Locus Coeruleus in mania

From all the mental disorders, bipolar disorder, a.k.a. manic-depressive disorder, has the highest risk for suicide attempt and completion. If the thought of suicide crosses your mind, stop reading this, it’s not that important; what’s important is for you to call the toll-free National Suicide Prevention Lifeline at 1-800-273-TALK (8255).

The bipolar disorder is defined by alternating manic episodes of elevated mood, activity, excitation, and energy with episodes of depression characterized by feelings of deep sadness, hopelessness, worthlessness, low energy, and decreased activity. It is also a more common disease than people usually expect, affecting about 1% or more of the world population. That means almost 80 million people! Therefore, it’s imperative to find out what’s causing it so we can treat it.

Unfortunately, the disease is very complex, with many brain parts, brain chemicals, and genes involved in its pathology. We don’t even fully comprehend how the best medication we have to lower the risk of suicide, lithium, works. The good news is the neuroscientists haven’t given up, they are grinding at it, and with every study we get closer to subduing this monster.

One such study freshly published last month, Cao et al. (2018), looked at a semi-obscure membrane protein, ErbB4. The protein is a tyrosine kinase receptor, which is a bit unfortunate because this means is involved in ubiquitous cellular signaling, making it harder to find its exact role in a specific disorder. Indeed, ErbB4 has been found to play a role in neural development, schizophrenia, epilepsy, even ALS (Lou Gehrig’s disease).

Given that ErbB4 is found in some neurons that are involved in bipolar and mutations in its gene are also found in some people with bipolar, Cao et al. (2018) sought to find out more about it.

First, they produced mice that lacked the gene coding for ErbB4 in neurons from locus coeruleus, the part of the brain that produces norepinephrine out of dopamine, better known for the European audience as nor-adrenaline. The mutant mice had a lot more norepinephrine and dopamine in their brains, which correlated with mania-like behaviors. You might have noticed that the term used was ‘manic-like’ and not ‘manic’ because we don’t know for sure how the mice feel; instead, we can see how they behave and from that infer how they feel. So the researchers put the mice thorough a battery of behavioral tests and observed that the mutant mice were hyperactive, showed less anxious and depressed behaviors, and they liked their sugary drink more than their normal counterparts, which, taken together, are indices of mania.

Next, through a series of electrophysiological experiments, the scientists found that the mechanism through which the absence of ErbB4 leads to mania is making another receptor, called NMDA, in that brain region more active. When this receptor is hyperactive, it causes neurons to fire, releasing their norepinephrine. But if given lithium, the mutant mice behaved like normal mice. Correspondingly, they also had a normal-behaving NMDA receptor, which led to normal firing of the noradrenergic neurons.

So the mechanism looks like this (Jargon alert!):

No ErbB4 –> ↑ NR2B NMDAR subunit –> hyperactive NMDAR –> ↑ neuron firing –> ↑ catecholamines –> mania.

In conclusion, another piece of the bipolar puzzle has been uncovered. The next obvious step will be for the researchers to figure out a medicine that targets ErbB4 and see if it could treat bipolar disorder. Good paper!

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P.S. If you’re not familiar with the journal eLife, go and check it out. The journal offers for every study a half-page summary of the findings destined for the lay audience, called eLife digest. I’ve seen this practice in other journals, but this one is generally very well written and truly for the lay audience and the non-specialist. Something of what I try to do here, minus the personal remarks and in parenthesis metacognitions that you’ll find in most of my posts. In short, the eLife digest is masterly done. As my continuous struggles on this blog show, it is tremendously difficult for a scientist to write concisely, precisely, and jargonless at the same time. But eLife is doing it. Check it out. Plus, if you care to take a look on how science is done and published, eLife publishes all the editor’s rejection notes, all the reviewers’ comments, and all the author responses for a particular paper. Reading those is truly a teaching moment.

