passionless Droning about autism

Considering the Scaffolds of Interconnectedness, “Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus” and How Seeing The Obvious Can Still Be A Pleasant Surprise

Posted on: March 9, 2012

I’ve been thinking a lot lately about the beauty and trials of the tightly coupled systems, the interconnected pathways that keep popping up when pubmed tells me something that might be of interest on journey autism.  One theme bubbling to the top of my thoughts is that there is a large set of inputs capable of tweaking the areas we see altered in autism; broken isn’t necessarily appropriate, but the research increasingly tells us that a delicately balanced set of connected processes is readily changed, and the way that the physics work out, there is no way to change just one thing when you have a polygamous marriage of chemical systems.

Imagine a orchestra where all of the musicians were physically bound to one or more of their counterparts, a system of wires, pulleys, springs and levers such that the musicians are actually participating in the playing of each other, not soccer players doing synchronized flips so much as a set of violin-em-cello-em robots, connected to play their instruments in unison, wind them up and create a symphony.  Different orchestras might have a tighter wire from one member to another, or an older spring, but when they worked together, you could tell what composition they were playing.  In this analogy, you cannot have the drummers start beating harder and faster without also changing how hard the French horn players blow.  The situation only gets more complicated if some of our musicians were connected to several other musicians simultaneously.  There would still be music if the cellist couldn’t keep a steady rhythm, but it would be different music, not just a different cello.

The communication between a lot of our “systems”, immune, endocrine, stress response and central nervous systems are a lot like musicians in the orchestra, interdependent and intimately connected.

The funny thing is, this same message is being blared to me, and to you, all the time, damn near every time you turn on the TV, but it is hidden in plain sight by legislatively mandated doublespeak.  Consider how many advertisements each of us have seen for pharmaceutical drugs where the number of complications and contra-indicated conditions far, far exceed the number of desired effects?

Here is a list of common side effects of Viagra:

Diarrhea, dizziness, flushing, headache, heartburn, stuffy nose, upset stomach

So right off the bat, besides what we are looking for, we can see it is common to expect Viagra to also affect your GI system, immune system, and/ or brain function.  These are the types of things that are “common”.  (One wonders how Viagra would sell if it always caused headaches and diarrhea, and sometimes transiently ameliorated erectile dysfunction? )  A list of ‘severe’ side effects includes memory loss and a sudden decrease in hearing or vision.  Even after decades of work by a lot of exceptionally smart people and hundreds of billions of dollars, the interlocked complexity of our bodies are continuing to prove very difficult to adjust in only the way we’d like, and seemingly minor perturbations in one area can pop up in very unpredictable fashion in other functions.

Trying to put my mind around the implications of this in regards to autism often leaves me with a sense of being profoundly humbled and woefully underprepared, not unlike a lot of my experiences with autism in the real world.  Secondarily, again with great similarity to personal experience, I (eventually) come to the (re-)realization that we should rejoice in opportunities to be challenged and learning more about something makes us richer in ways more important than dollars.

A superb example of all of this and more landed in my inbox the other day, Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus (Williamson et all).  [Also on this paper, blog favorite, Staci Bilbo]

Williamson reported that animals given a so called ‘enriched environment’ exhibited significantly decreased immune responses in certain portions of the brain following immune challenge, with reduced levels of several chemokines and cytokines in the hippocampus in the treatment group. (A previous discussion about environmental enrichment on this blog can be found here)   In this instance, the treatment group got to spend twelve hours a day in a different area, a housing unit with “a running wheel, a PVC tube and various small objects and toys”, while the control group of animals stayed in their drab, Soviet era proletariat cages all day and all night long.  Here is the abstract:

Neurogenesis is a well-characterized phenomenon within the dentate gyrus (DG) of the adult hippocampus. Environmental enrichment (EE) in rodents increases neurogenesis, enhances cognition, and promotes recovery from injury. However, little is known about the effects of EE on glia (astrocytes and microglia). Given their importance in neural repair, we predicted that EE would modulate glial phenotype and/or function within the hippocampus. Adult male rats were housed either 12h/day in an enriched environment or in a standard home cage. Rats were injected with BrdU at 1week, and after 7weeks, half of the rats from each housing group were injected with lipopolysaccharide (LPS), and cytokine and chemokine expression was assessed within the periphery, hippocampus and cortex. Enriched rats had a markedly blunted pro-inflammatory response to LPS within the hippocampus. Specifically, expression of the chemokines Ccl2, Ccl3 and Cxcl2, several members of the tumor necrosis factor (TNF) family, and the pro-inflammatory cytokine IL-1ß were all significantly decreased following LPS administration in EE rats compared to controls. EE did not impact the inflammatory response to LPS in the cortex. Moreover, EE significantly increased both astrocyte (GFAP+) and microglia (Iba1+) antigen expression within the DG, but not in the CA1, CA3, or cortex. Measures of neurogenesis were not impacted by EE (BrdU and DCX staining), although hippocampal BDNF mRNA was significantly increased by EE. This study demonstrates the importance of environmental factors on the function of the immune system specifically within the brain, which can have profound effects on neural function.

