Gut-brain connection: How the microbiome influences social behavior

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  • The gut microbiome can influence the development of the brain and behaviors, but the underlying mechanisms are not well understood.
  • A recent study in zebrafish larvae showed that gut microbes were necessary during early life for the typical expression of social behavior later in life.
  • Gut microbiota modulated the function of microglia, the immune cells in the brain, to influence the development of a forebrain region involved in social behavior.
  • Altered gut microbiome composition is associated with neurodevelopmental conditions like autism, and this study is a step toward understanding the mechanism underlying this association.

A recent study showed that an intact gut microbiome during early life is essential for the development of healthy social behavior in later life in zebrafish.

The gut microbiome influenced the development of a forebrain region involved in social behavior, and these effects of microbiota were mediated by modulating the gene expression and abundance of microglia in the aforementioned brain region.

The study’s author Dr. Judith Eisen, a neuroscientist at the University of Oregon, explained to Medical News Today:

“One of the most significant aspects of our study is that microbial inputs are required early in life for typical development of the nervous system later in life, at least in the context of a specific part of the zebrafish brain. Zebrafish brain development is very similar to the brain development of other vertebrates, including humans, so it seems likely that similar processes also occur during the development of the brains of other vertebrates. Since intestinal health and resident microbes are now implicated in many neurological conditions, we hope that understanding the basic mechanisms linking the gut and brain will lead to new interventions.”

The findings were recently published in PLOS Biology.

Prior studies have suggested that altered gut microbiome composition is associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia, which are characterized by deficits in social behavior.

But how the microbiome influences the development of brain regions involved in social behaviors in healthy and diseased states is not well understood.

Other research has shown that the gut microbiome can influence the development of the brain and associated social behaviors in animal models.

For instance, germ-free mice raised in the absence of exposure to microorganisms show deficits in social behaviors in adulthood. Moreover, the absence of typical levels of microbiota is associated with changes in gene expression and neurotransmitter levels in the brain regions involved in these social behaviors.

In the present study, the researchers used zebrafish to further examine pathways involved in mediating the effects of microbiota on the development of social behaviors. Zebrafish can be genetically modified, and their larvae are transparent, allowing the examination of structural changes in the brain during development.

Moreover, between 12 to 16 days after fertilization, zebrafish begin to display complex social behaviors, including shoaling, aggression, and social orienting.

Social orienting refers to the stereotypical behavior displayed by zebrafish when they first encounter another zebrafish across a transparent barrier. This behavior involves the zebrafish approaching another animal and orienting the body at a 45–90° angle.

Microbiota can influence social behaviors in zebrafish, but how microbiota influence the development of social behaviors is not well understood.

During early development, neurons extend appendages or processes (i.e., axons and dendrites) to form connections or synapses with other neurons. These axons and dendrites are often highly branched and from tree-like structures called arbors.

Early development is characterized by the overabundance of synaptic connections and extensive branching of neuronal processes. The pruning of these overabundant branches and connections during early development is essential to fine-tune the nervous system to produce the appropriate behavior.

For instance, studies have found deficits in pruning and excessive connections between neurons in animal models of autism. The fine-tuning of brain circuits that underlie various functions, including social behaviors, often relies on exposure to certain internal or external stimuli during a specific time window or critical period.

The researchers had previously identified a specific subpopulation of neurons, called vTely321, in the forebrain of the zebrafish that are necessary for expressing social orienting behavior.

These neurons likely develop their connections with other neurons during early development, and these connectivity patterns could be potentially modulated by microbiota during early life to influence social behavior.

In zebrafish, the gut becomes colonized by microorganisms about 4 days after fertilization, whereas social orienting behavior is robustly expressed 14 days after fertilization.

In the present study, the researchers were interested in understanding the role of gut microbiota in the healthy development of the vTely321 neurons in early life and its subsequent impact on social orienting behavior.

To examine the role of microbiota in the development of social-orienting behavior in early life, the researchers inoculated germ-free zebrafish with typical microbiota 7 days after fertilization.

The social behavior of the aforementioned experimental group was compared with the control group consisting of germ-free animals that were inoculated with microbiota on the day of fertilization.

