RESUMEN

Vitamin D deficiency is a global problem. Vitamin D, the vitamin D receptor, and its enzymes are found throughout neuronal, ependymal, and glial cells in the brain and are implicated in certain processes and mechanisms in the brain. To investigate the processes affected by vitamin D deficiency in adults, we studied vitamin D deficient, control, and supplemented diets over 6 weeks in male and female C57Bl/6 mice. The effect of the vitamin D diets on proliferation in the neurogenic niches, changes in glial cells, as well as on memory, locomotion, and anxiety-like behavior, was investigated. Six weeks on a deficient diet was adequate time to reach deficiency. However, vitamin D deficiency and supplementation did not affect proliferation, neurogenesis, or astrocyte changes, and this was reflected on behavioral measures. Supplementation only affected microglia in the dentate gyrus of female mice. Indicating that vitamin D deficiency and supplementation do not affect these processes over a 6-week period.

Asunto(s)

Cognición , Suplementos Dietéticos , Ratones Endogámicos C57BL , Neurogénesis , Deficiencia de Vitamina D , Vitamina D , Animales , Deficiencia de Vitamina D/complicaciones , Femenino , Masculino , Vitamina D/farmacología , Ratones , Proliferación Celular , Conducta Animal , Astrocitos/metabolismo , Giro Dentado , Ansiedad , Encéfalo/metabolismo , Memoria

RESUMEN

Memories of events are linked to the contexts in which they were encoded. This contextual linking ensures enhanced access to those memories that are most relevant to the context at hand, including specific associations that were previously learned in that context. This principle, referred to as encoding specificity, predicts that context-specific neural states should bias retrieval of particular associations over others, potentially allowing for the disambiguation of retrieval cues that may have multiple associations or meanings. Using a context-odor paired associate learning paradigm in mice, here, we show that chemogenetic manipulation of dentate gyrus ensembles corresponding to specific contexts reinstates context-specific neural states in downstream CA1 and biases retrieval toward context-specific associations.

Asunto(s)

Giro Dentado , Animales , Giro Dentado/fisiología , Ratones , Memoria/fisiología , Masculino , Recuerdo Mental/fisiología , Neuronas/fisiología , Ratones Endogámicos C57BL

RESUMEN

Astrocytes display context-specific diversity in their functions and respond to noxious stimuli between brain regions. Astrocytic mitochondria have emerged as key players in governing astrocytic functional heterogeneity, given their ability to dynamically adapt their morphology to regional demands on ATP generation and Ca2+ buffering functions. Although there is reciprocal regulation between mitochondrial dynamics and mitochondrial Ca2+ signaling in astrocytes, the extent of this regulation in astrocytes from different brain regions remains unexplored. Brain-wide, experimentally induced mitochondrial DNA (mtDNA) loss in astrocytes showed that mtDNA integrity is critical for astrocyte function, however, possible diverse responses to this noxious stimulus between brain areas were not reported in these experiments. To selectively damage mtDNA in astrocytes in a brain-region-specific manner, we developed a novel adeno-associated virus (AAV)-based tool, Mito-PstI expressing the restriction enzyme PstI, specifically in astrocytic mitochondria. Here, we applied Mito-PstI to two brain regions, the dorsolateral striatum and dentate gyrus, and we show that Mito-PstI induces astrocytic mtDNA loss in vivo, but with remarkable brain-region-dependent differences on mitochondrial dynamics, Ca2+ fluxes, and astrocytic and microglial reactivity. Thus, AAV-Mito-PstI is a novel tool to explore the relationship between astrocytic mitochondrial network dynamics and astrocytic mitochondrial Ca2+ signaling in a brain-region-selective manner.

