longevidad , Neurogénesis , Neuronas , Adulto , Envejecimiento/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Proliferación Celular , Giro Dentado/citología , Giro Dentado/patología , Perfilación de la Expresión Génica , Hipocampo/citología , Hipocampo/patología , Humanos , Longevidad/genética , Aprendizaje Automático , Ratones , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neurogénesis/genética , Neuronas/citología , Neuronas/metabolismo , Neuronas/patología , Reproducibilidad de los Resultados , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Transcripción Genética

RESUMEN

BACKGROUND: It has been demonstrated that reactive astrocytes can be polarized into pro-inflammatory A1 phenotype or anti-inflammatory A2 phenotype under neurotoxic and neurodegenerative conditions. Microglia have been suggested to play a critical role in astrocyte phenotype polarization by releasing pro- and anti-inflammatory mediators. In this study, we examined whether trimethyltin (TMT) insult can induce astrocyte polarization in the dentate gyrus of mice, and whether protein kinase Cδ (PKCδ) plays a role in TMT-induced astrocyte phenotype polarization. METHODS: Male C57BL/6 N mice received TMT (2.6 mg/kg, i.p.), and temporal changes in the mRNA expression of A1 and A2 phenotype markers were evaluated in the hippocampus. In addition, temporal and spatial changes in the protein expression of C3, S100A10, Iba-1, and p-PKCδ were examined in the dentate gyrus. Rottlerin (5 mg/kg, i.p. × 5 at 12-h intervals) was administered 3-5 days after TMT treatment, and the expression of A1 and A2 transcripts, p-PKCδ, Iba-1, C3, S100A10, and C1q was evaluated 6 days after TMT treatment. RESULTS: TMT treatment significantly increased the mRNA expression of A1 and A2 phenotype markers, and the increased expression of A1 markers remained longer than that of A2 markers. The immunoreactivity of the representative A1 phenotype marker, C3 and A2 phenotype marker, S100A10 peaked 6 days after TMT insult in the dentate gyrus. While C3 was expressed evenly throughout the dentate gyrus, S100A10 was highly expressed in the hilus and inner molecular layer. In addition, TMT insult induced microglial p-PKCδ expression. Treatment with rottlerin, a PKCδ inhibitor, decreased Iba-1 and C3 expression, but did not affect S100A10 expression, suggesting that PKCδ inhibition attenuates microglial activation and A1 astrocyte phenotype polarization. Consistently, rottlerin significantly reduced the expression of C1q and tumor necrosis factor-α (TNFα), which has been suggested to be released by activated microglia and induce A1 astrocyte polarization. CONCLUSION: We demonstrated the temporal and spatial profiles of astrocyte polarization after TMT insult in the dentate gyrus of mice. Taken together, our results suggest that PKCδ plays a role in inducing A1 astrocyte polarization by promoting microglial activation and consequently increasing the expression of pro-inflammatory mediators after TMT insult.

Asunto(s)

Astrocitos , Complemento C1q , Acetofenonas , Animales , Astrocitos/metabolismo , Benzopiranos , Complemento C1q/metabolismo , Giro Dentado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Fenotipo , ARN Mensajero/metabolismo , Compuestos de Trimetilestaño

RESUMEN

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsies. Pharmacological treatment with anti-seizure drugs (ASDs) remains the mainstay in epilepsy management. Levetiracetam (LEV) is a second-generation ASD with a novel SV2A protein target and is indicated for treating focal epilepsies. While there is considerable literature in acute models, its effect in chronic epilepsy is less clear. Particularly, its effects on neuronal excitability, synaptic plasticity, adult hippocampal neurogenesis, and histological changes in chronic epilepsy have not been evaluated thus far, which formed the basis of the present study. Six weeks post-lithium-pilocarpine-induced status epilepticus (SE), epileptic rats were injected with levetiracetam (54 mg/kg b.w. i.p.) once daily for two weeks. Following LEV treatment, Schaffer collateral - CA1 (CA3-CA1) synaptic plasticity and structural changes in hippocampal subregions CA3 and CA1 were evaluated. The number of doublecortin (DCX+) and reelin (RLN+) positive neurons was estimated. Further, mossy fiber sprouting was evaluated in DG by Timm staining, and splash test was performed to assess the anxiety-like behavior. Chronic epilepsy resulted in decreased basal synaptic transmission and increased paired-pulse facilitation without affecting post-tetanic potentiation and long-term potentiation. Moreover, chronic epilepsy decreased hippocampal subfields volume, adult hippocampal neurogenesis, and increased reelin expression and mossy fiber sprouting with increased anxiety-like behavior. LEV treatment restored basal synaptic transmission and paired-pulse facilitation ratio in CA3-CA1 synapses. LEV also restored the CA1 subfield volume in chronic epilepsy. LEV did not affect epilepsy-induced abnormal adult hippocampal neurogenesis, ectopic migration of newborn granule cells, mossy fiber sprouting in DG, and anxiety-like behavior. Our results indicate that in addition to reducing seizures, LEV has favorable effects on synaptic transmission and structural plasticity in chronic epilepsy. These findings add new dimensions to the use of LEV in chronic epilepsy and paves way for further research into its effects on cognition and affective behavior.

Asunto(s)

Epilepsia del Lóbulo Temporal , Epilepsia , Animales , Giro Dentado/patología , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Hipocampo/patología , Levetiracetam/farmacología , Fibras Musgosas del Hipocampo/patología , Fibras Musgosas del Hipocampo/fisiología , Plasticidad Neuronal/fisiología , Ratas