If I wanted to write about addiction today, my own NPR habit would be an excellent place to begin. News, blogs, radio, podcasts, it’s just so accessible! Today’s entry is not about addiction, but this story does start with “so I was reading NPR News…”

So I was reading NPR News, namely an article titled “What Makes You Feel Fear?” which turned out to be even more intriguing than I expected when I decided to read it. Evidently, researchers have used carbon dioxide inhalation to elicit panic and anxiety in patients with amygdala damage in both hemispheres: patients with no fear centers. How could this be?

(source: sciencedaily.com)

This startling discovery comes from a paper published this month in Nature Neuroscience by scientists at the University of Iowa. They tested three patients with Urbach-Wiethe disease (which resulted in bilateral amygdala lesions) by having them inhale CO₂. All three experienced panic attacks as a result, and showed significantly increased respiration rates – even with respect to healthy controls. This finding lead the authors to hypothesize that the amygdala may even be able to temporarily inhibit panic, as it has many GABAergic outputs to brainstem regions responsible for panic responses. All of this is pretty stunning. (Of course, the results would have been more stunning if there were a larger group of lesioned patients – all three of them did experience panic attacks in response to the CO₂ but so did three of the controls. Fortunately, though, people with bilateral amygdala damage are hard to come by. One could see how a lack of fear could be dangerous!)

The most curious question that this study evokes is whether there is a different mechanism for triggering fear in response to an internal stimulus (like inhaled CO₂) than there is for a response to an external stimulus (like a horror movie or a scary video game.) The amygdala is clearly implicated in the processing of inputs and outputs involved in fear responses, but how does it detect what it’s responding to in the first place?

Your amygdala definitely keeps you on the lookout for monsters in computer games like Amnesia: The Dark Descent! (source: amnesia-the-dark-descent.en.softonic.com)

A 2009 study published in Cell investigated this question in mice. Especially in light of the work in humans described above, the results are rather interesting. Another group of scientists looked at the acid-sensitive ion channel ASIC1a in mice as an indicator of the effects of CO₂ inhalation because it has been established that CO₂ inhalation results in a decrease in blood pH in mammals and generates a fear response. The researchers performed a number of experiments, and showed that the presence of this particular ion channel was necessary to evoke a freezing response in wild-type mice in the presence of 10% CO₂ and had no effect on knock-outs. They also looked at context conditioned fear responses with foot shocks – wild-type mice “froze” as expected, but in the presence of 10% CO₂ these mice showed freezing behavior before receiving the foot shocks. The next day, when returned to the context in which they were shocked (but not actually given shocks) the mice trained in the presence of CO₂ showed more freezing behavior than mice trained without it. In ASIC1a knockouts, the CO₂ exposure had no effect on context fear conditioning.

Then, the researchers looked directly at the effects of the CO₂ on amygdala pH, and when they confirmed that it was being lowered, they looked at firing rates of cultured amygdala neurons in response to lowered pH and saw an increase in firing as they brought the pH down in wild type cells. In line with these findings, the scientists figured that if low pH increased the fear response, perhaps it could be counteracted by raising amygdala pH with systemic injections of HCO₃ ^–. Indeed, this technique attenuated the fear response to CO₂ in wild-type mice but had no effect on knockouts. Lastly, by injecting a virus encoded with the ASIC1a gene to restrict its expression to the basolateral amygdala in knockout mice, the researchers restored the ability of these animals to demonstrate a fear response to inhaled CO₂.

All of this seems to indicate interoceptive capabilities in the amygdala. Even so…the knockout mice also showed an increase in ventilation in response to CO₂ inhalation, much like the lesioned patients in the human study – so the brain must have other detectors of acidosis…right? After all of this, does the amygdala play a chemosensory role? What other brain regions might be helping it out? Perhaps once we solve these puzzles, physicians may be able to take advantage of our brains’ pH sensitivity to treat panic and anxiety disorders.

What Makes You Feel Fear? – NPR

Fear and panic in humans with bilateral amygdala damage – Nature Neuroscience

The Amygdala Is a Chemosensor that Detects Carbon Dioxide and Acidosis to Elicit Fear Behavior - Cell

Ever been in a situation where you had to deal with someone/something that just really PISSED YOU OFF!?  Of course you have. After all, we’re all human; we’ve all felt that terrible tingle of insatiable rage wash over us from time to time.  It’s a pretty intense emotion, sometimes even frightening in its potential to completely change your whole disposition from that of a mild mannered undergrad to a rampaging Hulk wannabe.  Even more interesting (and a bit more terrifying perhaps) is how such an big emotion like anger can be generated by such a tiny section of your brain!

The amygdala, nexus of RAGE and mystery

Despite the nigh inevitable incorporation of the frontal lobe in interpreting and modulating emotional responses, when it comes to generating many of the basic motivated behaviors to which mammals are bound (anger, fear, attraction, hunger/thirst, etc.) the amygdala is usually the primary suspect (or at least an important accomplice).  The amygdala itself is a tiny, almond shaped bundle of neurons and fiber tracts located deep within the temporal lobes (usually near the end of the hippocampus). Countless studies from emotion-based research have targeted the amygdala as a playing a minor role in memory and, most famously, as a hot spot for emotional response.  Despite all this work, researchers are still relatively hazy as to how the amygdala is able to help us feel such different emotions as fear, anger and so on.  However, recent research from the Howard Hughes Medical Institute at Caltech may be starting to turn all of our uncertainty about the amygdala around, as well as shedding some light on the specific neuronal origins of our most primal emotions.

Yes, this actually is what activating those cells does to mice (minus the personality disorder)

Current investigations from the labs of Dayu Lin and David Anderson have led to the discovery of what seems to be a subset of neurons in the amygdala that exclusively help generate aggression in mice.  Upon activation, these “rage” neurons (or “fight cells” as Anderson has dubbed them) can turn an otherwise docile male mouse into a hyper-aggressive brawler.  Indeed, the effects are so strong that the mice can be induced to attack females and other males (usually castrated) that would otherwise not be viewed as a threat.  Talk about domestic violence!  To tease apart the action and sensitivity of these cells even more, Anderson and his team genetically modified a strain of these mice to express fight cells that respond to pulses of laser light.  Upon shining this light in the eyes of mutated mice, an aggressive response in the presence of females, castrated males and even a rubber glove was able to be stimulated!

In the midst of all this bio-molecular wizardry, Anderson and his team stumbled across another interesting discovery: a population of “mate” stimulating cells that seems to be closely knit with the fight cells in the amygdala.  As the name may imply, mate cells seem to play a large role in inducing and modulating sexual behavior.  Interestingly though, upon analyzing the brains of modified mice, after having previously been induced to attack a rubber glove (or something similar) and then allowed to mate, Anderson’s team that a healthy amount of fight cells were activated in concert with mate cells as the mice where engaging in sexual activity.

The fight cells' corner of the amygdala

It is this latest discovery that Anderson and his team have expressed the most excitement about, specifically because of its implications for potential remediation of violent sex offenders and predators who may be suffering from a massive “cross-wiring” of the fight cells and mate cells in their amygdalar/temporal regions. If enough homology can be drawn between these cells and their specific pathways in the mouse brain with that of the human brain, perhaps the future work of Hughes center could produce ways to untangle these connections and offer both sex offenders (and the general public) alternative solutions to their deeply ingrained problems.

Small Part of Brain Itching for a Fight – Science News