Asunto(s)

Astrocitos , Daño del ADN , ADN Mitocondrial , Mitocondrias , Astrocitos/metabolismo , Animales , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Ratones , Mitocondrias/metabolismo , Dependovirus/genética , Calcio/metabolismo , Encéfalo/metabolismo , Masculino , Señalización del Calcio , Ratones Endogámicos C57BL , Dinámicas Mitocondriales , Giro Dentado/metabolismo

RESUMEN

Developmental exposure to nonylphenol (NP) results in irreversible impairments of the central nervous system (CNS). The neural precursor cell (NPC) pool located in the subgranular zone (SGZ), a substructure of the hippocampal dentate gyrus, is critical for the development of hippocampal circuits and some hippocampal functions such as learning and memory. However, the effects of developmental exposure to NP on this pool remain unclear. Thus, our aim was to clarify the impacts of developmental exposure to NP on this pool and to explore the potential mechanisms. Animal models of developmental exposure to NP were created by treating Wistar rats with NP during pregnancy and lactation. Our data showed that developmental exposure to NP decreased Sox2-and Ki67-positive cells in the SGZ of offspring. Inhibited activation of Shh signaling and decreased levels of its downstream mediators, E2F1 and cyclins, were also observed in pups developmentally exposed to NP. Moreover, we established the in vitro model in the NE-4C cells, a neural precursor cell line, to further investigate the effect of NP exposure on NPCs and the underlying mechanisms. Purmorphamine, a small purine-derived hedgehog agonist, was used to specifically modulate the Shh signaling. Consistent with the in vivo results, exposure to NP reduced cell proliferation by inhibiting the Shh signaling in NE-4C cells, and purmorphamine alleviated this reduction in cell proliferation by restoring this signaling. Altogether, our findings support the idea that developmental exposure to NP leads to inhibition of the NPC proliferation and the NPC pool depletion in the SGZ located in the dentate gyrus. Furthermore, we also provided the evidence that suppressed activation of Shh signaling may contribute to the effects of developmental exposure to NP on the NPC pool.

Asunto(s)

Proliferación Celular , Giro Dentado , Proteínas Hedgehog , Células-Madre Neurales , Fenoles , Ratas Wistar , Transducción de Señal , Animales , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Giro Dentado/citología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Proteínas Hedgehog/metabolismo , Fenoles/farmacología , Fenoles/toxicidad , Femenino , Embarazo , Ratas , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Purinas/farmacología , Morfolinas/farmacología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Masculino , Factores de Transcripción SOXB1/metabolismo , Línea Celular

RESUMEN

The decline of microglia in the dentate gyrus is a new phenomenon that may explain the pathogenesis of depression, and reversing this decline has an antidepressant effect. The development of strategies that restore the function of dentate gyrus microglia in under stressful conditions is becoming a new focus. Lymphocyte-activating gene-3 (LAG3) is an immune checkpoint expressed by immune cells including microglia. One of its functions is to suppress the expansion of immune cells. In a recent study, chronic systemic administration of a LAG3 antibody that readily penetrates the brain was reported to reverse chronic stress-induced hippocampal microglia decline and depression-like behaviors. We showed here that a single intranasal infusion of a LAG3 antibody (In-LAG3 Ab) reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in a dose-dependent manner, which was accompanied by an increase in brain-derived neurotrophic factor (BDNF) in the dentate gyrus. Infusion of an anti-BDNF antibody into the dentate gyrus, construction of knock-in mice with the BDNF Val68Met allele, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of In-LAG3 Ab. Activation of extracellular signal-regulated kinase1/2 (ERK1/2) is required for the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and BDNF decrease in the dentate gyrus. Moreover, both inhibition and depletion of microglia prevented the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and impairment of ERK1/2-BDNF signaling in the dentate gyrus. These results suggest that In-LAG3 Ab exhibits an antidepressant effect through microglia-mediated activation of ERK1/2 and synthesis of BDNF in the dentate gyrus.

