Posts Tagged ‘Glial Priming’
A Brief Overview Of Glial Priming, How It (Probably) Applies To (Some Cases Of) Autism, And Worrisome Speculation On A Model Of A Low Penetrant Effect
Posted October 26, 2012
on:Hello friends –
The concept of glial priming (and implicit double multi hits) is the nexus of developmental programming, low penetrant effects, and an altered microglial responsiveness, a blueprint for a change in function in the tightly entangled neuroimmune environment; sort of an all time greats theory mashup for this blog. The basic idea is that microglia can become sensitized to insults and subsequently respond to similar insults with greater robustness and/or for increased timespans later in life. Here is a snippet from Microglia in the developing brain: A potential target with lifetime effects on the primed glial phenotype:
There is a significant amount of evidence regarding what is often termed ‘‘priming’’ and ‘‘preconditioning’’ events that serve to either exacerbate or provide neuroprotection from a secondary insult, respectively. In these states, the constitutive level of proinflammatory mediators would not be altered; however, upon subsequent challenge, an exaggerated response would be induced. The phenomena of priming represent a phenotypic shift of the cells toward a more sensitized state. Thus, primed microglia will respond to a secondary ‘‘triggering’’ stimulus more rapidly and to a greater degree than would be expected if non-primed.
Glial priming may be the fulcrum on which much of the underlying early immune activation research balances, the machinery that drives environmental influences during development leading to irregular neuroimmune functionality through the lifespan. Even though this type of finding is not really unexpected when considered within the prism of programming effects in other systems and the perturbed immune milieu in many (all?) neurological disorders, it is still pretty cool.
The first paper that I read that specifically mentioned glial priming was Glial activation links early-life seizures and long-term neurologic dysfunction: evidence using a small molecule inhibitor of proinflammatory cytokine upregulation, (Somera-Molina KC , 2007) which totally kicked ass. They brought a lot of heat at design time of the study; (very powerful) seizures were induced /saline given in animals at postnatal day 15 and 45; at day 55 animals were analyzed and showed distinct increases in microglial activation, neurologic injury, and future susceptibility to seizures in the ‘two hit’ group (i.e., animals that got seizure inducing kainic acid instead of saline on both day 15 and 45). Even better, it was shown that a CNS available inhibitor of inflammatory cytokine production rescued the effect of the seizure. In other words, it didn’t matter if the animals had a seizure, what mattered was the presence or absence of an unmitigated inflammatory response associated with the seizure.
Treatment with Minozac, a small molecule inhibitor of proinflammatory cytokine upregulation, following early-life seizures prevented both the long-term increase in activated glia and the associated behavioral impairment.
That is an important step in understanding the participation of inflammation in seizure pathology. There were also observable effects (worse) in animals that got seizures just once, if they got induced on day 15 versus 45, and even worse symptoms for the “double hit” animals. That was pretty fancy stuff in 2007. The similarity in terms of seizure susceptibility really reminded me of another paper, Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats, which also showed altered susceptibility to seizures in animals subjected to seizures in early life, with the effect mediated through inflammation related cytokines. Here, however, the same effect observed, but with the addition of clinical evidence of chronically perturbed microglia phenotype in the treatment group. Nice!
The same group followed up with Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a ‘two-hit’ seizure model (full version), with more of the same. Here is part of the Discussion:
First, in response to a second KA ‘hit’ in adulthood, there is an enhancement of both the upregulation of proinflammatory cytokines, microglial activation, and expression of the chemokine CCL2 in adult animals who had previously experienced early-life seizures. Consistent with the exaggerated proinflammatory cytokine and microglial activation responses after the second hit, these animals also show greater susceptibility to seizures and greater neuronal injury. Second, administration of Mzc to suppress of the upregulation of proinflammatory cytokines produced by early-life seizures prevents the exaggerated cytokine and microglial responses to the second KA hit in adulthood. Importantly, regulating the cytokine response to early-life seizures also prevents the enhanced neuronal injury, behavioral impairment, and increased susceptibility to seizures associated with the second KA insult. These results implicate microglial activation in the mechanisms by which early-life seizures lead to increased susceptibility to seizures and enhanced neurologic injury with a second hit in adulthood.
Not only that, but the authors speculated on the possibility of a rescue effect through neuroimmune modulation!