REFERENCE: Cao SX, Zhang Y, Hu XY, Hong B, Sun P, He HY, Geng HY, Bao AM, Duan SM, Yang JM, Gao TM, Lian H, Li XM (4 Sept 2018). ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines. Elife, 7. pii: e39907. doi: 10.7554/eLife.39907. PMID: 30179154 ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 14 October 2018

Cats and uncontrollable bursts of rage in humans

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That many domestic cats carry the parasite Toxoplasma gondii is no news. Nor is the fact that 30-50% of the global population is infected with it, mainly as a result of contact with cat feces.

The news is that individuals with toxoplasmosis are a lot more likely to have episodes of uncontrollable rage. It was previously known that toxoplasmosis is associated with some psychological disturbances, like personality changes or cognitive impairments. In this new longitudinal study (that means a study that spanned more than a decade) published three days ago, Coccaro et al. (2016) tested 358 adults with or without psychiatric disorders for toxoplasmosis. They also submitted the subjects to a battery of psychological tests for anxiety, impulsivity, aggression, depression, and suicidal behavior.

The results showed that the all the subjects who were infected with T. gondii had higher scores on aggression, regardless of their mental status. Among the people with toxoplasmosis, the aggression scores were highest in the patients previously diagnosed with intermittent explosive disorder, a little lower in patients with non-aggressive psychiatric disorders, and finally lower (but still significantly higher than non-infected people) in healthy people.

The authors are adamant in pointing out that this is a correlational study, therefore no causality direction can be inferred. So don’t kick out you felines just yet. However, as CDC points out, a little more care when changing the cat litter or a little more vigorous washing of the kitchen counters would not hurt anybody and may protect against T. gondii infection.

Reference: Coccaro EF, Lee R, Groer MW, Can A, Coussons-Read M, & Postolache TT (23 march 2016). Toxoplasma gondii Infection: Relationship With Aggression in Psychiatric Subjects. The Journal of Clinical Psychiatry, 77(3): 334-341. doi: 10.4088/JCP.14m09621. Article Abstract | FREE Full Text | The Guardian cover

By Neuronicus, 26 March 2016

Stricter gun control laws lower suicide rate

Logos of the National Rifle Association and the Brady foundation, respectively, who have opposite views regarding gun legislation.
Logos of the National Rifle Association and the Brady foundation, respectively, who have opposite views regarding gun legislation.

In U.S.A., more than 50% of the suicides were committed with firearms in 2010 (source: Center for Disease Control – CDC), which is the 10th leading cause of death. Intuitively, you would think that if people who wish to commit suicide do not have access to their desired method of offing themselves, they will find alternatives, right? Wrong.

Anestis et al. (2015) wondered whether passing stricter gun legislature (such as requirements to have a permit to purchase a handgun, a registration of handguns, or/and a license to own a handgun) has any impact in the suicide rates. These three laws have been chosen because these are the only ones tracked by the National Rifle Association (NRA) Institute for Legislative Action and the authors din not want to be accused of being “biased toward the regulation of handguns” (p. e2). They looked at publicly available databases regarding suicide rates and demographics (e.g. CDC) and legislature (statal publications) for 2010. Then they SPSS-ed the hell out of the data, i.e. conducted a lot of statistics.

In a nutshell, the results show that the states with any of these three laws in place had fewer suicide rates. The authors would have looked at more laws, like the waiting time required to purchase the gun (which the authors believe would also influence the suicide rates) but, as they said, they analyzed only what NRA tracks so they are not accused of biases.

Reference: Anestis, M. D., Khazem, L. R., Law, K. C., Houtsma, C., LeTard, R., Moberg, F., Martin, R. (October 2015, Epub 16 Apr 2015). The Association Between State Laws Regulating Handgun Ownership and Statewide Suicide Rates. American Journal of Public Health, 105(10): 2059-2067. doi: 10.2105/AJPH.2014.302465.  Article | Full text PDF via Research Gate

By Neuronicus, 3 October 2015