Neuroscience Must Consider the Rest of the Body as Well

Why haven’t They Done That Yet?

Today’s post comes from a conversation twitter I was engaged in that turned to neuroscience expanding beyond the brain toward the peripheral nervous system and enteric nervous system (Link). This got me thinking about a topic I think is constantly neglected in neuroscience, the effects of the peripheral nervous system, enteric nervous system, and rest of the body on brain function, particularly in cases of genetic disease. Or as I like to put it, the body does not stop at the neck. Ignoring the rest of the organism stunts our ability to understand any disorder we are studying or modeling.

Now the reason I become passionate on this topic is from an experience in my own life. My twin brother with autism died at 32 years of age from acute tubular necrosis that resulted in complete renal and pulmonary failure. At the time this seemed to come out of nowhere, but in retrospect there were signs that we all overlooked in the weeks prior to his downward course as they seemed unimportant. At that point time I had just completed the work I am going to talk about in this post, and perspective on the role of the brain and body in genetic disease changed to be a more holistic (and thus less brain-centric) approach.

I had never intended to do this in this blog, but I am going to talk about one of my own studies and how it changed how I think about genetic disease. This post is going to cover the following paper: “Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice.” by myself and a number of colleagues in the US and The Netherlands. It appeared in Acta Neuropathologica in 2011.


What Should be Studied and Why?

We set out to study non brain pathology since it had been reported that there were a number of unexplained medical co-morbid disorders in the disorder we were studying (Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS), a neurodegenerative disorder that results in a movement disorder and cognitive decline (Link). We wondered if any of these co-morbid conditions could be explained by non central nervous system pathology, since the gene mutation underlying FXTAS was present throughout the organ systems in fetal tissues.

Some of these medical co-morbidities include type II diabetes, hypo and hypthyroidism, hypertension, fibromyalgia, peripheral neuropathy, migraines, chronic anxiety and clinical depression, among many others.


A Proposed Approach

Unlike a lot of my posts which tend to be somewhat technical, this is actually rather straightforward an approach. For this study we were able to obtain the somatic organs and the associated nerve plexi from a number of patients that had FXTAS during life during autopsy. We sent the tissues to the hospital’s central histology lab and had them processed for an H&E stain for a pathological analysis. Follow up studies using immunohistochemistry were done to confirm the H&E findings. We did the same experiment in male and female CGG KI mice, the mouse model originally developed to model the genetics underlying FXTAS.

Now, during this time I was working in this study I was fortunate enough to have access to trained pathologists that were able to teach me the skills necessary to identify pathology across organ systems. Although simple enough in theory, this was a difficult experiment since often times neuro-centric folks like myself have a very steep learning curve when any other organ has to be studied. That said, if a neuroscientist has medical collaborators they can easily do this toe of an experiment so long as they contact a pathology department for assistance.

Image 1

FXTAS Cases a Intranuclear inclusions in cardiomyocytes. Insert Extremely large, oval-shaped inclusion in a cardiomyocyte. b Intranuclear inclusions in pinealocytes and astrocytes in pineal gland. c Autonomic ganglion of the myenteric/Auerbach’s plexus is seen between longitudinal and circular muscular layers of the rectosigmoid colon. Intranuclear inclusions in ganglion cells. d Intranuclear inclusions in cells of the distal tubule of the kidney. e Intranuclear inclusions in thyroid. f Intranuclear inclusion in pancreas


The same experiment was performed in mice. In mice, however, the entire organism was sampled because we had access and did not want to miss any pathology if it were present. That being the case, some mice were sent to central histology and some were processed by me unsigned different methods.

Image 2

CGG KI Mouse a Intranuclear inclusions in cardiomyocytes. b Intranuclear inclusions in pinealocytes of CGG KI mouse pineal gland. c Intranuclear inclusions in ganglion cells of the myenteric plexus of the colon. d Intranuclear inclusions in adrenal gland. e Intranuclear inclusions in thyroid. f Intranuclear inclusions in pancreas. g Immunofluorescence of intranuclear inclusions (red) and somatostatin (green) in pancreas. h Immunofluorescence of intranuclear inclusions (red) and glucagon (green)


What was found was that the mice showed nearly all the same pathology as the human patients. Importantly, whenever we saw pathology in mice, it was present in the human tissues. There were some pathology in human tissues (testicular pathology primarily) that were not recapitulated by the mouse model.


Potential Interpretation

The interpretations from our study is clear, we suggested the medical co-morbidities were due to organ system pathology as well as peripheral and enteric nervous system dysfunction. What remains unknown is the role for any reciprocal signaling between the body and the hypothalamus, for example, for disease pathogenesis.

I would assert that in any other disorder with a genetic basis, ignoring the body and only focusing on the brain is myopic at best. One good use for any associated mouse models is to look at the distribution of whatever genetic loci underlying the genetic disorder throughout the body, not just in the brain.

Moving back to the personal side of is post (e.g., renal failure in autism), one example of why we need to study the body and not just the brain is the proposed role of vasopressin in the nervous system in autism. as a field, we ignore the fact that vasopressin is important for renal function. In fact, outside of neuroscience vasopressin is thought of as critical for kidney and cardiovascular function (Link).

This begs the question, what is going on in the heart and kidneys of individuals with autism. It has been suggested that this population dies on average earlier than the general population, but the reasons remain elusive ([Link](Http://dx.doi.org/10.1007/s10803-012-1664-z.
)). It seems to me that studying the peripheral pathology associated with autism this question as well as why there are many other chronic health issues associated with autism may be answered.

Advertisements

I would love to hear your thoughts on this!

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s