The microbiota regulate neuronal function and fear extinction learning

Abstract

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota. In mammals, changes in the composition of the microbiota can influence a wide range of physiologic processes (including development, metabolism, and immune cell function) and are associated with susceptibility to multiple diseases. Alterations in the microbiota can also modulate host behaviors such as social activity, stress, and anxiety-related responses that are linked to diverse neuropsychiatric disorders. However, the mechanisms through which the microbiota influence neuronal activity and host behavior remain poorly defined. Here we demonstrate that manipulation of the microbiota in either antibiotictreated or germ-free adult mice results in significant deficits in fear extinction learning. Single nucleus RNA-sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in multiple cell types including excitatory neurons and glial cells. Transcranial two-photon imaging following deliberate manipulation of the microbiota demonstrated that extinction learning deficits were associated with defective learning-related remodeling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition to effects of manipulating the microbiota on behavior in adult mice, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Lastly, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and were previous reported to be related to human and mouse models of neuropsychiatric disorders, suggesting that microbiota-derived compounds may directly affect brain function and behavior. Together, these data indicate that fear extinction learning requires microbiota-derived signals during both early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.

Imprinting of the immune system by the microbiota early in life

“…In that line of ideas, it was demonstrated that exposure to microbiota during the neonatal period restores fear extinction learning in adulthood. 86…”

Peripheral Routes to Neurodegeneration: Passing Through the Blood–Brain Barrier

“…Within the complex interplay between the gut microbiome and the CNS, a role for brain barriers and neuroinflammation is becoming important (Braniste et al, 2014;Cerovic et al, 2019;Parker et al, 2019;Wang et al, 2019). The impact of the gut microbiome composition on CNS health was reported (Amedei and Boem, 2018;Chu et al, 2019;Sherwin et al, 2019;Virtue et al, 2019). Recent work demonstrated that GM composition controls BBB development and permeability in mice (Braniste et al, 2014).…”

Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

“…A growing body of evidence shows that the resident bacteria in the gastrointestinal tract, collectively the gut microbiome, play a role in normal brain function and behavior, and may have relevance for neurodevelopmental disorders. Disruptions of the gut microbiome lead to alterations in gene expression and epigenetic regulation in the brain as well as alterations in neuronal activity patterns and synaptic plasticity in multiple limbic substructures [6][7][8] . Studies examining the composition of the microbiome in patients with ASD have repeatedly found that patients have differences in microbiome composition [9][10][11] , but specific microbial changes associated with a diagnosis have varied between studies.…”

“…mice that are raised completely sterile with no internal or external microbiome) have marked deficits in social behaviors and in gene expression profiles in multiple brain regions related to regulation of these behaviors [12][13][14] . Additionally, mice who have had their microbiomes depleted with antibiotics show deficits in social behavior, cognitive flexibility, and multiple other ASD-like behaviors 6,15,16 . At a cellular and molecular level, disruption of the microbiome with prolonged antibiotics leads to changes in neuronal and glial structure, changes in cell firing patterns, and altered transcriptional and epigenetic signatures in multiple brain structures 6,[17][18][19] .…”