Asunto(s)

Administración Intranasal , Antidepresivos , Antígenos CD , Factor Neurotrófico Derivado del Encéfalo , Depresión , Hipocampo , Proteína del Gen 3 de Activación de Linfocitos , Sistema de Señalización de MAP Quinasas , Estrés Psicológico , Animales , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Depresión/tratamiento farmacológico , Antígenos CD/metabolismo , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Anticuerpos/farmacología , Carbazoles/farmacología , Carbazoles/administración & dosificación , Transducción de Señal/efectos de los fármacos , Alcaloides Indólicos

RESUMEN

Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explored the contribution of NAT10-mediated messenger RNA (mRNA) acetylation in cognitive dysfunction associated with SAE, utilizing a cecal ligation and puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression and mRNA acetylation in the excitatory neurons of the hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved cognitive function in septic mice, highlighting its critical role in SAE. Proteomic analysis, RNA immunoprecipitation, and real-time qPCR identified GABABR1 as a key downstream target of NAT10. Nat10 deletion reduced GABABR1 expression, and subsequently weakened inhibitory postsynaptic currents in hippocampal DG neurons. Further analysis revealed that microglia activation and the release of inflammatory mediators lead to the increased NAT10 expression in neurons. Microglia depletion with PLX3397 effectively reduced NAT10 and GABABR1 expression in neurons, and ameliorated cognitive dysfunction induced by SAE. In summary, our findings revealed that after CLP, NAT10 in hippocampal DG neurons promotes GABABR1 expression through mRNA acetylation, leading to cognitive dysfunction.

Asunto(s)

Disfunción Cognitiva , ARN Mensajero , Encefalopatía Asociada a la Sepsis , Animales , Masculino , Ratones , Acetilación , Acetiltransferasas/metabolismo , Acetiltransferasas/genética , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/genética , Giro Dentado/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Microglía/metabolismo , Neuronas/metabolismo , ARN Mensajero/metabolismo , ARN Mensajero/genética , Sepsis/metabolismo , Sepsis/complicaciones , Sepsis/genética , Encefalopatía Asociada a la Sepsis/metabolismo , Encefalopatía Asociada a la Sepsis/genética , Receptores de GABA-B

RESUMEN

The hippocampus (HPC) is well-known for its involvement in declarative (consciously accessible) memory, but there is evidence that it may also play a role in complex perceptual discrimination. Separate research has demonstrated separable contributions of HPC subregions to component memory processes, with the dentate gyrus (DG) required for mnemonic discrimination of similar inputs and the CA1 subfield required for retention and retrieval, but contributions of these subregions to perceptual processes is understudied. The current study examined the nature and extent of a double dissociation between the dentate gyrus (DG) to discrimination processes and CA1 subfield to retention/retrieval by testing two unique individuals with bilateral damage to the DG (case BL) and CA1 (case BR). We tested BL and BR on a wide range of standardized neuropsychological tests to assess information encoding and retention/retrieval and co-opted many measures to assess perceptual discrimination. Compared to normative data, BL exhibited performance below expectations on most measures requiring perceptual discrimination and on measures of encoding but demonstrated intact retention. Conversely, BR showed no difficulties with perceptual discrimination or verbal encoding but exhibited poor verbal retention, as well as poor encoding and retention of spatial/integrative tasks (e.g., object in a location). These results indicate that, despite its prominent role in memory, the DG is necessary for perceptual discrimination and encoding, whereas CA1 is necessary for retention/retrieval and encoding of spatial information. The pattern of results highlights the critical nature of individual case studies in the nuanced understanding of HPC subfield contributions to different memory processes, as well as the utility of repurposing neuropsychological measures to capture individual differences.

Asunto(s)

Región CA1 Hipocampal , Giro Dentado , Discriminación en Psicología , Pruebas Neuropsicológicas , Humanos , Giro Dentado/fisiopatología , Masculino , Persona de Mediana Edad , Discriminación en Psicología/fisiología , Femenino , Adulto , Memoria/fisiología , Anciano

