ABSENCE OF GUT MICROBIOTA CAUSES STRESS-INDUCED ANXIETY AND AMYGDALA HYPEREXCITABILITY IN MICE

Abstract

Dysbiosis of the gut microbiota has been strongly associated with anxiety, but the underlying mechanisms have been largely unknown. Here, we investigated the role of gut microbes on anxiety-related behaviors using Germ-Free (GF) mice, which are free from all microorganisms. Our results showed that GF mice displayed increased anxiety-related behavior and fear response. The major stress hormone of hypothalamus-pituitary-adrenal (HPA) axis, corticosterone (CORT), is significantly elevated. We further measured the neuronal activity of basolateral amygdala (BLA), the key brain region for emotional processing. We observed that c-fos expression after stressful stimuli is significantly increased within BLA of GF mice. Besides, BLA principle neurons in GF mice showed elevated intrinsic excitability and excitatory synaptic transmission. Moreover, We uncovered that decreased SK channel mediated medium afterhyperpolarization (mAHP) is responsible for the increased excitability of BLA neurons. Lastly, when GF mice were conventionalized with fecal contents of conventional raised mice, the increased anxiety and BLA hyperexcitability were fully normalized. Overall, this study revealed an elevated CORT level and BLA excitability in GF mice, which corelates to the increased anxiety. The BLA hyperactivity of GF mice is potentially induced by dysfunction of SK channel.