RESUMEN

Aging is a multifaceted biological process characterized by progressive molecular and cellular damage accumulation. The brain hippocampus undergoes functional deterioration with age, caused by cellular deficits, decreased synaptic communication, and neuronal death, ultimately leading to memory impairment. One of the factors contributing to this dysfunction is the loss of mitochondrial function. In neurons, mitochondria are categorized into synaptic and non-synaptic pools based on their location. Synaptic mitochondria, situated at the synapses, play a crucial role in maintaining neuronal function and synaptic plasticity, whereas non-synaptic mitochondria are distributed throughout other neuronal compartments, supporting overall cellular metabolism and energy supply. The proper function of synaptic mitochondria is essential for synaptic transmission as they provide the energy required and regulate calcium homeostasis at the communication sites between neurons. Maintaining the structure and functionality of synaptic mitochondria involves intricate processes, including mitochondrial dynamics such as fission, fusion, transport, and quality control mechanisms. These processes ensure that mitochondria remain functional, replace damaged organelles, and sustain cellular homeostasis at synapses. Notably, deficiencies in these mechanisms have been increasingly associated with aging and the onset of age-related neurodegenerative diseases. Synaptic mitochondria from the hippocampus are particularly vulnerable to age-related changes, including alterations in morphology and a decline in functionality, which significantly contribute to decreased synaptic activity during aging. This review comprehensively explores the critical roles that mitochondrial dynamics and quality control mechanisms play in preserving synaptic activity and neuronal function. It emphasizes the emerging evidence linking the deterioration of synaptic mitochondria to the aging process and the development of neurodegenerative diseases, highlighting the importance of these organelles from hippocampal neurons as potential therapeutic targets for mitigating cognitive decline and synaptic degeneration associated with aging. The novelty of this review lies in its focus on the unique vulnerability of hippocampal synaptic mitochondria to aging, underscoring their importance in maintaining brain function across the lifespan.

Asunto(s)

Envejecimiento , Hipocampo , Mitocondrias , Sinapsis , Humanos , Hipocampo/fisiología , Hipocampo/metabolismo , Mitocondrias/metabolismo , Envejecimiento/fisiología , Envejecimiento/metabolismo , Sinapsis/fisiología , Sinapsis/metabolismo , Animales

RESUMEN

Cell replacement therapies using medial ganglionic eminence (MGE)-derived GABAergic precursors reduce seizures by restoring inhibition in animal models of epilepsy. However, how MGE-derived cells affect abnormal neuronal networks and consequently brain oscillations to reduce ictogenesis is still under investigation. We performed quantitative analysis of pre-ictal local field potentials (LFP) of cortical and hippocampal CA1 areas recorded in vivo in the pilocarpine rat model of epilepsy, with or without intrahippocampal MGE-precursor grafts (PILO and PILO+MGE groups, respectively). The PILO+MGE animals had a significant reduction in the number of seizures. The quantitative analysis of pre-ictal LFP showed decreased power of cortical and hippocampal delta, theta and beta oscillations from the 5 min. interictal baseline to the 20 s. pre-ictal period in both groups. However, PILO+MGE animals had higher power of slow and fast oscillations in the cortex and lower power of slow and fast oscillations in the hippocampus compared to the PILO group. Additionally, PILO+MGE animals exhibited decreased cortico-hippocampal synchrony for theta and gamma oscillations at seizure onset and lower hippocampal CA1 synchrony between delta and theta with slow gamma oscillations compared to PILO animals. These findings suggest that MGE-derived cell integration into the abnormally rewired network may help control ictogenesis.

Asunto(s)

Corteza Cerebral , Modelos Animales de Enfermedad , Epilepsia , Hipocampo , Pilocarpina , Animales , Pilocarpina/toxicidad , Hipocampo/fisiopatología , Masculino , Corteza Cerebral/fisiopatología , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Ratas , Ondas Encefálicas/fisiología , Ratas Wistar , Electroencefalografía , Eminencia Ganglionar

RESUMEN

Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions.

Asunto(s)

Trastorno del Espectro Autista , Histona Demetilasas con Dominio de Jumonji , Ratones Noqueados , Transmisión Sináptica , Animales , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Transmisión Sináptica/genética , Trastorno del Espectro Autista/genética , Ratones , Encéfalo/metabolismo , Plasticidad Neuronal/genética , Conducta Animal , Hipocampo/metabolismo , Epigénesis Genética , Masculino , Sinapsis/metabolismo