RESUMEN

Real-time approaches are typically needed in studies of learning and memory, and in vivo calcium imaging provides the possibility to investigate neuronal activity in awake animals during behavior tasks. Since the hippocampus is closely associated with episodic and spatial memory, it has become an essential brain region in this field's research. In recent research, engram cells and place cells were studied by recording the neural activities in the hippocampal CA1 region using the miniature microscope in mice while performing behavioral tasks including open-field and linear track. Although the dentate gyrus is another important region in the hippocampus, it has rarely been studied with in vivo imaging due to its greater depth and difficulty for imaging. In this protocol, we present in detail a calcium imaging process, including how to inject the virus, implant a GRIN (Gradient-index) lens, and attach a base plate for imaging the dentate gyrus of the hippocampus. We further describe how to preprocess the calcium imaging data using MATLAB. Additionally, studies of other deep brain regions that require imaging may benefit from this method.

Asunto(s)

Calcio , Giro Dentado , Neuronas , Animales , Giro Dentado/citología , Giro Dentado/diagnóstico por imagen , Ratones , Calcio/metabolismo , Calcio/análisis , Neuronas/citología

RESUMEN

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a successful treatment option in Parkinson's disease (PD) for different motor and non-motor symptoms, but has been linked to postoperative cognitive impairment. AIM: Since both dopaminergic and norepinephrinergic neurotransmissions play important roles in symptom development, we analysed STN-DBS effects on dopamine and norepinephrine availability in different brain regions and morphological alterations of catecholaminergic neurons in the 6-hydroxydopamine PD rat model. METHODS: We applied one week of continuous unilateral STN-DBS or sham stimulation, respectively, in groups of healthy and 6-hydroxydopamine-lesioned rats to quantify dopamine and norepinephrine contents in the striatum, olfactory bulb and dentate gyrus. In addition, we analysed dopaminergic cell counts in the substantia nigra pars compacta and area tegmentalis ventralis and norepinephrinergic neurons in the locus coeruleus after one and six weeks of STN-DBS. RESULTS: In 6-hydroxydopamine-lesioned animals, one week of STN-DBS did not alter dopamine levels, while striatal norepinephrine levels were decreased. However, neither one nor six weeks of STN-DBS altered dopaminergic neuron numbers in the midbrain or norepinephrinergic neuron counts in the locus coeruleus. Dopaminergic fibre density in the dorsal and ventral striatum also remained unchanged after six weeks of STN-DBS. In healthy animals, one week of STN-DBS resulted in increased dopamine levels in the olfactory bulb and decreased contents in the dentate gyrus, but had no effects on norepinephrine availability. CONCLUSIONS: STN-DBS modulates striatal norepinephrinergic neurotransmission in a PD rat model. Additional behavioural studies are required to investigate the functional impact of this finding.

Asunto(s)

Estimulación Encefálica Profunda , Modelos Animales de Enfermedad , Dopamina , Norepinefrina , Oxidopamina , Núcleo Subtalámico , Transmisión Sináptica , Animales , Núcleo Subtalámico/metabolismo , Estimulación Encefálica Profunda/métodos , Masculino , Oxidopamina/toxicidad , Transmisión Sináptica/fisiología , Dopamina/metabolismo , Norepinefrina/metabolismo , Ratas , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/terapia , Neuronas Dopaminérgicas/metabolismo , Bulbo Olfatorio/metabolismo , Ratas Sprague-Dawley , Cuerpo Estriado/metabolismo , Giro Dentado/metabolismo , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/terapia , Trastornos Parkinsonianos/fisiopatología

RESUMEN

Hippocampus is a critical component of the central nervous system. SRSF10 is expressed in central nervous system and plays important roles in maintaining normal brain functions. However, its role in hippocampus development is unknown. In this study, using SRSF10 conditional knock-out mice in neural progenitor cells (NPCs), we found that dysfunction of SRSF10 leads to developmental defects in the dentate gyrus of hippocampus, which manifests as the reduced length and wider suprapyramidal blade and infrapyramidal blade.Furthermore, we proved that loss of SRSF10 in NPCs caused inhibition of the differentiation activity and the abnormal migration of NPCs and granule cells, resulting in reduced granule cells and more ectopic granule cells dispersed in the molecular layer and hilus. Finally, we found that the abnormal migration may be caused by the radial glia scaffold and the reduced DISC1 expression in NPCs. Together, our results indicate that SRSF10 is required for the cell migration and formation of dentate gyrus during the development of hippocampus.

