29 Recently the amygdala was also implicated in CO2 and acid chemosensation and CO2-evoked fear.32 The amygdala is a chemosensor that detects CO2 and acidosis to PFT�� datasheet elicit fear It is well established that the amygdala integrates sensory input from other brain structures to orchestrate fear behavior; however, the amygdala itself was not previously known to act as a pH sensor. Ziemann et al suspected this possibility after observing that the acid sensing ion channel-1a (ASIC1a) was abundantly expressed in the basolateral amygdala and

other fear circuit structures,91,92 and it was found that breathing 10% CO2 lowered pH to levels sufficiently to activate ASIC1a in amygdala neurons.32 Inhibitors,research,lifescience,medical To test CO2 triggered fear Inhibitors,research,lifescience,medical in mice, four behavioral paradigms were developed: (i) CO2-evoked

freezing; (ii) CO2-potentiated center avoidance in the open field; (iii) CO2 aversion; and (iv) CO2-enhanced fear conditioning.32 Genetically disrupting or pharmacologically inhibiting ASIC1a reduced fear-like behavior in these paradigms.32 Particularly striking was the freezing behavior, which is often used as a correlate of fear and panic in mice. Like other fear-evoking stimuli, breathing 10% CO2 induced a dramatic freezing response in wild-type Inhibitors,research,lifescience,medical mice. Disrupting or inhibiting ASIC1a significantly blunted this response.32 To test whether the amygdala itself might sense pH, acidic artificial cerebrospinal fluid was microinfused into the amygdala to lower pH to ~6.8 Inhibitors,research,lifescience,medical from

normal pH 7.35. Acidifying the amygdala produced freezing behavior in wild-type mice that resembled the freezing evoked by CO2 inhalation. Interestingly, in the ASIC1a knockout mice amygdala acidosis induced little or no freezing. The freezing deficit was likely specific to low pH because the ASIC1a knockouts froze normally when the amygdala was electrically stimulated. Inhibitors,research,lifescience,medical Finally, the authors tested whether ASIC1a in the amygdala might be sufficient Src inhibitor to produce CO2-evoked freezing. Restoring ASIC1a expression to the amygdala of ASIC1a-null mice with an ASIC1a-expressing adeno-associated virus corrected the CO2-evoked freezing deficit ((Figure 1).)Together these findings suggest that the amygdala itself can act as a chemosensor. These experiments further identify ASIC1a as key molecular mediator of this chemosensitive response. Figure 1. Expressing acid-sensing ion channel (ASIC)1a bilaterally in the basolateral amygdala of ASIC1a knockout (ASIC1a-/–) mice increased CO2 -evoked freezing behavior, (a) Examples of adeno-associated virus vector (AAV) injections that led to ASIC1a expression … Interoception and false alarms It is intriguing that a brain structure that mediates fear has a chemosensory role.