RESUMEN

Individuals considered resilient can overcome adversity, achieving normal physical and psychological development, while those deemed vulnerable may not. Adversity promotes structural and functional alterations in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, activity-dependent synaptic plasticity is intricately linked to neuronal shaping resulting from experiences. We hypothesize that this plasticity plays a crucial role in resilience processes. However, there is a notable absence of studies investigating this plasticity and behavioral changes following social adversity at different life stages. Consequently, we evaluated the impact of social adversity during early postnatal development (maternal separation [MS]), adulthood (social defeat [SD]), and a combined exposure (MS + SD) on behavioral outcomes (anxiety, motivation, anhedonia, and social interaction). We also examined cFos expression induced by social interaction in mPFC and hippocampus of adult male rats. Behavioral analyses revealed that SD-induced anhedonia, whereas MS + SD increased social interaction and mitigated SD-induced anhedonia. cFos evaluation showed that social interaction heightened plasticity in the prelimbic (PrL) and infralimbic (IL) cortices, dentate gyrus (DG), CA3, and CA1. Social interaction-associated plasticity was compromised in IL and PrL cortices of the MS and SD groups. Interestingly, social interaction-induced plasticity was restored in the MS + SD group. Furthermore, plasticity was impaired in DG by all social stressors, and in CA3 was impaired by SD. Our findings suggest in male rats (i) two adverse social experiences during development foster resilience; (ii) activity-dependent plasticity in the mPFC is a foundation for resilience to social adversity; (iii) plasticity in DG is highly susceptible to social adversity.

Asunto(s)

Privación Materna , Plasticidad Neuronal , Corteza Prefrontal , Resiliencia Psicológica , Animales , Plasticidad Neuronal/fisiología , Masculino , Ratas , Anhedonia/fisiología , Interacción Social , Derrota Social , Hipocampo , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicología , Ratas Wistar , Conducta Animal/fisiología , Conducta Social , Ansiedad/fisiopatología

RESUMEN

AIMS: Perinatal asphyxia is one of the major causes of neonatal death at birth. Survivors can progress but often suffer from long-term sequelae. We aim to determine the effects of perinatal asphyxia on mitochondrial dynamics and whether mesenchymal stem cell secretome (MSC-S) treatment can alleviate the deleterious effects. MATERIALS AND METHODS: Animals were subjected to 21 min of asphyxia at the time of delivery. MSC-S or vehicle was intranasally administered 2 h post-delivery. Mitochondrial mass (D-loop, qPCR), mitochondrial dynamics proteins (Drp1, Fis1 and OPA1, Western blot), mitochondrial dynamics (TOMM20, Immunofluorescence), as well as mitochondrial membrane potential (ΔΨm) (Safranin O) were evaluated at P1 and P7 in the hippocampus. KEY FINDINGS: Perinatal asphyxia increased levels of mitochondrial dynamics proteins Drp1 and S-OPA1 at P1 and Fis1 at P7. Mitochondrial density and mass were decreased at P1. Perinatal asphyxia induced sex-specific differences, with increased L-OPA1 in females at P7 and increased mitochondria circularity. In males, asphyxia-exposed animals exhibited a reduced ΔΨm at P7. MSC-S treatment normalised levels of mitochondrial dynamics proteins involved in fission. SIGNIFICANCE: This study provides novel insights into the effects of perinatal asphyxia on mitochondrial dynamics in the developing brain and on the therapeutic opportunities provided by mesenchymal stem cell secretome treatment. It also highlights on the relevance of considering sex as a biological variable in perinatal brain injury and therapy development. These findings contribute to the development of targeted, personalised therapies for infants affected by perinatal asphyxia.

Asunto(s)

Hipocampo , Células Madre Mesenquimatosas , Mitocondrias , Dinámicas Mitocondriales , Animales , Hipocampo/metabolismo , Hipocampo/patología , Femenino , Masculino , Células Madre Mesenquimatosas/metabolismo , Ratas , Mitocondrias/metabolismo , Asfixia Neonatal/terapia , Asfixia Neonatal/metabolismo , Asfixia Neonatal/patología , Animales Recién Nacidos , Trasplante de Células Madre Mesenquimatosas/métodos , Potencial de la Membrana Mitocondrial , Ratas Sprague-Dawley

RESUMEN

BACKGROUND: Blackcurrant (Ribes nigrum L.) is a berry rich in anthocyanins, bioactive compounds known for their antioxidant and neuroprotective properties that benefit human health. AIMS: This study aimed to investigate the effects of blackcurrant and its association with Donepezil on memory impairment, cholinergic neurotransmission, and antioxidant systems in a mouse model of amnesia induced by chronic administration of Scopolamine. METHODS: Adult male Swiss mice were given saline, blackcurrant (50 mg/kg, orally), and/or Donepezil (5 mg/kg, orally) and/or Scopolamine (1 mg/kg, intraperitoneally). RESULTS: Behavioral tests revealed that blackcurrant and/or Donepezil prevented the learning and memory deficits induced by Scopolamine. In the cerebral cortex and hippocampus, blackcurrant and/or Donepezil treatments prevented the increase in acetylcholinesterase and butyrylcholinesterase activities induced by Scopolamine. Scopolamine also disrupted the glutathione redox system and increased levels of reactive species; nevertheless, blackcurrant and/or Donepezil treatments were able to prevent oxidative stress. Furthermore, these treatments prevented the increase in gene expression and protein density of acetylcholinesterase and the decrease in gene expression of the choline acetyltransferase enzyme induced by Scopolamine. CONCLUSIONS: Findings suggest that blackcurrant and Donepezil, either alone or in combination, have anti-amnesic effects by modulating cholinergic system enzymes and improving the redox profile. Therefore, blackcurrant could be used as a natural supplement for the prevention and treatment of memory impairment in neurodegenerative diseases.