Asunto(s)

Movimiento Celular , Giro Dentado , Ratones Noqueados , Células-Madre Neurales , Factores de Empalme Serina-Arginina , Animales , Ratones , Diferenciación Celular/fisiología , Movimiento Celular/fisiología , Giro Dentado/metabolismo , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Células-Madre Neurales/metabolismo , Neurogénesis/fisiología , Neuronas/metabolismo , Factores de Empalme Serina-Arginina/metabolismo , Factores de Empalme Serina-Arginina/genética

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

Exposure to light has been demonstrated to stimulate brain regions associated with cognition; however, investigations into its cognitive-enhancing effects have primarily focused on wild-type rodents. This study seeks to elucidate how bright light exposure mitigates cognitive deficits associated with schizophrenia by examining its impact on hippocampal neurogenesis and its potential to alleviate sub-chronic MK-801-induced cognitive impairments in mice. Following three weeks of juvenile bright light exposure (5-8 weeks old), significant increases in proliferating neurons (BrdU+) and immature neurons (DCX+ cells) were observed in the dentate gyrus (DG) and lateral ventricle of MK-801-treated mice. Long-term bright light treatment further promoted the differentiation of BrdU+ cells into immature neurons (BrdU+ DCX+ cells), mature neurons (BrdU+ NeuN+ cells), or astrocytes (BrdU+ GFAP+ cells) in the hippocampal DG. This augmented neurogenesis correlated with the attenuation of sub-chronic MK- 801-induced cognitive deficits, as evidenced by enhancements in Y-maze, novel object recognition (NOR), novel location recognition (NLR), and Morris water maze (MWM) test performances. These findings suggest a promising noninvasive clinical approach for alleviating cognitive impairments associated with neuropsychiatric disorders.

Asunto(s)

Disfunción Cognitiva , Modelos Animales de Enfermedad , Proteína Doblecortina , Neurogénesis , Esquizofrenia , Animales , Neurogénesis/fisiología , Esquizofrenia/terapia , Esquizofrenia/fisiopatología , Esquizofrenia/metabolismo , Disfunción Cognitiva/terapia , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Ratones , Masculino , Hipocampo/metabolismo , Maleato de Dizocilpina/farmacología , Conducta Animal/fisiología , Giro Dentado/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Ratones Endogámicos C57BL , Luz

RESUMEN

Highly specialized cells are fundamental for the proper functioning of complex organs. Variations in cell-type-specific gene expression and protein composition have been linked to a variety of diseases. Investigation of the distinctive molecular makeup of these cells within tissues is therefore critical in biomedical research. Although several technologies have emerged as valuable tools to address this cellular heterogeneity, most workflows lack sufficient in situ resolution and are associated with high costs and extremely long analysis times. Here, we present a combination of experimental and computational approaches that allows a more comprehensive investigation of molecular heterogeneity within tissues than by either shotgun LC-MS/MS or MALDI imaging alone. We applied our pipeline to the mouse brain, which contains a wide variety of cell types that not only perform unique functions but also exhibit varying sensitivities to insults. We explored the distinct neuronal populations within the hippocampus, a brain region crucial for learning and memory that is involved in various neurological disorders. As an example, we identified the groups of proteins distinguishing the neuronal populations of the dentate gyrus (DG) and the cornu ammonis (CA) in the same brain section. Most of the annotated proteins matched the regional enrichment of their transcripts, thereby validating the method. As the method is highly reproducible, the identification of individual masses through the combination of MALDI-IMS and LC-MS/MS methods can be used for the much faster and more precise interpretation of MALDI-IMS measurements only. This greatly speeds up spatial proteomic analyses and allows the detection of local protein variations within the same population of cells. The method's general applicability has the potential to be used to investigate different biological conditions and tissues and a much higher throughput than other techniques making it a promising approach for clinical routine applications.

