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Neural Regeneration Research Feb 2024Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness. Exosomes are widely distributed in a range of body... (Review)
Review
Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness. Exosomes are widely distributed in a range of body fluids, including urine, blood, milk, and saliva. Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells. As an important form of intercellular communication, exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids, proteins, mRNAs, and microRNAs between cells, and because they can regulate physiological and pathological processes in the central nervous system. Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches: the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus. An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches. In recent studies, exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo, thereby participating in the progression of neurodegenerative disorders in patients and in various disease models. Here, we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases. We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults. In addition, exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.
PubMed: 37488879
DOI: 10.4103/1673-5374.379036 -
Science Advances Nov 2023Infantile amnesia is possibly the most ubiquitous form of memory loss in mammals. We investigated how memories are stored in the brain throughout development by...
Infantile amnesia is possibly the most ubiquitous form of memory loss in mammals. We investigated how memories are stored in the brain throughout development by integrating engram labeling technology with mouse models of infantile amnesia. Here, we found a phenomenon in which male offspring in maternal immune activation models of autism spectrum disorder do not experience infantile amnesia. Maternal immune activation altered engram ensemble size and dendritic spine plasticity. We rescued the same apparently forgotten infantile memories in neurotypical mice by optogenetically reactivating dentate gyrus engram cells labeled during complex experiences in infancy. Furthermore, we permanently reinstated lost infantile memories by artificially updating the memory engram, demonstrating that infantile amnesia is a reversible process. Our findings suggest not only that infantile amnesia is due to a reversible retrieval deficit in engram expression but also that immune activation during development modulates innate, and reversible, forgetting switches that determine whether infantile amnesia will occur.
Topics: Humans; Infant; Male; Mice; Animals; Autism Spectrum Disorder; Amnesia; Brain; Disease Models, Animal; Head; Mammals
PubMed: 37939176
DOI: 10.1126/sciadv.adg9921 -
Bio-protocol Oct 2023Adult neural stem/progenitor cells (NSPCs) in two neurogenic areas of the brain, the dentate gyrus and the subventricular zone, are major players in adult neurogenesis....
Adult neural stem/progenitor cells (NSPCs) in two neurogenic areas of the brain, the dentate gyrus and the subventricular zone, are major players in adult neurogenesis. Addressing specific questions regarding NSPCs outside of their niche entails in vitro studies through isolation and culture of these cells. As there is heterogeneity in their morphology, proliferation, and differentiation capacity between these two neurogenic areas, NSPCs should be isolated from each area through specific procedures and media. Identifying region-specific NPSCs provides an accurate pathway for assessing the effects of extrinsic factors and drugs on these cells and investigating the mechanisms of neurogenesis in both healthy and pathologic conditions. A great number of isolation and expansion techniques for NSPCs have been reported. The growth and expansion of NSPCs obtained from the dentate gyrus of aged rats are generally difficult. There are relatively limited data and protocols about NSPCs isolation and their culture from aged rats. Our approach is an efficient and reliable strategy to isolate and expand NSPCs obtained from young adult and aged rats. NSPCs isolated by this method maintain their self-renewal and multipotency. Key features • NSPCs isolated from the hippocampal dentate gyrus of young adult and aged rats, based on Kempermann et al. (2014) and Aligholi et al. (2014). • Maintenance of NSPCs isolated from the dentate gyrus of aged rats (20-24 months) in our culture condition is feasible. • According to our protocol, maximum growth of primary neurospheres obtained from isolated NSPCs of young and aged rats took 15 and 35 days, respectively.
PubMed: 37817897
DOI: 10.21769/BioProtoc.4843 -
Neurotoxicology Dec 2023Organophosphate flame retardant (OPFR) contamination is ubiquitous and bio-monitoring studies have shown that human exposure is widespread and may be unavoidable. OPFRs...
Organophosphate flame retardant (OPFR) contamination is ubiquitous and bio-monitoring studies have shown that human exposure is widespread and may be unavoidable. OPFRs bear structural similarities to known neurotoxicants such as organophosphate insecticides and have been shown to have both endocrine disrupting and developmental neurotoxic effects. The perinatal period in rodents represents a critical period in the organization of the developing nervous system and insults during this time can impart profound changes on the trajectory of neural development and function, lasting into adulthood. Adult hippocampal neurogenesis (AHN) facilitates dentate gyrus function and broader hippocampal circuit activity in adults; however, the neurogenic potential of this process in adulthood is vulnerable to disruption by exogenous factors during early life. We sought to assess the impact of OPFRs on AHN in offspring of dams exposed during gestation and lactation. Results indicate that developmental OPFR exposure has significant, sex specific impacts on multiple markers of AHN in the dentate gyrus of rats. In males, OPFR exposure significantly reduced the number of neural progenitors the number of new/immature neurons and reduced dentate gyrus volume. In females, exposure increased the number of neural progenitors, decreased the number of new/immature neurons, but had no significant effect on dentate gyrus volume. These results further elucidate the developmental neurotoxic properties of OPFRs, emphasize the long-term impact of early life OPFR exposure on neural processes, and highlight the importance of including sex as a biological variable in neurotoxicology research.