Asunto(s)

Acetilcolinesterasa , Antioxidantes , Donepezilo , Trastornos de la Memoria , Estrés Oxidativo , Extractos Vegetales , Ribes , Escopolamina , Animales , Masculino , Ratones , Donepezilo/farmacología , Ribes/química , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Trastornos de la Memoria/metabolismo , Acetilcolinesterasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Antioxidantes/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Fármacos Neuroprotectores/farmacología , Modelos Animales de Enfermedad , Piperidinas/farmacología , Indanos/farmacología , Butirilcolinesterasa/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Glutatión/metabolismo , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Amnesia/metabolismo , Amnesia/prevención & control , Transducción de Señal/efectos de los fármacos

RESUMEN

Epilepsy is a disorder characterized by a predisposition to generate seizures. Levetiracetam (LEV) is an antiseizure drug that has demonstrated oxidant-antioxidant effects during the early stages of epilepsy in several animal models. However, the effect of LEV on oxidant-antioxidant activity during long-term epilepsy has not been studied. Therefore, the objective of the present study was to determine the effects of LEV on the concentrations of five antioxidant enzymes and on the levels of four oxidant stress markers in the hippocampus of rats with temporal lobe epilepsy at 5.7 months after status epilepticus (SE). The results revealed that superoxide dismutase (SOD) activity was significantly greater in the epileptic group (EPI) than in the control (CTRL), CTRL + LEV and EPI + LEV groups. No significant differences were found among the groups' oxidant markers. However, the ratios of SOD/hydrogen peroxide (H2O2), SOD/glutathione peroxidase (GPx) and SOD/GPx + catalase (CAT) were greater in the EPI group than in the CTRL and EPI + LEV groups. Additionally, there was a positive correlation between SOD activity and GPx activity in the EPI + LEV group. LEV-mediated modulation of the antioxidant system appears to be time dependent; at 5.7 months after SE, the role of LEV may be as a stabilizer of the redox state.

Asunto(s)

Antioxidantes , Catalasa , Epilepsia del Lóbulo Temporal , Glutatión Peroxidasa , Levetiracetam , Estrés Oxidativo , Superóxido Dismutasa , Animales , Levetiracetam/farmacología , Levetiracetam/uso terapéutico , Ratas , Antioxidantes/metabolismo , Antioxidantes/farmacología , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/metabolismo , Masculino , Superóxido Dismutasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Catalasa/metabolismo , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Oxidantes/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Modelos Animales de Enfermedad , Peróxido de Hidrógeno/metabolismo , Ratas Wistar

RESUMEN

Aging is characterized by a functional decline in several physiological systems. α-Klotho-hypomorphic mice (Kl-/-) exhibit accelerated aging and cognitive decline. We evaluated whether male and female α-Klotho-hypomorphic mice show changes in the expression of synaptic proteins, N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, postsynaptic density protein 95 (PSD-95), synaptophysin and synapsin, and the activity of Na+, K+-ATPase (NaK) isoforms in the cerebellum and hippocampus. In this study, we demonstrated that in the cerebellum, Kl-/- male mice have reduced expression of GluA1 (AMPA) compared to wild-type (Kl+/+) males and Kl-/- females. Also, Kl-/- male and female mice show reduced ɑ2/ɑ3-NaK and Mg2+-ATPase activities in the cerebellum, respectively, and sex-based differences in NaK and Mg2+-ATPase activities in both the regions. Our findings suggest that α-Klotho could influence the expression of AMPAR and the activity of NaK isoforms in the cerebellum in a sex-dependent manner, and these changes may contribute, in part, to cognitive decline.