Asunto(s)

Proteómica , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masas en Tándem , Animales , Proteómica/métodos , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Ratones , Ratones Endogámicos C57BL , Hipocampo/metabolismo , Masculino , Neuronas/metabolismo , Encéfalo/metabolismo , Giro Dentado/metabolismo , Cromatografía Líquida con Espectrometría de Masas

RESUMEN

The integration of spatial information in the mammalian dentate gyrus (DG) is critical to navigation. Indeed, DG granule cells (DGCs) rely upon finely balanced inhibitory neurotransmission in order to respond appropriately to specific spatial inputs. This inhibition arises from a heterogeneous population of local GABAergic interneurons (INs) that activate both fast, ionotropic GABAA receptors (GABAAR) and slow, metabotropic GABAB receptors (GABABR), respectively. GABABRs in turn inhibit pre- and postsynaptic neuronal compartments via temporally long-lasting G-protein-dependent mechanisms. The relative contribution of each IN subtype to network level GABABR signal setting remains unknown. However, within the DG, the somatostatin (SSt) expressing IN subtype is considered crucial in coordinating appropriate feedback inhibition on to DGCs. Therefore, we virally delivered channelrhodopsin 2 to the DG in order to obtain control of this specific SSt IN subpopulation in male and female adult mice. Using a combination of optogenetic activation and pharmacology, we show that SSt INs strongly recruit postsynaptic GABABRs to drive greater inhibition in DGCs than GABAARs at physiological membrane potentials. Furthermore, we show that in the adult mouse DG, postsynaptic GABABR signaling is predominantly regulated by neuronal GABA uptake and less so by astrocytic mechanisms. Finally, we confirm that activation of SSt INs can also recruit presynaptic GABABRs, as has been shown in neocortical circuits. Together, these data reveal that GABABR signaling allows SSt INs to control DG activity and may constitute a key mechanism for gating spatial information flow within hippocampal circuits.

Asunto(s)

Giro Dentado , Interneuronas , Receptores de GABA-B , Somatostatina , Animales , Somatostatina/metabolismo , Interneuronas/metabolismo , Interneuronas/fisiología , Giro Dentado/metabolismo , Receptores de GABA-B/metabolismo , Masculino , Femenino , Optogenética , Ratones Endogámicos C57BL , Ratones , Ratones Transgénicos , Ácido gamma-Aminobutírico/metabolismo , Sinapsis/metabolismo

RESUMEN

Puberty is a critical period of emotional development and neuroplasticity. However, most studies have focused on early development, with limited research on puberty, particularly the parental presence. In this study, four groups were established, and pubertal maternal presence (PMP) was assessed until postnatal days 21 (PD21), 28 (PD28), 35 (PD35), and 42 (PD42), respectively. The social interaction and anxiety behaviors, as well as the expression of oxytocin (OT) in the paraventricular nucleus (PVN) and supraoptic nucleus (SON), and the number of new generated neurons and the expression of estrogen receptor alpha (ERα) in the dentate gyrus (DG) were assessed. The results suggest that there is a lot of physical contact between the mother and offspring from 21 to 42 days of age, which reduces anxiety in both female and male offspring in adulthood; for example, the PMP increased the amount of time mice spent in the center area in the open field experiment and in the bright area in the light-dark box experiment. PMP increased OT expression in the PVN and SON and the number of newly generated neurons in the DG. However, there was a sexual difference in ERα, with ERα increasing in females but decreasing in males. In conclusion, PMP reduces the anxiety of offspring in adulthood, increases OT in the PVN and SON, and adult neurogenesis; ERα in the DG may be involved in this process.