Total interconnectedness kick ass!

Considering the wide ranging and predominantly ‘rather-not-have-than-have’ properties of ‘extra’ TNF-alpha and IL-1beta in the CNS, this is a pretty interesting finding.  Not only that, animals ‘protected’ through environmental enrichment also showed increased levels of growth factors known to be altered in autism, again in the hippocampus.  In a very real and measurable sense, it was possible to shuffle the neuroimmune cocktail of the brain by changing things like the availability of quality leisure time.  As we have seen in other areas, altering the chemical milieu of immunomodulatory factors in the brain isn’t trivial, and is increasingly associated with a variety of conditions classically diagnosed through the study of behaviors.

It should be noted that there were unexpected, and generally negative findings from this study, namely, a relative lack of biomarkers indicative of increased neurogenesis in the environmental enrichment group; something that I think took the authors by a bit of surprise.

There is a short discussion on the possibilities on why the findings of differential neuroimmune responses were found only in the hippocampus, with reference being made to previous studies indicating that this area of the brain has been found to be more susceptible to a variety of insults.

There were some other findings that struck me as particularly intriguing; something that has been hinted at previously in other studies (or transcripts), but not yet well described, likely due to the fact that the area is still largely unknown to us.  Specifically, the authors reported a state of glial activation, somewhat the opposite of what they expected.

The data instead suggest that EE changes the phenotype of glia, altering their activation and attenuating their pro-inflammatory response to peripheral LPS, although this remains to be directly tested. Interestingly, the blunted neuroinflammatory response within the DG of EE rats occurring concomitant with the increase in classical glial ‘‘activation’’ markers runs counter to our initial prediction. However, we believe these data simply highlight the fact that little is known about the function of these markers. Moreover, there is a growing literature that distinguishes classical versus alternative activation states in microglia, the latter of which is associated more strongly with repair (Colton, 2009; Colton and Wilcock, 2010).


Thus, it is possible that EE shifts microglia into an alternatively activated phenotype, an intriguing possibility that we are currently exploring.

(Totally sweet!)

The authors discuss the fact that their findings were highly spatially specific within the brain, involved a subset of cytokines and chemokines, and environmental enrichment did not seem to affect immune response in the periphery.

The immune response within the hippocampi of EE rats was markedly attenuated for a subset of cytokines and chemokines measured in our study. Importantly, not all measured immune molecules were blunted in the hippocampi of EE rats. Furthermore, the immune response was similar for each housing group in the parietal cortex as well as in the periphery. Within the hippocampus, however, EE rats had an attenuated response of interleukin-1b (IL-1b), the TNF family of genes, and several chemokines involved in the recruitment of leukocytes and monocytes. These families of genes indicate an altered hippocampal milieu in EE rats that may be less pro-inflammatory, more neuroprotective and less permeable to peripheral infiltrating immune cells.

There is a short discussion on the existing knowledge concerning IL-B and TNF-alpha in normal and pathological conditions, and how these findings are consistent with other findings involving environmental enrichment and cognition.

Tumor necrosis factor alpha (TNFa) is well characterized for its roles in inflammation and host defense, sepsis and, most intriguing for this study, apoptosis cascades (for review, see Hehlgans and Pfeffer, 2005). The observed attenuation after an immune challenge of TNFa and several associated genes in EE rats compared to HC controls indicates a potential enduring change in the hippocampal microenvironment of enriched rats, such that one mechanism by which EE may increase neuroprotection following insults to the CNS (Briones et al., 2011; Goldberg et al., 2011; Young et al., 1999) is via altered TNF tone and function, increasing the likelihood of cell survival by reducing apoptotic signaling. In addition to attenuated IL-1b and TNF responses, EE rats showed blunted responses for several chemokines known to influence the recruitment of circulating monocytes and leukocytes to the CNS.

Finally, the authors conclude how their findings add to the literature on environmental enrichment and brain function.

