The amygdala, an almond-shaped structure deep in the brain, has a critical role in the circuits that control the experience of fear, both instinctive fear (like being afraid of snakes or large carnivores) and fear that is learned from life experiences. The Iowa study shows that a very basic metabolic factor, pH -- acidity -- also has an essential role in fear. 
 
In general, the pH of our brain is carefully regulated. A large increase or decrease in brain acidity can seriously disrupt brain functioning. This new study indicates that pH can sometimes rise and fall in synapses, the points of communication between individual neurons in the brain. Some synapses include specialized proteins that "sense" acidity.  These proteins (called "'acid-sensing ion channels", or ASICs) stimulate neurons when increased acid is detected. 
 
The Iowa study shows that genetically modified mice lacking these acid-sensing proteins have a greatly reduced capacity to show either instinctive or learned fear.  When the researchers restored the ASIC gene only in the amygdala of these genetically modified mice, they observed a normalization of fear behaviors. So their studies suggest that the ability to detect changes in synaptic pH in the amygdala is essential for normal fear behavior. 
 
The Iowa paper also examined another element in the panic equation: Carbon dioxide. Carbon dioxide acts like an acid in the body and the brain. Several of the experiments described in the Iowa paper showed that inhaling elevated concentrations of carbon dioxide triggered strong fear reactions in normal mice, and that some of these fear reactions required the presence of the acid-sensing protein in the amygdala. 

These experiments are especially relevant to understanding panic disorder. One of the most consistent findings in patients with panic disorder is that they are unusually sensitive to carbon dioxide inhalation and other laboratory procedures that increase brain acidity. Most patients with panic disorder will experience a panic attack when they inhale air containing 35% carbon dioxide, while most healthy volunteers will not.  
 
Interestingly, the close relatives of panic patients will also panic during carbon dioxide inhalation, even if they have never suffered from an anxiety disorder.  A hypersensitivity to acid in the brain appears to be part of the inherited vulnerability to panic attacks. The recent studies in mice lacking the ASIC protein add further credence to this understanding of why some people are more prone to having panic attacks.

The Iowa findings might help explain the significance of another curious observation: patients with panic disorder tend to generate excess lactic acid in their brains. Scientists have long hypothesized that an abnormality affecting basic cellular metabolism or pH lay at the heart of the genetic vulnerability to panic disorder.  One of the products of glucose metabolism is lactic acid, or lactate. Lactate is constantly being produced and consumed during brain activity, but if it accumulates in the brain, it will make the brain more acidic.  Recent studies have shown that patients with panic disorder consistently build up excess lactate in their brains during ordinary mental activities. The results of the Iowa studies suggest that one of the triggers for “spontaneous” panic attacks in patients with panic disorder might be lactic acid accumulating in acid-sensitive fear circuits.    
 
Although there are several effective treatments available for people with panic disorder, current treatments do not work for all patients. It is unlikely that any of the current treatments specifically act on the underlying genetic vulnerability in panic disorder patients. The new studies show that brain pH changes are a crucial part of the mechanism of many fear behaviors. At present, no available medications affect the responses of acid-sensing ion channels in the brain. It may be possible to develop medications that inhibit these ASICs or otherwise modify the metabolic or neurochemical pathways involved in the regulation of fear and anxiety by brain acidity. 

For example, one of the many beneficial effects of aerobic exercise training (like running or cycling) is that metabolically active tissues (including the brain) become more efficient at consuming -- removing -- lactic acid. There is growing evidence that exercise training has powerful anti-anxiety and anti-panic effects. This invites the speculation that exercise training may reduce anxiety in part by improving the brain's ability to prevent excess acid accumulation in acid-sensitive brain regions involved in fear. If experiments support this idea, then specific exercise training regimens could be designed to take maximum advantage of this anti-anxiety mechanism.