“Butterflies in the stomach”
The amygdala is an almond-shaped area in each half of the brain involved in the experiencing of emotions. Scientific perspective on the regulation of neural and psychological processes is expanding beyond the brain to include interactions with other body systems, in particular the gut-brain axis and regulation by the gut microbiome.
Current evidence does indeed point to an influence of the gut microbiota in central nervous system (CNS) function, appropriate brain development, as well as psychological and behavioral outcomes.
To date, much of the investigation of the effects of manipulation of the microbiota on brain function has been difficult to map to specific brain regions. Even so, most of this research has focused on other areas, like the prefrontal cortex and hippocampus.
From its central location within the temporal lobe, the amygdala is connected with several other regions of the brain and receives inputs from other regions in the limbic system – including the prefrontal cortex and hippocampus. The amygdaloid complex continues to develop well past birth. Brain imaging studies have shown that total amygdala volume peaks between 9-11 years of age.
Connectivity with other areas of the brain also continues to develop and mature at least into early adulthood. This ongoing development, combined with its high density of glucocorticoid receptors. makes it vulnerable to the effects of stress, particularly during early development and aging. These timeframes, coincidentally, coincide with periods of low gut diversity and instability in the microbiome.
The amygdala is a critical regulator of fear, stress, and anxiety disorders. Fear and anxiety are overlapping, threat-related emotions that are mediated by similar neurocircuits. The amygdala is also involved in the development of anxiety-like behavior. Imaging studies show that patients with PTSD and other anxiety disorders show increased activation of the amygdala.
Fear and anxiety are commonly made worse by chronic stress and the amygdala appears to have a role in mediating this relationship. Those who have experienced prolonged exposure to express even have larger amygdala, likely due to its role in regulating the body’s hormonal stress response via the hypothalamic-pituitary-adrenal axis and the autonomic nervous system.
The amygdala also plays an important role in other stress-related disorders, like depression. Clinically, increased activity in the amygdala has been found in bipolar disorder and major depression. This relationship begins early in life.
Many neurodevelopmental disorders are also associated with amygdala abnormalities. Changes in the volume, activity, and/or connectivity have been reported in individuals with schizophrenia, ADHD, and autism spectrum disorders. Amygdala lesions seem to diminish social inhibition and limit social perception, thereby increasing social interaction and interfering with adherence to social norms.
The amygdala also plays a role in pain experience, particularly the emotional-affective dimensions of pain perceptions and the emotional relevance of pain. Because of this, the amygdala has been implicated in irritable bowel syndrome (IBS), a disorder of the gut associated with microbiota alterations and characterized by gastrointestinal discomfort, pain, and affective dysfunction. IBS patients typically exhibit amygdala hyperactivity and in connected brain regions.
Our current understanding of the microbiota-gut-brain axis suggests that there are several possible routes of communication, including the vagus nerve, spinal cord, tryptophan metabolism, and immune modulation.
In addition to the microbiota themselves, the GI tract is also home to roughly 50,000 extrinsic and 100 million intrinsic sensory afferent neurons in the enteric nervous system. Signals produced by these microbial-neural interactions may reach the brain via the vagus nerve.
Microbial signals may also be communicated to the CNS via the spinal cord, thought to be important for the perception of visceral pain. Many different types of afferent spinal nerve endings innervate the GI tract, where they may detect the release of neuroactive compounds. It is now known the gut microbiota can produce many neurotransmitters (GABA, norepinephrine, dopamine, acetyl-choline, serotonin) and stimulate the production of others.
One key pathway for neurotransmitter production that is highly influenced by the microbiota is the metabolism of the amino acid tryptophan. Tryptophan is an essential amino acid obtained from the diet and metabolized primarily into serotonin or kynurenine. Serotonin is well-known for its involvement in mood and cognition with first-line therapeutics for depression and other mood disorders being selective serotonin reuptake inhibitors (SSRIs). In fact, the majority of the body’s serotonin is produced in the gut. Pre- and probiotic treatments have shown to alter central levels of serotonin or serotonin receptors in the brain.
The microbiome is crucial for the establishment and development of the host’s immune system. When the microbiota is depleted, such as after antibiotic use, the immune response is altered, some of which can be restored by proper recolonization with a normal microbiota or specific probiotic strains. The amygdala is response to peripheral immune activation, so systemic inflammation, such as in the gut, stimulates activity in the amygdala.
Preclinical studies have shown that anxiety- and/or depression-like behaviors are altered by certain probiotic treatments, prebiotics, and antibiotics. Also, fecal microbiota transfer of samples from depressed individuals has been shown to alter the behavioral profile of recipient mice and rats – increasing anxiety- and depression0like behaviors.
The main problem with using anxiety- and depression-related symptom tests as an indicator of amygdala dysfunction is that these behaviors are not specific or exclusively dependent on the amygdala, however, cued fear conditioning is considered a more specific indicator of amygdala function.
It has been theorized that the co-evolution of humans with our microbiome may have been a driving force in our sociability. High levels of social interaction allows for greater transfer of microbial species between hosts – and indeed, those who live in the same household and spend a good deal of time in close proximity do tend to show similar gut microbiome characteristics. Also, individuals with autism spectrum disorder (ASD) often exhibit GI problems and alterations in the microbiota. Preliminary pilot studies are promisingly showing that probiotics may reduce symptom severity in children diagnosed with ASD.
Recent functional MRI (fMRI) studies suggest that the microbiota can alter amygdala connectivity. Further, microbiota-depletion has been shown to alter expression of mRNA for a number of genes related to anxiety and mood disorders, stress responses, and fear learning and extinction.
The amygdala is an area of the brain that regulates responses to stress and emotional stimuli.
By improving our understanding of how this area is regulated could offer strategies for treating disturbances in emotion regulation.
Cowan CSM, Hoban AE, Ventura-Silva AP, Dinan TG, CLarke G, and Cryan JF. “Gutsy Moves; The Amygdala as a Critical Node in Microbiota to Brain Signaling”. BioEssays (2017) 1700172.