In summary, environmental enrichment is a relatively simple manipulation that results in robust beneficial outcomes for the brain. While previous studies have shown a role in post-insult rehabilitation for EE, our study provides evidence that enrichment need not follow the insult in order to be beneficial. Indeed, neuroinflammatory disease states might be attenuated or delayed in their onset in the face of ongoing EE. The translational reach of this manipulation remains to be explored, but in animal models of neuroinflammation, EE may provide a simple preventative measure for negative outcomes.

The bottom line is that a fuller rat life experience resulted in different neuroimmune profiles, findings with some consistency with previous observations that an enriched rat house resulted in improved behavioral manifestations of cognitive performance.  The qualities of these different neuroimmune profiles are also consistent with chemical profiles associated with positive outcomes in several conditions.

There is a deceivingly startling realization hidden in these finding, startling because it reveals the malleable nature of the seemingly different, but basic systems interacting and deceptive because it is so obvious.   How many of us have known someone who deteriorated upon entering a nursing home, or even retiring from working?  How many of us have kept their children inside for a week due to weather and watched their children go crazy after the already inferior indoor entertainment options are long exhausted?  Those changes in emotion, in behaviors and function, just like the findings from this study, are founded by chemistry.

But seeing evidence that relatively simple environmental modifications can rejigger the molecular atmosphere of the brain is still more than a little awe inspiring.   Knowing there is machinery underneath the hood is a little different than observing the cogs of cognition swell , shrink, or slow down; nothing less than a deeper understanding of the chemical basis of thought.  And that is pretty cool.

–          pD


8 Responses to "Considering the Scaffolds of Interconnectedness, “Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus” and How Seeing The Obvious Can Still Be A Pleasant Surprise"

Honey, I know how hard you work, and I hate to add to your burden…but give me a clue about this: “apoptosis cascades (for review, see Hehlgans and Pfeffer, 2005).” and why you find it intriguiging. Put it in dummy-talk.

I am a firm believer in serendipity, and I do believe our minds go places that we cannot articulate. I was bringing up immunilogical cascades in an anti-vaxxer tirade ( and it struck me funny that you would include this here. I am too lazy to work as hard as you do, but if you could just give me a clue, I’ll take it from there. Hehlgans and Pfeffer’s work seemed much more complete than 99% of what you see on Pubmed. I could read it over about 20 times and get some understanding of it, but you seem to have a clue.

Thanks, the pest.

Hi Rose / usethebrainsgodgiveyou –

Thanks for stopping by my blog, and to be sure, a clue is about all I have, so please bear that in mind.

In any case, I hadn’t read that reference, but Hehlgans and Pfeffer 2005 is for The intriguing biology of the tumour necrosis factor/ tumour necrosis factor receptor superfamily: players, rules and the games., a paper with a title that I totally love. I still haven’t had a chance to read it yet , but these guys do have their names on a lot of very cool looking stuff. I’ll add it to the pile.

Regarding apoptosis cascades and why I highlighted that section of the discussion, it wasn’t the cascading component so much as that I’ve seen a lot of other evidence in the autism realm of apoptosis pathways being nudged, so it struck me as serendipitous that a paper on environmental enrichment would touch on alterations to this system; just more evidence that systems we used to think of as being discretely compartmentalized are actually tightly entangled.

For some examples of papers discussing apoptosis related findings in autism, there are many, but a few very neat ones include

Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain: A very neat paper that found reduced levels of a very multi function protein, RORA, in autism. I discussed this paper on my blog, here, but for purposes of brevity, from Hu:

… many of the associated processes within the network, including synaptic regulation, fetal development, morphogenesis, apoptosis, inflammation, digestion, steroid biosynthesis, and mental deficiency, have been associated with autism. Two genes from this network, BCL-2 and RORA, were selected for further study because of their respective roles in apoptosis and morphogenesis/inflammation.

BCL-2, a protein with known anti-apoptotic effects had previously shown to be reduced in the autism brain, i.e., Reduction in anti-apoptotic protein Bcl-2 in autistic cerebellum

These results indicate for the first time that autistic cerebellum may be vulnerable to pro-apoptotic stimuli and to neuronal atrophy as a consequence of decreased Bcl-2 levels.

