Around 5% of people are claustrophobic, fearing tight spaces and restricted movements. One of the major sources of fear by claustrophobics is the fear of suffocating. As it turns out, suffocating is downright terrifying all by itself, and it's not just the overall fear of death kicking in: according to new research published in Cell, increases in CO₂ can actually induce fear via pH levels in our brains.

In humans, the amygdala serves as the brain's 'fear center,' directly involved in the inputs and outputs that create fear behavior. However, until recently, exactly how the amygdala senses fear-evoking stimuli, or if it did so directly, were unknown. Neuroscientist Adam Ziemann and colleagues at the University of Iowa had been looking into a specific protein they'd found in high amounts in the amygdala, an acid-sensing ion channel called ASIC1a. They determined that it is particularly important in the sensation of fear^2,3. For example, mice whose gene for ASIC1a has been removed don't freeze in place, a common indicator of mouse fear, when exposed to fearful conditions. Now, they have found that CO₂ levels can play directly into this fear pathway¹.

The scientists noticed that normal mice (genotype +/+) tended to show fear when they breathed 10% CO₂. Curious to see how the ASIC1a knockout mice responded, Ziemann and his colleagues exposed the ASIC1a knockout mice (genotype +/-) to high CO₂. As expected, compared to their normal counterparts, these mice showed reduced fear reactions (Fig A). Furthermore, inhibiting the ASIC1a of normal mice with one of two known inhibitors also reduced the CO₂-evoked freezing (Fig B). Further studies using different methods of CO₂ exposure, including fear-based conditioning in the presence of CO₂, had supportive results (Fig C, D, E&F).

But the scientists took it a step further to show that ASIC1a was responsible for the fear reaction; they injected a virus encoding the gene into the knockout mice's amygdalas, thus restoring the protein levels. Localized ASIC1a expression in the amygdala of ASIC1a knockout mice rescued the CO₂-induced fear.

But how come CO₂ elicited such a strong fear response? They hypothesized that CO₂ inhalation was directly causing a decrease in amygdala pH, which ASIC1a was involved in sensing. Previous research had found that brain pH rapidly falls when the enzyme carbonic anhydrase catalyzes the conversion of CO₂ and water to carbonic acid, so they first looked to see if this occured in their model. The team showed that inhaling CO₂ did indeed cause a drop in amygdala pH in both normal mice and knockout mice. This pH change was sufficient to cause the stimulation of ASIC1a channels in cultured neurons from these mice.

To further test if this kind of drop in pH was the chemical signal for the fear response, the team injected the amygdalas of the mice with bicarbonate buffer, which reduces the pH change due to carbonic acid. Indeed, when normal mice were injected with bicarbonate, they not only showed reduced fear responses, they also were less able to learn via fear conditioning. The ASIC1a knockout mice, however, showed no reduction in fear response or ability to be conditioned with fear. All together, this paper presents strong evidence that fear is sensed via a pH change which stimulates the ASIC1a channel.

So it makes sense that suffocation is, by itself, quite scary. When we begin to suffocate, our CO₂ levels rise due to a lack of oxygen. This rise in CO₂then raises the acid level in the amygdala, thereby activating ASIC1a and altering the electrical signaling of amygdala neurons to produce a fear response. It also explains why panic attacks characterized by hyperventilation often spiral out of control. Fear-induced fast breathing leads to reduced oxygen intake, higher CO₂ levels, and more fear.

This new information might open up the door for a number of treatments for panic and anxiety disorders. It provides for the first time a link between genetics and anxiety, giving researchers an area to look at to potentially uncover the hereditary basis or these disorders. But what's really interesting about this study is that these channels, or the pH of the amygdala in general, may be able to serve as novel targets for treatment of anxiety disorders like phobias or post-traumatic stress disorder.

References:

1. Ziemann, A.E.,
Allen, J.E., Dahdaleh, N.S., Drebot, I.I., Coryell, M.W., Wunsch, A.M.,
Lynch, C.M., Faraci, F.M., Howard, M.A., Welsh, M.J., et al. (2009). The Amygdala Is a Chemosensor that Detects Carbon Dioxide and Acidosis to Elicit Fear Behavior. Cell 139, 1012-1020.

2. Wemmie, J.A., Askwith, C.C., Lamani, E., Cassell, M.D., Freeman, J.H.J., and Welsh, M.J. (2003). Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning. J. Neurosci. 23, 5496–5502.

3. Coryell, M.,
Ziemann, A.E., Westmoreland, P.J., Haenfler, J.M., Kurjakovic, Z.,
Zha, X.M., Price, M., Schnizler, M.K., and Wemmie, J. (2007). Targeting ASIC1a reduces innate fear and alters neuronal activity in the fear circuit. Biol. Psychiatry 62, 1140–1148.