Asunto(s)

Cerebelo , Hipocampo , Proteínas Klotho , Receptores AMPA , Caracteres Sexuales , ATPasa Intercambiadora de Sodio-Potasio , Animales , Femenino , Masculino , Ratones , Cerebelo/metabolismo , Homólogo 4 de la Proteína Discs Large/metabolismo , Homólogo 4 de la Proteína Discs Large/genética , Hipocampo/metabolismo , Proteínas Klotho/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores AMPA/metabolismo , Receptores AMPA/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/genética , Sinapsinas/metabolismo , Sinapsinas/genética , Sinaptofisina/metabolismo

RESUMEN

Seizures are neurological disorders triggered by an imbalance in the activity of excitatory and inhibitory neurotransmitters in the brain. When triggered chronically, this imbalance can lead to epilepsy. Critically, many of the affected individuals are refractory to treatment. Given this, anti-inflammatory drugs, in particular glucocorticoids, have been considered as a potential antiepileptogenic therapy. Glucocorticoids are currently used in the treatment of refractory patients, although there have been contradictory results in terms of their use in association with antiepileptic drugs, which reinforces the need for a more thorough investigation of their effects. In this context, the present study evaluated the effects of dexamethasone (DEX, 0.6 mg/kg) on the electroencephalographic (EEG) and histopathological parameters of male Wistar rats submitted to acute seizure induced by pentylenetetrazol (PTZ). The EEG monitoring revealed that DEX reduced the total brainwave power, in comparison with PTZ, in 12 h after the convulsive episode, exerting this effect in up to 36 h (p < 0.05 for all comparisons). An increase in the accommodation of the oscillations of the delta, alpha, and gamma frequencies was also observed from the first 12 h onwards, with the accommodation of the theta frequency occurring after 36 h, and that of the beta frequency 24 h after the seizure. The histopathological analyses showed that the CA3 region and hilum of the hippocampus suffered cell loss after the PTZ-induced seizure (control vs. PTZ, p < 0.05), although DEX was not able to protect these regions against cell death (PTZ vs. DEX + PTZ, p > 0.05). While DEX did not reverse the cell damage caused by PTZ, the data indicate that DEX has beneficial properties in the EEG analysis, which makes it a promising candidate for the attenuation of the epileptiform wave patterns that can precipitate refractory seizures.

Asunto(s)

Ondas Encefálicas , Dexametasona , Electroencefalografía , Pentilenotetrazol , Ratas Wistar , Convulsiones , Animales , Dexametasona/farmacología , Dexametasona/efectos adversos , Pentilenotetrazol/toxicidad , Convulsiones/tratamiento farmacológico , Convulsiones/inducido químicamente , Convulsiones/fisiopatología , Masculino , Ratas , Ondas Encefálicas/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Anticonvulsivantes/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/fisiopatología

RESUMEN

INTRODUCTION: Brain glucose hypometabolism, indexed by the fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) imaging, is a metabolic signature of Alzheimer's disease (AD). However, the underlying biological pathways involved in these metabolic changes remain elusive. METHODS: Here, we integrated [18F]FDG-PET images with blood and hippocampal transcriptomic data from cognitively unimpaired (CU, n = 445) and cognitively impaired (CI, n = 749) individuals using modular dimension reduction techniques and voxel-wise linear regression analysis. RESULTS: Our results showed that multiple transcriptomic modules are associated with brain [18F]FDG-PET metabolism, with the top hits being a protein serine/threonine kinase activity gene cluster (peak-t(223) = 4.86, P value < 0.001) and zinc-finger-related regulatory units (peak-t(223) = 3.90, P value < 0.001). DISCUSSION: By integrating transcriptomics with PET imaging data, we identified that serine/threonine kinase activity-associated genes and zinc-finger-related regulatory units are highly associated with brain metabolic changes in AD. HIGHLIGHTS: We conducted an integrated analysis of system-based transcriptomics and fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) at the voxel level in Alzheimer's disease (AD). The biological process of serine/threonine kinase activity was the most associated with [18F]FDG-PET in the AD brain. Serine/threonine kinase activity alterations are associated with brain vulnerable regions in AD [18F]FDG-PET. Zinc-finger transcription factor targets were associated with AD brain [18F]FDG-PET metabolism.

Asunto(s)

Enfermedad de Alzheimer , Encéfalo , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico por imagen , Humanos , Fluorodesoxiglucosa F18/metabolismo , Masculino , Femenino , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Anciano , Transcriptoma , Hipocampo/metabolismo , Hipocampo/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/genética , Disfunción Cognitiva/diagnóstico por imagen , Anciano de 80 o más Años

RESUMEN

Glutamate is involved in fundamental functions, including neuronal plasticity and memory. Astrocytes are integral elements involved in synaptic function, and the GLT-1 transporter possesses a critical role in glutamate uptake. Here, we study the role of GLT-1, specifically located in astrocytes, in the consolidation, expression, reconsolidation and persistence of spatial object recognition memory in rats. Administration of dihydrokainic acid (DHK), a selective GLT-1 inhibitor, into the dorsal hippocampus around a weak training which only induces short-term memory, promotes long-term memory formation. This promotion is prevented by hippocampal administration of protein-synthesis translation inhibitor, blockade of Activity-regulated cytoskeleton-associated protein (Arc) translation or Brain-Derived Neurotrophic Factor (BDNF) action, which are plasticity related proteins necessary for memory consolidation. However, DHK around a strong training, which induces long-term memory, does not affect memory consolidation. Administration of DHK before the test session impairs the expression of long-term memory, and this effect is dependent of Arc translation. Furthermore, DHK impairs reconsolidation if applied before a reactivation session, and this effect is independent of Arc translation. These findings reveal specific consequences on spatial memory stages developed under hippocampal GLT-1 blockade, shedding light on the intricate molecular mechanisms, governed in part for the action of glia.