A more recent study looked at a variety of proteins known to interact with apoptosis:

Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects

Recent studies suggest that apoptotic mechanisms may partially contribute to the pathogenesis of this disorder. Cathepsin D is the predominant lysosomal protease and is abundantly expressed in the brain. It plays an important role in regulation of cellular apoptosis and has been shown to mediate apoptosis induced by cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. In this study, we examined the expression levels of cathepsin D in the autistic brain. We found that cathepsin D protein expression was significantly increased in the frontal cortex, in pyramidal and granule cells of the hippocampus, and in cerebellar neurons in autistic subjects as compared to controls. In addition, we found that the expression of the anti-apoptotic protein Bcl-2 was significantly decreased, while caspase-3, a critical executioner of apoptosis, was increased in the cerebellum of autistic subjects. Previously our studies have shown that Bcl-2 expression is decreased and the BDNF-Akt-Bcl-2 pathway is compromised in the frontal cortex of autistic subjects, which suggested that increased apoptosis may be involved in the pathogenesis of autism.

I noticed that you linked me @ In general, I think it is safe to say that there aren’t too many people on that board that have a very high opinion of my thoughts. Hah.


– pD

Thanks. I’ll study this and get back to you. They don’t love me there, either, sorry about that…

I became familiar with you when I occasionally would visit LBRB. You always seemed kind of sensible, able to see 2 sides to a story, and take the best from both,ha! I have found your writings always interesting and well thought out, and far less opinionated than my own.

“Being sexually or emotionally abused as a child can affect the development of a part of the brain that controls memory and the regulation of emotions, a study suggests.

The results add to the growing body of evidence that childhood maltreatment or abuse raises the risk of mental illnesses such as depression, personality disorders and anxiety well into adulthood.

Martin Teicher of the department of psychiatry at Harvard University scanned the brains of almost 200 people who had been questioned about any instances of abuse or stress during childhood. He found that the volumes of three important areas of the hippocampus were reduced by up to 6.5% in people exposed to several instances of maltreatment – such as physical or verbal abuse from parents – in their early years.

“The exquisite vulnerability of the hippocampus to the ravages of stress is one of the key translational neuroscience discoveries of the 20th century,” wrote Teicher on Monday in the journal Proceedings of the National Academy of Sciences.”


Although this particular research focuses on sexual and / or emotional abuse it seems there are continuing implications for all sorts of stress conditions previously discussed.

Hi Blackheart –

Very nice link. Well, actually it is terrible in a sense, but the data is the data and this study would seem to be largely consistent with lots of data in the animal realm and the common sense realm.

Thanks for posting this.

– pD
I’ve just found your blog through Patterson’s and I can’t express just how great it is. As the mother of a young man with Asperger’s i have been thinking about this for a long time and like you (but nowhere near as thoroughly… my son calls me “meanderbrain” !) researching since the internet arrived. Family history of atopy, atypical types of mental illness (alcoholism/ bipolar/epilepsy) and idiosyncratic reactions to things like antihistamines led me to inflammation, microglia and cilia and a vague idea that the IDO pathway and evolved resistance to malaria (possibly plasmodium vivax, in this context the experience of emigrant Somali families with autism is really interesting) might be at the foot of some of this. I really appreciate this additional window 🙂
I think the above link has interest in the environmental interactions area.

Something in modern life seems to be taking the random/idiopathic out of the autism thing and loading the dice for families with propensities. Eventually all research roads will converge I expect and there’ll be a cultural change. The great thing is that our autistic selves love truth and justice (and lots of research!) so it’s just a matter of time!

Gut Microbes Keep Rare Immune Cells in Line

“The idea that exposure to microbes can be good for us—by tuning up our immune systems and preventing overreactions like asthma and autoimmune diseases—is catching. Now, a new study of this provocative notion, known as the hygiene hypothesis, suggests that microbes furnish some of their benefits in an unexpected way. Researchers have found that the typical intestinal bacteria in mice rein in a rare type of immune cell, curtailing asthma and colitis in the rodents. Scientists following the long-running discussion over the hygiene hypothesis give the new work, reported online in Science this week, top marks.”

The abstract presented below …

“Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that, in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma compared to specific pathogen-free (SPF) mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal—but not adult—GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.”

Does this tie in with the work undertaken here …

Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances.

Hi Happyhorse –

I can’t reply to you directly due to the template, but thanks for stopping by my blog and your kind words!

That is quite an interesting link you’ve got there and it is a nice example of being surprised again. Very nicely done. Along similar lines, you may or may not have seen this study, which is similar in that it reports a non-expected interaction of microglia during ‘resting’ state, in this case, involved with sensory input.

Microglial interactions with synapses are modulated by visual experience

– pD

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