Adult microbiota‐deficient mice have distinct dendritic morphological changes: differential effects in the amygdala and hippocampus

Abstract

Increasing evidence implicates the microbiota in the regulation of brain and behaviour. Germ-free mice (GF; microbiota deficient from birth) exhibit altered stress hormone signalling and anxiety-like behaviours as well as deficits in social cognition. Although the mechanisms underlying the ability of the gut microbiota to influence stress responsivity and behaviour remain unknown, many lines of evidence point to the amygdala and hippocampus as likely targets. Thus, the aim of this study was to determine if the volume and dendritic morphology of the amygdala and hippocampus differ in GF versus conventionally colonized (CC) mice. Volumetric estimates revealed significant amygdalar and hippocampal expansion in GF compared to CC mice. We also studied the effect of GF status on the level of single neurons in the basolateral amygdala (BLA) and ventral hippocampus. In the BLA, the aspiny interneurons and pyramidal neurons of GF mice exhibited dendritic hypertrophy. The BLA pyramidal neurons of GF mice had more thin, stubby and mushroom spines. In contrast, the ventral hippocampal pyramidal neurons of GF mice were shorter, less branched and had less stubby and mushroom spines. When compared to controls, dentate granule cells of GF mice were less branched but did not differ in spine density. These findings suggest that the microbiota is required for the normal gross morphology and ultrastructure of the amygdala and hippocampus and that this neural remodelling may contribute to the maladaptive stress responsivity and behavioural profile observed in GF mice.

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

“…[16] It was observed that the amygdala is enlarged in GF adult mice, reminiscent of findings in clinical studies of children with ASD albeit that differences in amygdala size typically resolve by adulthood in clinical samples, and dendritic morphology in amygdala neurons is also altered.…”

“…It receives sensory inputs from the thalamus and cortical areas as well as extensive inputs from other regions in the limbic system, including the prefrontal cortex and hippocampus, [15] both of which are markedly altered in germ-free (GF) animals. [10,12,16] In fact, the connectivity between these three major regions, not just the function of the individual structures, is fundamental to appropriate emotional responses. [17] Although tracer studies have shown afferents reaching all amygdala nuclei, sensory inputs often reach the amygdala through the LA while inputs from other brain regions target primarily the LA and BLA.…”

“…Alterations in the volume, activity, and/ or connectivity of the amygdala (features influenced by the gut microbiota) [16,[35][36][37] have been reported in individuals diagnosed with schizophrenia, [38,39] attention deficit hyperactivity disorder (ADHD), [40] and autism spectrum disorders (ASD). [41,42] In particular, functional dysregulation of the amygdala is considered central to the social deficits observed in individuals with ASD.…”

“…Morphology Enlarged volume, increases in dendritic length, branch points and spine density in mice [16] No correlation between microbiota composition and amygdala volume in healthy women or IBS patients [95,123] Actinobacteria correlated with enhanced microstructure (increased fractional anisotropy) [128] Activity and connectivity Dampened activity during emotional faces task, altered resting state connectivity with distributed network including hippocampus and thalamus [35] Microbiota profile associated with structural white-matter connectivity in healthy women and with functional connectivity in young children [95,129] Gene expression Specific mRNA expression: NGFI-A, BDNF decreased, NR2B decreased in CeA of mice [5,9] Whole genome sequencing: broad alterations suggestive of upregulation of neuronal activity, differential gene regulation in response to fear and social stimuli [36,101] (Stilling et al, unpublished observations) mRNA expression: Nr3c1, CRH-R1 decreased, BDNF increased in rats [94] Protein expression: BDNF decreased in mice [4] Lactobacillus rhamnosus (JB-1) decreased GABA B1b mRNA in BLA and CeA of mice [62] Broad dysregulation of miRNA in mice [37] www.advancedsciencenews.com www.bioessays-journal.com amygdala was altered for the probiotic-treated participants. Essentially, these data provide the first evidence of a clinical link between the microbiota and functional connectivity of the amygdala.…”

Social Buffering Prevents Stress-Induced Decreases in Dendritic Length, Branching in Dentate Granule Cells and Hippocampus-Related Memory Performance

“…Interestingly, a recent study indicates that the dendritic trees of dentate granule cells of germ-free mice are less branched as compared to conventionally colonized mice [63]. Moreover, germ-free and conventionally colonized mice display comparable spine density in the dentate gyrus [63].…”