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Written by Leo
SourceLilac Academic
.
Impaired social behavior has been reported to be a hallmark of a variety of neurodevelopmental disorders, including autism and schizophrenia
.
We tend to think of neurodevelopment as being regulated by the brain, but in recent years, some scientific studies have found that the brain is also influenced
by the gut microbiome.
On November 1, 2022, Judith Eisen's team from the Institute of Neuroscience at the University of Oregon published a paper in the journal PLOS Biology titled: The microbiota promotes social behavior by modulating microglial remodeling of forebrain neurons
.
The study found that gut microbes influence social behavior in zebrafish and found ways
to link the gut microbiota to neurons associated with social behavior in the brain.
In healthy zebrafish, gut microbes stimulate microglia to prune excess connections
between neurons.
Pruning is a normal part
of healthy brain development.
Like clutter over the counter, extra neural connections get in the way of really important neural connections, leading to information clutter
.
In zebrafish without these gut microbes, pruning did not occur, and zebrafish showed deficits
in social interaction.
Social behavior is a complex phenomenon that involves many parts of the brain, and the team previously identified a group of neurons in zebrafish brains that are necessary for
a specific social interaction.
Usually, if two zebrafish see each other through a glass partition, they will approach each other and swim
side by side.
But zebrafish that lack these neurons will not show interest
.
Here, the team found a pathway
to link microbes in the gut to these neurons in the brain.
Microbiota promotes social behavior
in zebrafish, and socialization among zebrafish is evident approximately 14 days after fertilization, while neurodevelopment affecting sociability should occur earlier
。 To test the hypothesis that the normal development of social behavior in zebrafish requires the involvement of the microbiome, the researchers aseptically reared zebrafish for the first week after fertilization, then inoculated them with normal microbiota on day 7 after fertilization, and assessed their social behavior at 14 days after fertilization (this experimental group is called XGF).
The results showed that XGF zebrafish had social deficits, which indicated that an early intact microbiota is required for the late development of normal social behavior.
The microbiota inhibits the complication of vTel y321 neuronal dendrites due to normal social behavior needs
vTely321 neurons, so the researchers hypothesized that the microbiota might promote social behavior
by regulating the number of vTely321 cells.
They observed an average number of vTely321 neurons in zebrafish containing normal microbiota at 7 days post-fertilization at 229, decreasing
in sterile zebrafish.
However, after inoculating the microbiota on day 7, by day 14, both had essentially the same number of vTel y321 neurons, suggesting that predevelopmental microbiota does not affect the expression of the y321Et promoter or modulates social behavior by promoting the proliferation of vTel y321 neurons.
Subsequently, the researchers hypothesized that the microbiota might influence social behavior
by modulating the connectivity of vTely321 neurons.
To test this possibility, the researchers visualized individual vTely321 dendrites
using sparse labeling techniques.
The total length of vTel y321 dendrites in XGF zebrafish was significantly increased compared to zebrafish with normal microbiota, but there was no significant difference in the average length of vTely321 branches
.
To examine whether impaired early vTel y321 dendritic development affects subsequent social behavior in zebrafish, the investigators reconstructed and quantified vTely321 dendrites
in sterile zebrafish 14 days after fertilization.
The average branch length of sterile zebrafish vTely321 dendrites at 14 days post-fertilization was comparable relative to normal zebrafish, and an increase
in total dendritic length was observed in sterile zebrafish 7 days post-fertilization.
Since the dendritic structure of vTely321 in sterile zebrafish 7 days after fertilization persists into the late developmental stage, impaired
social behavior is exhibited despite reintroduction of the normal microbiota at this time.
This result indicates the existence of an early developmental window during which neurodevelopmental microbial regulation is critical
for the normal connections of neurons required for later social behavioral expression.
Microbiota promotes forebrain microglial abundance and inhibits vTely321 neurite density
Microglia are brain resident immune cells that regulate neurite growth and pruning, and the researchers hypothesize that the microbiota may inhibit the complications of vTely321 dendrites through microglia
.
Although the social phenotype was not observed until 14 days after fertilization, the experimental results showed that the microbiota regulated vTel y321 neuronal morphology and inhibited vTely321 neuronal dendritic density
as early as 7 days after fertilization.
If the microbiota exerts this effect by regulating the development of the forebrain microglia population, then altered microglia
should be visible in zebrafish up to 7 days after fertilization.
To test this hypothesis, the researchers compared
sterile zebrafish forebrain microglia with fluorescent labels to normal zebrafish forebrain microglia.
They found a significant reduction in sterile zebrafish forebrain microglia compared to the control group, which reinforced the conclusion that normal microglia in the zebrafish forebrain require gut microbiota.
Microbiota affects the expression of microglial genes Microglia have different morphology in different brain regions or when performing different activities,
Therefore, measurements of microglial morphology can be used to assess the proportion of
microglial populations for each function.
But by analyzing the morphology and dynamics of forebrain microglia, the researchers found that the microbiota did not affect the morphology or dynamics
of forebrain microglia.
However, the microbiota affects the expression
of genes in microglia.
In amoeba-like microglia and branched microglia, the microbiota inhibits the expression of genes of the crystalline protein family.
In amoeba-like microglia, the microbiota also inhibits the expression of migration and chemotaxis genes while promoting the expression of genes related to lysosomal function, nucleotide metabolism, and mitochondrial function.
In branched microglia, the microbiota inhibits the expression of lysosomal genes while promoting the expression of proteasomal genes.
In these cells, the microbiota also promotes the expression of other parts of the gene, including the defense response to gram-positive bacteria, the regulation of I-kB kinase/NF-kB signaling, which indicates that the microglia's response to microbial signals is affected.
GO analysis showed that the microbiota altered the function of
lysosomes and proteasomes in microglia.
In addition, the microbiota promotes other pathways that remodel microglia, particularly the complement signaling pathway, and significantly promotes the expression of synaptic remodeling factor C1q in branched microglia.
This study shows that the microbiota of zebrafish is required for normal social behavior and reveals molecular pathways that connect microbiota, microglial remodeling of neural circuits, and social behavior in zebrafish
。
By studying neurons associated with behavior, they found that the microbiota inhibited the complexity of neuronal dendrites and the targeting of forebrain neurons required for normal social behavior
.
The microbiota also influences the molecular function of microglia, including promoting the complement signaling pathway and the expression of synaptic remodeling factor C1q.
Overall, this result suggests that during early neurodevelopment, the microbiota influences the social behavior of zebrafish by stimulating microglial remodeling and provides pathways
for novel interventions for multiple neurodevelopmental disorders.
Both gut microbiome disruption and poor synaptic pruning have been linked
to a range of neuropsychiatric disorders, such as autism spectrum disorder.
"If we can tie these together, it may help better treat a variety of diseases," said
Joseph J.
Bruckner, the paper's lead author.
In the future, the researchers will work to identify the molecules that link the gut microbiota to microglia, mapping the pathways
between microbes and behavior in more detail.
Link to the paper: https://doi.
org/10.
1371/journal.
pbio.
3001838
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