Asunto(s)

Ansiedad , Giro Dentado , Receptor alfa de Estrógeno , Neurogénesis , Oxitocina , Núcleo Hipotalámico Paraventricular , Animales , Ansiedad/metabolismo , Ratones , Masculino , Femenino , Receptor alfa de Estrógeno/metabolismo , Oxitocina/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Giro Dentado/metabolismo , Maduración Sexual , Núcleo Supraóptico/metabolismo , Conducta Materna/fisiología , Conducta Animal , Interacción Social

RESUMEN

Adult neural stem cells (NSCs) in the hippocampal dentate gyrus continuously proliferate and generate new neurons throughout life. Although various functions of organelles are closely related to the regulation of adult neurogenesis, the role of endoplasmic reticulum (ER)-related molecules in this process remains largely unexplored. Here we show that Derlin-1, an ER-associated degradation component, spatiotemporally maintains adult hippocampal neurogenesis through a mechanism distinct from its established role as an ER quality controller. Derlin-1 deficiency in the mouse central nervous system leads to the ectopic localization of newborn neurons and impairs NSC transition from active to quiescent states, resulting in early depletion of hippocampal NSCs. As a result, Derlin-1-deficient mice exhibit phenotypes of increased seizure susceptibility and cognitive dysfunction. Reduced Stat5b expression is responsible for adult neurogenesis defects in Derlin-1-deficient NSCs. Inhibition of histone deacetylase activity effectively induces Stat5b expression and restores abnormal adult neurogenesis, resulting in improved seizure susceptibility and cognitive dysfunction in Derlin-1-deficient mice. Our findings indicate that the Derlin-1-Stat5b axis is indispensable for the homeostasis of adult hippocampal neurogenesis.

Asunto(s)

Hipocampo , Proteínas de la Membrana , Células-Madre Neurales , Neurogénesis , Factor de Transcripción STAT5 , Animales , Ratones , Proliferación Celular , Giro Dentado/metabolismo , Giro Dentado/citología , Hipocampo/metabolismo , Hipocampo/citología , Homeostasis , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Noqueados , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Convulsiones/metabolismo , Convulsiones/genética , Transducción de Señal , Factor de Transcripción STAT5/metabolismo , Factor de Transcripción STAT5/genética

RESUMEN

Quiescence, a hallmark of adult neural stem cells (NSCs), is required for maintaining the NSC pool to support life-long continuous neurogenesis in the adult dentate gyrus (DG). Whether long-lasting epigenetic modifications maintain NSC quiescence over the long term in the adult DG is not well-understood. Here we show that mice with haploinsufficiency of Setd1a, a schizophrenia risk gene encoding a histone H3K4 methyltransferase, develop an enlarged DG with more dentate granule cells after young adulthood. Deletion of Setd1a specifically in quiescent NSCs in the adult DG promotes their activation and neurogenesis, which is countered by inhibition of the histone demethylase LSD1. Mechanistically, RNA-sequencing and CUT & RUN analyses of cultured quiescent adult NSCs reveal Setd1a deletion-induced transcriptional changes and many Setd1a targets, among which down-regulation of Bhlhe40 promotes quiescent NSC activation in the adult DG in vivo. Together, our study reveals a Setd1a-dependent epigenetic mechanism that sustains NSC quiescence in the adult DG.

Asunto(s)

Giro Dentado , Epigénesis Genética , Hipocampo , N-Metiltransferasa de Histona-Lisina , Células-Madre Neurales , Neurogénesis , Animales , Femenino , Masculino , Ratones , Células Madre Adultas/metabolismo , Células Madre Adultas/citología , Giro Dentado/citología , Giro Dentado/metabolismo , Hipocampo/metabolismo , Hipocampo/citología , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Neurogénesis/genética

RESUMEN

Adult neurogenesis is a unique form of neuronal plasticity in which newly generated neurons are integrated into the adult dentate gyrus in a process that is modulated by environmental stimuli. Adult-born neurons can contribute to spatial memory, but it is unknown whether they alter neural representations of space in the hippocampus. Using in vivo two-photon calcium imaging, we find that male and female mice previously housed in an enriched environment, which triggers an increase in neurogenesis, have increased spatial information encoding in the dentate gyrus. Ablating adult neurogenesis blocks the effect of enrichment and lowers spatial information, as does the chemogenetic silencing of adult-born neurons. Both ablating neurogenesis and silencing adult-born neurons decreases the calcium activity of dentate gyrus neurons, resulting in a decreased amplitude of place-specific responses. These findings are in contrast with previous studies that suggested a predominantly inhibitory action for adult-born neurons. We propose that adult neurogenesis improves representations of space by increasing the gain of dentate gyrus neurons and thereby improving their ability to tune to spatial features. This mechanism may mediate the beneficial effects of environmental enrichment on spatial learning and memory.