Asunto(s)

Astrocitos , Factor Neurotrófico Derivado del Encéfalo , Proteínas del Citoesqueleto , Ácido Glutámico , Hipocampo , Memoria Espacial , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Memoria Espacial/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Ratas , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/genética , Ácido Glutámico/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Transportador 2 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/antagonistas & inhibidores , Ratas Wistar , Ácido Kaínico/farmacología , Ácido Kaínico/análogos & derivados , Consolidación de la Memoria/efectos de los fármacos

RESUMEN

Synaptic dysfunction is an early feature in Alzheimer's disease (AD) pathogenesis and a major morphological correlate of memory deficits. Given the main synaptic location of N-methyl-D-aspartate receptors (NMDARs), their dysregulation has been implicated in these pathological effects. Here, to detect possible alterations in the expression and synaptic localisation of the GluN1 subunit in the brain of amyloidogenic APP/PS1 mice, we employed histoblot and SDS-digested freeze-fracture replica labelling (SDS-FRL) techniques. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus in a layer-dependent manner, in the cortex and the caudate putamen of APP/PS1 transgenic mice at 12 months of age but was unaltered at 1 and 6 months. Using quantitative SDS-FRL, we unravelled the molecular organisation of GluN1 in seven excitatory synapse populations at a high spatial resolution in the CA1 and CA3 fields and the DG of the hippocampus in 12-month-old APP/PS1 mice. In the CA1 field, the labelling density for GluN1 in the excitatory synapses established on spines and interneurons, was significantly reduced in APP/PS1 mice compared to age-matched wild-type mice in the stratum lacunosum-moleculare but unaltered in the stratum radiatum. In the CA3 field, synaptic GluN1 was reduced in mossy fibre-CA3 pyramidal cell synapses but unaltered in the A/C-CA3 pyramidal cell synapses. In the DG, the density of GluN1 in granule cell-perforant pathway synapses was reduced in APP/PS1 mice. Altogether, our findings provide evidence of specific alterations of synaptic GluN1 in the trisynaptic circuit of the hippocampus in Aß pathology. This differential vulnerability in the disruption of NMDARs may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit and cognitive impairment characteristic of APP/PS1 mice.

Asunto(s)

Enfermedad de Alzheimer , Hipocampo , Receptores de N-Metil-D-Aspartato , Sinapsis , Animales , Masculino , Ratones , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Ratones Transgénicos , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Sinapsis/patología

RESUMEN

Resistance exercise training (RET) is considered an excellent tool for preventing diseases with an inflammatory background. Its neuroprotective, antioxidant, and anti-inflammatory properties are responsible for positively modulating cholinergic and oxidative systems, promoting neurogenesis, and improving memory. However, the mechanisms behind these actions are largely unknown. In order to investigate the pathways related to these effects of exercise, we conducted a 12-week long-term exercise training protocol and used lipopolysaccharide (LPS) to induce damage to the cortex and hippocampus of male Wistar rats. The cholinergic system, oxidative stress, and histochemical parameters were analyzed in the cerebral cortex and hippocampus, and memory tests were also performed. It was observed that LPS: (1) caused memory loss in the novel object recognition (NOR) test; (2) increased the activity of acetylcholinesterase (AChE) and Iba1 protein density; (3) reduced the protein density of brain-derived neurotrophic factor (BDNF) and muscarinic acetylcholine receptor M1 (CHRM1); (4) elevated the levels of lipid peroxidation (TBARS) and reactive species (RS); and (5) caused inflammatory damage to the dentate gyrus. RET, on the other hand, was able to prevent all alterations induced by LPS, as well as increase per se the protein density of the alpha-7 nicotinic acetylcholine receptor (nAChRα7) and Nestin, and the levels of protein thiols (T-SH). Overall, our study elucidates some mechanisms that support resistance physical exercise as a valuable approach against LPS-induced neuroinflammation and memory loss.