Topics: Pregnancy; Female; Male; Humans; Rats; Animals; Organophosphates; Rats, Wistar; Flame Retardants; Hippocampus; Neurogenesis
PubMed: 37783313
DOI: 10.1016/j.neuro.2023.09.009 -
Scientific Reports Jul 2023In socially monogamous prairie voles (Microtus ochrogaster), parental behaviors not only occur in mothers and fathers, but also exist in some virgin males. In contrast,...
In socially monogamous prairie voles (Microtus ochrogaster), parental behaviors not only occur in mothers and fathers, but also exist in some virgin males. In contrast, the other virgin males display aggressive behaviors towards conspecific pups. However, little is known about the molecular underpinnings of this behavioral dichotomy, such as gene expression changes and their regulatory mechanisms. To address this, we profiled the transcriptome and DNA methylome of hippocampal dentate gyrus of four prairie vole groups, namely attacker virgin males, parental virgin males, fathers, and mothers. While we found a concordant gene expression pattern between parental virgin males and fathers, the attacker virgin males have a more deviated transcriptome. Moreover, numerous DNA methylation changes were found in pair-wise comparisons among the four groups. We found some DNA methylation changes overlapping with transcription differences, across gene-bodies and promoter regions. Furthermore, the gene expression changes and methylome alterations are selectively enriched in certain biological pathways, such as Wnt signaling, which suggest a canonical transcription regulatory role of DNA methylation in paternal behavior. Therefore, our study presents an integrated view of prairie vole dentate gyrus transcriptome and epigenome that provides a DNA epigenetic based molecular insight of paternal behavior.
Topics: Male; Animals; Paternal Behavior; DNA Methylation; Grassland; Hippocampus; Arvicolinae; Dentate Gyrus; Social Behavior
PubMed: 37419920
DOI: 10.1038/s41598-023-37521-2 -
Molecular Psychiatry Apr 2024At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal...
At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.
Topics: Animals; Dentate Gyrus; Mossy Fibers, Hippocampal; Synapses; Mice, Knockout; Mice; Neurotrophin 3; Male; Female; CA3 Region, Hippocampal; Pyramidal Cells; Excitatory Postsynaptic Potentials; Synaptic Transmission; Cognition; Hippocampus; Mice, Inbred C57BL; Memory; Receptors, AMPA
PubMed: 38212372
DOI: 10.1038/s41380-023-02404-5 -
Biology Dec 2023Ageing is a biological phenomenon that determines the impairment of cognitive performances, in particular, affecting memory. Inflammation and cellular senescence are...
Ageing is a biological phenomenon that determines the impairment of cognitive performances, in particular, affecting memory. Inflammation and cellular senescence are known to be involved in the pathogenesis of cognitive decline. The gut microbiota-brain axis could exert a critical role in influencing brain homeostasis during ageing, modulating neuroinflammation, and possibly leading to inflammaging. Due to their anti-ageing properties, medicinal mushrooms can be utilised as a resource for developing pharmaceuticals and functional foods. Specifically, (He), thanks to its bioactive metabolites, exerts numerous healthy beneficial effects, such as reinforcing the immune system, counteracting ageing, and improving cognitive performance. Our previous works demonstrated the capabilities of two months of He1 standardised extract oral supplementation in preventing cognitive decline in elderly frail mice. Herein, we showed that this treatment did not change the overall gut microbiome composition but significantly modified the relative abundance of genera specifically involved in cognition and inflammation. Parallelly, a significant decrease in crucial markers of inflammation and cellular senescence, i.e., CD45, GFAP, IL6, p62, and γH2AX, was demonstrated in the dentate gyrus and hippocampal areas through immunohistochemical experiments. In summary, we suggested beneficial and anti-inflammatory properties of He1 in mouse hippocampus through the gut microbiome-brain axis modulation.