Asunto(s)

Giro Dentado , Hipocampo , Neurogénesis , Neuronas , Memoria Espacial , Animales , Neurogénesis/fisiología , Masculino , Femenino , Giro Dentado/fisiología , Giro Dentado/citología , Ratones , Neuronas/fisiología , Neuronas/metabolismo , Hipocampo/fisiología , Hipocampo/citología , Hipocampo/metabolismo , Memoria Espacial/fisiología , Ratones Endogámicos C57BL , Plasticidad Neuronal/fisiología , Calcio/metabolismo , Aprendizaje Espacial/fisiología

RESUMEN

Fear memory is essential for survival and adaptation, yet excessive fear memories can lead to emotional disabilities and mental disorders. Despite previous researches have indicated that histamine H1 receptor (H1R) exerts critical and intricate effects on fear memory, the role of H1R is still not clarified. Here, we show that deletion of H1R gene in medial septum (MS) but not other cholinergic neurons selectively enhances contextual fear memory without affecting cued memory by differentially activating the dentate gyrus (DG) neurons in mice. H1R in cholinergic neurons mediates the contextual fear retrieval rather than consolidation by decreasing acetylcholine release pattern in DG. Furthermore, selective knockdown of H1R in the MS is sufficient to enhance contextual fear memory by manipulating the retrieval-induced neurons in DG. Our results suggest that H1R in MS cholinergic neurons is critical for contextual fear retrieval, and could be a potential therapeutic target for individuals with fear-related disorders.

Asunto(s)

Neuronas Colinérgicas , Giro Dentado , Miedo , Receptores Histamínicos H1 , Animales , Miedo/fisiología , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/fisiología , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H1/genética , Giro Dentado/metabolismo , Ratones , Masculino , Ratones Endogámicos C57BL , Memoria/fisiología , Ratones Noqueados , Acetilcolina/metabolismo , Núcleos Septales/metabolismo , Núcleos Septales/fisiología , Núcleos Septales/citología

RESUMEN

In mammals, the subgranular zone of the dentate gyrus is one of two brain regions (with the subventricular zone of the olfactory bulb) that continues to generate new neurons throughout adulthood, a phenomenon known as adult hippocampal neurogenesis (AHN) (Eriksson et al., Nat Med 4:1313-1317, 1998; García-Verdugo et al., J Neurobiol 36:234-248, 1998). The integration of these new neurons into the dentate gyrus (DG) has implications for memory encoding, with unique firing and wiring properties of immature neurons that affect how the hippocampal network encodes and stores attributes of memory. In this chapter, we will describe the process of AHN and properties of adult-born cells as they integrate into the hippocampal circuit and mature. Then, we will discuss some methodological considerations before we review evidence for the role of AHN in two major processes supporting memory that are performed by the DG. First, we will discuss encoding of contextual information for episodic memories and how this is facilitated by AHN. Second, will discuss pattern separation, a major role of the DG that reduces interference for the formation of new memories. Finally, we will review clinical and translational considerations, suggesting that stimulation of AHN may help decrease overgeneralization-a common endophenotype of mood, anxiety, trauma-related, and age-related disorders.

Asunto(s)

Giro Dentado , Neurogénesis , Neurogénesis/fisiología , Humanos , Animales , Giro Dentado/fisiología , Hipocampo/fisiología , Memoria Episódica , Neuronas/fisiología , Neuronas/metabolismo , Memoria/fisiología