Asunto(s)

Lipopolisacáridos , Trastornos de la Memoria , Enfermedades Neuroinflamatorias , Condicionamiento Físico Animal , Ratas Wistar , Animales , Masculino , Lipopolisacáridos/toxicidad , Condicionamiento Físico Animal/fisiología , Condicionamiento Físico Animal/métodos , Ratas , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Entrenamiento de Fuerza/métodos , Corteza Cerebral/metabolismo , Corteza Cerebral/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Receptor Muscarínico M1/metabolismo

RESUMEN

Calcified cysticerci are often associated with hippocampal atrophy (HA). While most studies suggest that repetitive seizures cause HA in these patients, others have demonstrated that HA may also occur in persons without epilepsy. Little is known about mechanisms triggering HA in seizure-free individuals with calcified cysticerci. Here, we aimed to assess whether the size of the calcification is associated with HA. Using a population-based design, we selected apparently seizure-free individuals with a single calcified cysticercus in whom interictal paroxysmal activity and other causes of HA have been discarded. A total of 55 individuals (mean age, 58.3 ± 13 years, 62% women) fulfilled inclusion criteria. Unadjusted and multivariate models were fitted to assess the association between the size of the calcification dichotomized into <3 mm and ≥3 mm (exposure) and the presence of HA (outcome). Sixteen participants (29%) had HA, which was asymmetric in eight (50%) cases. Hippocampal atrophy was noted in 11/20 (55%) participants with large calcifications and in 5/35 (14%) with small calcifications (P = 0.001). A multivariate logistic regression model showed a significant association between the presence of large calcifications and HA, after adjustment for relevant confounders (odds ratio: 7.78; 95% CI: 1.72-35.1). Participants with calcifications ≥3 mm in diameter were 7.8 times more likely to have HA than those with smaller ones. Study results open avenues of research for the use of agents to prevent HA progression.

Asunto(s)

Atrofia , Calcinosis , Hipocampo , Humanos , Femenino , Hipocampo/patología , Masculino , Persona de Mediana Edad , Atrofia/patología , Calcinosis/patología , Anciano , Neurocisticercosis/complicaciones , Neurocisticercosis/patología , Neurocisticercosis/diagnóstico por imagen , Adulto , Convulsiones/patología , Encéfalo/patología , Encéfalo/diagnóstico por imagen

RESUMEN

Astrocytes play key roles in the brain. When astrocyte support fails, neurological disorders follow, resulting in disrupted synaptic communication, neuronal degeneration, and cell death. We posit that astrocytes overexpressing neurotrophic factors, such as Insulin Like Growth Factor 1 (IGF1), prevent the onset of neurodegeneration. We overexpressed IGF1 and the reporter TdTomato (TOM) in hippocampal astrocytes with bicistronic Adeno-Associated Virus (AAV) harboring the Glial Fibrillary Acidic Protein (GFAP) promoter and afterwards induced neurodegeneration by the intracerebroventricular (ICV) injection of streptozotocin (STZ), a rat model of behavioral impairment, neuroinflammation and shortening of hippocampal astrocytes. We achieved a thorough transgene expression along the hippocampus with a single viral injection. Although species typical behavior was impaired, memory deficit was prevented by IGF1. STZ prompted astrocyte shortening, albeit the length of these cells in animals injected with GFP and IGF1 vectors did not statistically differ from the other groups. In STZ control animals, hippocampal microglial reactive cells increased dramatically, but this was alleviated in IGF1 rats. We conclude that overexpression of IGF1 in astrocytes prevents neurodegeneration onset. Hence, individuals with early neurotrophic exhaustion would be vulnerable to age-related neurodegeneration.

Asunto(s)

Astrocitos , Dependovirus , Hipocampo , Factor I del Crecimiento Similar a la Insulina , Animales , Astrocitos/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Hipocampo/metabolismo , Dependovirus/genética , Ratas , Masculino , Ratas Wistar , Proteína Ácida Fibrilar de la Glía/metabolismo

RESUMEN

To contribute to research on female models of Alzheimer's disease (AD), our aim was to study the effect of intracerebroventricular (ICV) injection of streptozotocin (STZ) in female rats, and to evaluate a potential neuroprotective action of ovarian steroids against STZ. Female rats were either ovariectomized (OVX) or kept with ovaries (Sham) two weeks before ICV injections. Animals were injected with either vehicle (artificial cerebrospinal fluid, aCSF) or STZ (3 mg/kg) and separated into four experimental groups: Sham + aCSF, Sham + STZ, OVX + aCSF and OVX + STZ. Nineteen days post-injection, we assessed different behavioral aspects: burying, anxiety and exploration, object recognition memory, spatial memory, and depressive-like behavior. Immunohistochemistry and Immunoblot analyses were performed in the hippocampus to examine changes in AD-related proteins and neuronal and microglial populations. STZ affected burying and exploratory behavior depending on ovarian status, and impaired recognition but not spatial memory. STZ and ovariectomy increased depressive-like behavior. Interestingly, STZ did not alter the expression of ß-amyloid peptide or Tau phosphorylated forms. STZ affected the neuronal population from the Dentate Gyrus, where immature neurons were more vulnerable to STZ in OVX rats. Regarding microglia, STZ increased reactive cells, and the OVX + STZ group showed an increase in the total cell number. In sum, STZ partially affected female rats, compared to what was previously reported for males. Although AD is more frequent in women, reports about the effect of ICV-STZ in female rats are scarce. Our work highlights the need to deepen into the effects of STZ in the female brain and study possible sex differences.