PubMed: 38248449
DOI: 10.3390/biology13010018 -
CNS Neuroscience & Therapeutics Feb 2024Amyotrophic lateral sclerosis (ALS) is a progressive motor and extra-motor neurodegenerative disease. This systematic review aimed to examine MRI biomarkers and... (Review)
Review
BACKGROUND AND OBJECTIVE
Amyotrophic lateral sclerosis (ALS) is a progressive motor and extra-motor neurodegenerative disease. This systematic review aimed to examine MRI biomarkers and neuropsychological assessments of the hippocampal and parahippocampal regions in patients with ALS.
METHODS
A systematic review was conducted in the Scopus and PubMed databases for studies published between January 2000 and July 2023. The inclusion criteria were (1) MRI studies to assess hippocampal and parahippocampal regions in ALS patients, and (2) studies reporting neuropsychological data in patients with ALS.
RESULTS
A total of 46 studies were included. Structural MRI revealed hippocampal atrophy, especially in ALS-FTD, involving specific subregions (CA1, dentate gyrus). Disease progression and genetic factors impacted atrophy patterns. Diffusion tensor imaging (DTI) showed increased mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and decreased fractional anisotropy (FA) in the hippocampal tracts and adjacent regions, indicating loss of neuronal and white matter integrity. Functional MRI (fMRI) revealed reduced functional connectivity (FC) between the hippocampus, parahippocampus, and other regions, suggesting disrupted networks. Perfusion MRI showed hypoperfusion in parahippocampal gyri. Magnetic resonance spectroscopy (MRS) found changes in the hippocampus, indicating neuronal loss. Neuropsychological tests showed associations between poorer memory and hippocampal atrophy or connectivity changes. CA1-2, dentate gyrus, and fimbria atrophy were correlated with worse memory.
CONCLUSIONS
The hippocampus and the connected regions are involved in ALS. Hippocampal atrophy disrupted connectivity and metabolite changes correlate with cognitive and functional decline. Specific subregions can be particularly affected. The hippocampus is a potential biomarker for disease monitoring and prognosis.
Topics: Humans; Diffusion Tensor Imaging; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Frontotemporal Dementia; Magnetic Resonance Imaging; Hippocampus; Biomarkers; Neuropsychological Tests; Atrophy
PubMed: 38334254
DOI: 10.1111/cns.14578 -
BioRxiv : the Preprint Server For... Oct 2023Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although...
Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although hippocampal dentate AACs are structurally altered in epilepsy, physiological analyses of dentate AACs are lacking. We demonstrate that parvalbumin neurons in the dentate molecular layer express PTHLH, an AAC marker, and exhibit morphology characteristic of AACs. Dentate AACs show high-frequency, non-adapting firing but lack persistent firing in the absence of input and have higher rheobase than basket cells suggesting that AACs can respond reliably to network activity. Early after pilocarpine-induced status epilepticus (SE), dentate AACs receive fewer spontaneous excitatory and inhibitory synaptic inputs and have significantly lower maximum firing frequency. Paired recordings and spatially localized optogenetic stimulation revealed that SE reduced the amplitude of unitary synaptic inputs from AACs to granule cells without altering reliability, short-term plasticity, or AIS GABA reversal potential. These changes compromised AAC-dependent shunting of granule cell firing in a multicompartmental model. These early post-SE changes in AAC physiology would limit their ability to receive and respond to input, undermining a critical brake on the dentate throughput during epileptogenesis.
PubMed: 37873292
DOI: 10.1101/2023.10.01.560378 -
Philosophical Transactions of the Royal... Jul 2024Commentaries about long-term potentiation (LTP) generally proceed with an implicit assumption that largely the same physiological effect is sampled across different... (Review)
Review
Commentaries about long-term potentiation (LTP) generally proceed with an implicit assumption that largely the same physiological effect is sampled across different experiments. However, this is clearly not the case. We illustrate the point by comparing LTP in the CA3 projections to CA1 with the different forms of potentiation in the dentate gyrus. These studies lead to the hypothesis that specialized properties of CA1-LTP are adaptations for encoding unsupervised learning and episodic memory, whereas the dentate gyrus variants subserve learning that requires multiple trials and separation of overlapping bodies of information. Recent work has added sex as a second and somewhat surprising dimension along which LTP is also differentiated. Triggering events for CA1-LTP differ between the sexes and the adult induction threshold is significantly higher in females; these findings help explain why males have an advantage in spatial learning. Remarkably, the converse is true before puberty: Females have the lower LTP threshold and are better at spatial memory problems. A mechanism has been identified for the loss-of-function in females but not for the gain-of-function in males. We propose that the many and disparate demands of natural environments, with different processing requirements across ages and between sexes, led to the emergence of multiple LTPs. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Animals; Female; Humans; Male; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dentate Gyrus; Long-Term Potentiation; Memory; Sex Factors
PubMed: 38853551
DOI: 10.1098/rstb.2023.0223