At 14 days after fertilization, the researchers found that the zebrafish in the experimental group spent less time both in the proximity of a stimulus fish and in the stereotypical 45–90˚ orientation than the control group fish.

These deficits in social orienting suggest that the presence of gut microbes before 7 days post-fertilization was necessary for developing social behaviors that were expressed 1 week later.

In other words, the exposure to microbiota after the initial critical period was not able to rescue deficits in social orienting behavior.

Given the role of the vTely321neurons in mediating social orienting behavior, the researchers examined the impact of microbiota on the proliferation and connectivity patterns of these neurons.

The researchers found that the absence of microbiota before 7 days post fertilization did not influence the proliferation of vTely321 neurons.

However, at 7 days post fertilization, the branching patterns of the vTely321 neurons were more complex in germ-free zebrafish than in control animals with typical microbiota.

In addition, the increased complexity of branching patterns persisted at 14 days post-fertilization even after inoculation of the germ-free zebrafish with typical microbiota at 7 days post-fertilization.

These results suggest the absence of gut microbiota during the initial 7 days after fertilization led to altered connectivity patterns in the vTely321 forebrain region and, subsequently, deficits in social orienting behavior.

Microglia, the primary immune cells in the brain, are involved in the pruning of synapses and play an important role in mediating the development of healthy social behaviors.

The study’s authors found that germ-free zebrafish showed fewer microglia in the forebrain than control animals with normal microbiota.

Moreover, inoculation of germ-free animals with individual gut microbe species after fertilization helped to partially restore the number of microglia and reduce the density of neuronal branches in the forebrain to a varying degree.

This suggests that differences in the overall microbiome composition could influence the number of microglia and density of neuronal branches in regions involved in social behavior and predispose certain individuals to disorders such as autism.

To further examine the role of microglia, the researcher inhibited a specific gene in microglia in zebrafish embryos to induce a sustained decline in microglia levels in the forebrain until at least 7 days after fertilization.

Zebrafish with lower levels of microglia in the forebrain showed higher neuronal branch density at 7 days post-fertilization than control animals with healthy microglia levels. The zebrafish with lower microglia levels also spent a shorter duration in the proximity of the stimulus fish in the social orienting test.

These findings suggest that gut microbes may influence the distribution of microglia in the forebrain to restrain the complexity of branching patterns and, subsequently, modulate social behavior.

The researchers also examined differences in gene expression patterns in microglia at 6 days post-fertilization in germ-free zebrafish larvae and control animals with intact gut microbiota.

The differently expressed genes in germ-free zebrafish included those for proteins that are a part of the complement system. Complement proteins are a part of the immune system and can facilitate the clearance of damaged cells and pathogens.

Moreover, studies suggest complement proteins can bind to axons and synapses and facilitate their removal by microglia.

These results suggest that microbiota modulate the expression of genes in the microglia, including those encoding complement proteins, during early development, which may facilitate the pruning of neuronal branches in vTely321 neurons.

Dr. John Cryan, a neuroscientist at the University of Cork, Ireland, told MNT:

“This study adds further evidence for the role of the microbiome, especially in early life, in shaping social behavior. The mechanistic insights implicating microglia as a key player highlight the power of the zebrafish model to disentangle microbiome-brain interactions. The key goal of the field is to see if the implications of this elegant work can translate to humans under normal social conditions or in disorders with altered sociability.”

Dr. Eisen added: “Learning more about how gut microbes influence brain development will help us understand how to foster a healthy gut microbiome that supports early nervous system development and function.”

In another paper published by the same team in BMC Genomics, the researchers further examined the gene expression profile of the vTely321 neurons.

The researchers had previously shown that these neurons produce the neurotransmitter acetylcholine.

In the current study, the researchers characterized the gene expression profile of these neurons and showed that they also express another neurotransmitter, gamma-aminobutyric acid (GABA).

Another distinguishing feature of the vTely32 neurons was that they simultaneously expressed three transcription factors belonging to the LIM transcription factor family.

These transcription factors and the two neurotransmitters together served as markers specific to the vTely321 neurons. Based on the expression of these transcription factors and the two neurotransmitters, the researchers were able to identify a similar population of cells in the mouse forebrain using an electronic database.

Further research is needed to determine whether this cluster of neurons in the mouse forebrain is also involved in social behavior.

Read the full article here

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