Asunto(s)

Enfermedad de Alzheimer , Ovariectomía , Estreptozocina , Animales , Femenino , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/metabolismo , Ratas , Inyecciones Intraventriculares , Ratas Wistar , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ovario/efectos de los fármacos , Ovario/metabolismo , Depresión/inducido químicamente , Depresión/metabolismo , Péptidos beta-Amiloides/metabolismo , Memoria Espacial/efectos de los fármacos

RESUMEN

The present study aimed to evaluate the protective potential of carvacrol against depressive-like behavior and cognitive impairment prompted by chronic unpredictable mild stress (CUMS) in mice. The animals were divided into six groups: Control (non-stressed), CARV (carvacrol at 50 mg/kg, p.o.), FLU (fluoxetine at 10 mg/kg, p.o.), CUMS (stressed), CUMS + CARV and CUMS + FLU, and the groups with CUMS were subjected to different stressors for 28 days. After treatment, mice underwent behavioral testing (open field, forced swimming, sucrose preference, social interaction, novel object recognition and Y-maze) and brain areas were removed for oxidative stress (MDA, nitrite/nitrate and GSH levels) and cytokine (IL-1ß and TNF-α) content assays. The results revealed that CARV administration reversed depressive-like behavior and significantly ameliorated the cognitive deficit induced by CUMS, as well as was able to attenuate oxidative stress (decreased MDA and nitrite/nitrate levels and increased GSH levels). In addition, a significant reduction in hippocampal IL-1ß and TNF-α levels was observed, demonstrating a potential anti-neuroinflammatory activity. Taken together, the antioxidant and anti-inflammatory activities observed in this study indicate that CARV is a promising drug for antidepressant treatment.

Asunto(s)

Conducta Animal , Disfunción Cognitiva , Cimenos , Depresión , Modelos Animales de Enfermedad , Enfermedades Neuroinflamatorias , Estrés Oxidativo , Estrés Psicológico , Animales , Estrés Oxidativo/efectos de los fármacos , Ratones , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Depresión/etiología , Masculino , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Cimenos/farmacología , Cimenos/administración & dosificación , Conducta Animal/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Antioxidantes/farmacología , Fluoxetina/farmacología , Fluoxetina/administración & dosificación , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Interleucina-1beta/metabolismo

RESUMEN

BACKGROUND: The nucleus incertus (NI) was originally described by Streeter in 1903, as a midline region in the floor of the fourth ventricle of the human brain with an 'unknown' function. More than a century later, the neuroanatomy of the NI has been described in lower vertebrates, but not in humans. Therefore, we examined the neurochemical anatomy of the human NI using markers, including the neuropeptide, relaxin-3 (RLN3), and began to explore the distribution of the NI-related RLN3 innervation of the hippocampus. METHODS: Histochemical staining of serial, coronal sections of control human postmortem pons was conducted to reveal the presence of the NI by detection of immunoreactivity (IR) for the neuronal markers, microtubule-associated protein-2 (MAP2), glutamic acid dehydrogenase (GAD)-65/67 and corticotrophin-releasing hormone receptor 1 (CRHR1), and RLN3, which is highly expressed in NI neurons in diverse species. RLN3 and vesicular GABA transporter 1 (vGAT1) mRNA were detected by fluorescent in situ hybridization. Pons sections containing the NI from an AD case were immunostained for phosphorylated-tau, to explore potential relevance to neurodegenerative diseases. Lastly, sections of the human hippocampus were stained to detect RLN3-IR and somatostatin (SST)-IR. RESULTS: In the dorsal, anterior-medial region of the human pons, neurons containing RLN3- and MAP2-IR, and RLN3/vGAT1 mRNA-positive neurons were observed in an anatomical pattern consistent with that of the NI in other species. GAD65/67- and CRHR1-immunopositive neurons were also detected within this area. Furthermore, RLN3- and AT8-IR were co-localized within NI neurons of an AD subject. Lastly, RLN3-IR was detected in neurons within the CA1, CA2, CA3 and DG areas of the hippocampus, in the absence of RLN3 mRNA. In the DG, RLN3- and SST-IR were co-localized in a small population of neurons. CONCLUSIONS: Aspects of the anatomy of the human NI are shared across species, including a population of stress-responsive, RLN3-expressing neurons and a RLN3 innervation of the hippocampus. Accumulation of phosphorylated-tau in the NI suggests its possible involvement in AD pathology. Further characterization of the neurochemistry of the human NI will increase our understanding of its functional role in health and disease.

