Evidence from humans suggests that most chronic pain patients (without brain involvement) experience working memory deficits. However, the mechanism responsible for this effect has remained elusive. This effect does not seem dependent on pain level though, as acute pain patients do not have memory deficits, nor do the deficits improve in chronic pain patients on opioid therapy.
To look at the mechanisms responsible, researchers performed spared nerve injury (SNI) on a group of rats. They found that SNI rats performed worse on a radial arm maze, specifically a test designed to test short-term memory (whether they re-entered an arm they had already entered). This memory effect was present even in a small number of animals who received an SNI, but did not develop pain-related behaviors.
TNF-a has been shown to inhibit LTP in the hippocampus, and the researchers looked at the relationship between TNF-a and working memory deficits. TNF-a levels were increased in the CSF and hippocampus of SNI rats, and administration of TNF-a antibody or synthesis inhibitor reduced the amount of working memory errors. Conversely, administration of recombinant TNF-a into the ventricles or hippocampus of non-SNI animals resulted in working memory deficits similar to those in the SNI animals.
This shows that elevated levels on TNF-a in chronic disease states can cause impairment of working memory, and that reductions of TNF-a improves these deficits. It highlights how uncontrolled inflammation or cytokine secretion can have detrimental effects on cognition, even when there is no brain involvement in the original problem.
http://www.ncbi.nlm.nih.gov/pubmed/21289602
SBrookshire495K
The article talks about a few receptors for TNFa that are found in the brain, which I find interesting as we identify TNFa primarily as a immunomodulatory molecule. To me, this means that the brain shouldn't have a TNFa receptor as the blood brain barrier keeps the immune system out. So then why does the brain have receptors for a cytokine that works on immune cells that are normally barred from crossing the BBB?
ReplyDeleteThis is all really interesting and seems to tie into something I recently heard on the radio. A man, Dr. Weil (who actually worked at the U of A) was discussing his book on positive psychology, specifically on overcoming depression. He talked about previous research that suggests a relationship between depression and inflammation, specifically the release of cytokines. Looking a little deeper I found more research supporting this connection. I feel like emotion could have an impact on cognition, and there seems to be some research surrounding depression and memory specifically.
ReplyDeleteEither way, there seems to be a connection between inflammatory markers and higher mental processes. I agree that it is interesting that the brain has receptors for TNF-a. Dr. Weil also gave a suggestion on how this could benefit an organism, though it seems more like an inference…
“Loss of interest in food and ability to take pleasure in eating make sense as a short-term response to infection -- it frees up energy used for digestion and makes it available for immune defense. Once the immune system gains the upper hand, it can turn down the cytokines, allowing brain centers that control appetite and taste to resume normal activity.”
http://www.huffingtonpost.com/andrew-weil-md/depression-and-inflammation_b_1071714.html
In response to the question of how TNF-a can act on receptors the brain, I did some research and found that TNF-a is actively transported from the blood into the brain, bypassing the blood-brain barrier. One study done on mice showed that the actual receptors for TNF-a in the brain may also be the transporters. By knocking out both the p55 and p75 receptors, the researchers were able to completely block TNF-a from entering the brain.
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pubmed/11922661
It turns out that TNF-a has a variety of effects on the brain. It suppresses appetite and raises body temperature. It may help regulate the sleep-wake cycle, and higher levels are related to lethargy. For example, sheep injected with TNF-a induced higher levels of slow-wave sleep.
http://www.ncbi.nlm.nih.gov/pubmed/10198380
Does this partly explain why we feel tired during illness? TNF-a also plays a role in activating the HPA-axis in the hypothalamus, which is interesting to me because of the inhibitory effects cortisol has on the immune system.
http://www.ncbi.nlm.nih.gov/pubmed/9096159
After reading this post, I was curious about a possible connection between TNF-a and alzheimer's. I found that there is evidence for quite a few increased peripheral inflammatory cytokines in alzheimer's disease, including TNF-a. However, TNF-a levels were normal in these alzheimer patients' cerebrospinal fluid (but TGF-B was elevated).
http://www.ncbi.nlm.nih.gov/pubmed/20692646
From these articles, it seems to me that TNF-a might be partly responsible for many of the symptoms that make us "feel ill." It seems remarkable to me that one cytokine can have so many different systemic effects, all arguably adaptive to encourage recovery.