Asunto(s)

Puente , Humanos , Puente/metabolismo , Masculino , Hipocampo/química , Hipocampo/metabolismo , Femenino , Relaxina/metabolismo , Relaxina/genética , Anciano , Neuronas/química , Memoria/fisiología , Proteínas Asociadas a Microtúbulos/metabolismo , Persona de Mediana Edad , Anciano de 80 o más Años , Inmunohistoquímica , Hibridación Fluorescente in Situ , Glutamato Descarboxilasa/metabolismo , Glutamato Descarboxilasa/genética , Receptores de Hormona Liberadora de Corticotropina

RESUMEN

The adult hippocampus generates new granule cells (aGCs) with functional capabilities that convey unique forms of plasticity to the preexisting circuits. While early differentiation of adult radial glia-like cells (RGLs) has been studied extensively, the molecular mechanisms guiding the maturation of postmitotic neurons remain unknown. Here, we used a precise birthdating strategy to study aGC differentiation using single-nuclei RNA sequencing. Transcriptional profiling revealed a continuous trajectory from RGLs to mature aGCs, with multiple immature stages bearing increasing levels of effector genes supporting growth, excitability, and synaptogenesis. Analysis of differential gene expression, pseudo-time trajectory, and transcription factors (TFs) revealed critical transitions defining four cellular states: quiescent RGLs, proliferative progenitors, immature aGCs, and mature aGCs. Becoming mature aGCs involved a transcriptional switch that shuts down pathways promoting cell growth, such SoxC TFs, to activate programs that likely control neuronal homeostasis. aGCs overexpressing Sox4 or Sox11 remained immature. Our results unveil precise molecular mechanisms driving adult RGLs through the pathway of neuronal differentiation.

Asunto(s)

Diferenciación Celular , Hipocampo , Neurogénesis , Neuronas , Factores de Transcripción SOXC , Animales , Hipocampo/metabolismo , Hipocampo/citología , Neuronas/metabolismo , Neuronas/citología , Factores de Transcripción SOXC/metabolismo , Factores de Transcripción SOXC/genética , Diferenciación Celular/genética , Neurogénesis/genética , Ratones , Transcripción Genética , Perfilación de la Expresión Génica , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Células Ependimogliales/metabolismo , Células Ependimogliales/citología

RESUMEN

BACKGROUND: Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated whether changes occur in brain structures. METHODS: Three groups of gerbils were used: control (1), orogastrically inoculated on day 3 after birth with trophozoites of two isolates of Giardia intestinalis (HGINV/WB) group (2 and 3). Estimates were made at five ages covering: establishment of infection, Giardia population growth, natural parasite clearance and a post-infection age. QuantiChrome zinc assay kit, cresyl violet staining and TUNEL technique were used. RESULTS: A significant decrease (p<0.01) in tissue zinc was observed and persisted after infection. Cytoarchitectural changes were observed in 75% of gerbils in the HGINV or WB groups. Ectopic pyramidal neurons were found in the cornus ammonis (CA1-CA3). At 60 and 90 days of age loss of lamination was clearly visible in CA1. In the dentate gyrus (DG), thinning of the dorsal lamina and abnormal thickening of the ventral lamina were observed from 30 days of age. In the cerebellum, we found an increase (p<0.01) in the thickness of the external granular layer (EGL) at 14 days of age that persisted until day 21 (C 3 ± 0.3 µm; HGINV 37 ± 5 µm; WB 28 ± 3 µm); Purkinje cell population estimation showed a significant decrease; a large number of apoptotic somas were observed scattered in the molecular layer; in 60 and 90 days old gerbils we found granular cell heterotopia and Purkinje cell ectopia. The pattern of apoptosis was different in the cerebellum and hippocampus of parasitized gerbils. CONCLUSION: The morphological changes found suggest that neuronal migration is affected by zinc depletion caused by giardiasis in early postnatal life; for the first time, the link between giardiasis-zinc depletion and damaged brain structures is shown. This damage may explain the psychomotor/cognitive delay associated with giardiasis. These findings are alarming. Alterations in zinc metabolism and signalling are known to be involved in many brain disorders, including autism.

Asunto(s)

Cerebelo , Gerbillinae , Giardia lamblia , Giardiasis , Hipocampo , Zinc , Animales , Gerbillinae/parasitología , Zinc/deficiencia , Zinc/metabolismo , Giardiasis/parasitología , Giardiasis/patología , Cerebelo/patología , Cerebelo/parasitología , Hipocampo/patología , Hipocampo/parasitología , Giardia lamblia/crecimiento & desarrollo , Masculino , Modelos Animales de Enfermedad