Our data support a role for activated glia responses in the mechanisms by which early-life seizures produce greater susceptibility to a second neurologic insult. The improved outcomes with Mzc administration in multiple acute or chronic injury models where proinflammatory cytokine upregulation contributes to neurologic injury (Hu et al., 2007; Somera-Molina et al., 2007; Karpus et al., 2008; Lloyd et al., 2008) suggest that disease-specific interventions may be more effective if combined with therapies that modulate glial responses. These results are additional evidence that glial activation may be a common pathophysiologic mechanism and therapeutic target in diverse forms of neurologic injury (Akiyama et al., 2000; Craft et al., 2005; Emsley et al., 2005; Hu et al., 2005; Perry et al., 2007). Therapies, which selectively target glial activation following acute brain injury in childhood, may serve to prevent neurologic disorders in adulthood. These findings raise the possibility that interventions after early-life seizures with therapies that modulate the acute microglial activation and proinflammatory cytokine response may reduce the long-term neurologic sequelae and increased vulnerability to seizures in adulthood.
(Please note, the agent used in the above studies, kainic acid, is powerful stuff, and the seizures induced were status epileptcus, a big deal and a lot different than febrile seizures. That doesn’t mean that febrile seizures are without effect, I don’t think we are nearly clever enough to understand that question with the level of detail that is needed, but they are qualitatively different and not to be confused.)
The idea of modulating glial function as a preventative measure seems especially salient to the autism community alongside the recent (totally great) bone marrow studies observing benefits to a Rett model and an early life immune activation model of neurodevelopment.
A lot of kids with autism go on to develop epilepsy in adolescence, with some studies finding prevalence in the range of 30%, which terrifies the shit out of me. Is a primed microglial phenotype, a sensitization and increased susceptibility to seizures one of the mechanisms that drive this finding?
After Somera-Molina, I started noticing a growing mention of glial priming as a possible explanation for altered neuroimmune mechanics in a lot of places. Much of the early life immune literature has sections on glial priming, Early-Life Programming of Later-Life Brain and Behavior: A Critical Role for the Immune System (full / highly recommended / Staci Bilbo!) is a nice review of 2010 data that includes this:
However, there is increasing support for the concept of “glial priming”, in which cells can become sensitized by an insult, challenge, or injury, such that subsequent responses to a challenge are exaggerated (Perry et al., 2003). For instance, a systemic inflammatory challenge in an animal with a chronic neurodegenerative disease leads to exaggerated brain inflammation compared to a control animal (Combrinck et al., 2002). The morphology of primed glial cells is similar to that of “activated” cells (e.g. amoeboid, phagocytic), but primed glial cells do not chronically produce cytokines and other pro-inflammatory mediators typical of cells in an activated state. Upon challenge, however, such as infection or injury in the periphery, these primed cells will over-produce cytokines within the brain compared to cells that were not previously primed or sensitized (Perry et al., 2002). This overproduction may then lead to cognitive and/or other impairments (Cunningham et al., 2005; Frank et al., 2006; Godbout et al., 2005).
Other studies included increased effects of pesticide exposure following immune challenge, Inflammatory priming of the substantia nigra influences the impact of later paraquat exposure: Neuroimmune sensitization of neurodegeneration, which includes, “These data suggest that inflammatory priming may influence DA neuronal sensitivity to subsequent environmental toxins by modulating the state of glial and immune factors, and these findings may be important for neurodegenerative conditions, such as Parkinson’s disease (PD).” Stress was also found to serve as a priming agent in Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses, which studied the effect of stress mediated chemicals on inflammatory challenges; the authors get bonus points for using glucocorticoid receptor agonists and surgical procedures to eliminate glucocorticoid creation to observe a priming effect of stress on neuroimmune response.
Here is a terrifying but increasingly unsurprising study on how neonatal experience modifies the physical experience of pain in adulthood, recently published in Brain, Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity
Adult brain connectivity is shaped by the balance of sensory inputs in early life. In the case of pain pathways, it is less clear whether nociceptive inputs in infancy can have a lasting influence upon central pain processing and adult pain sensitivity. Here, we show that adult pain responses in the rat are ‘primed’ by tissue injury in the neonatal period. Rats that experience hind-paw incision injury at 3 days of age, display an increased magnitude and duration of hyperalgesia following incision in adulthood when compared with those with no early life pain experience. This priming of spinal reflex sensitivity was measured by both reductions in behavioural withdrawal thresholds and increased flexor muscle electromyographic responses to graded suprathreshold hind-paw stimuli in the 4 weeks following adult incision. Prior neonatal injury also ‘primed’ the spinal microglial response to adult injury, resulting in an increased intensity, spatial distribution and duration of ionized calcium-binding adaptor molecule-1-positive microglial reactivity in the dorsal horn. Intrathecal minocycline at the time of adult injury selectively prevented both the hyperalgesia and early microglial reactivity associated with prior neonatal injury. The enhanced neuroimmune response seen in neonatally primed animals could also be demonstrated in the absence of peripheral tissue injury by direct electrical stimulation of tibial nerve fibres, confirming that centrally mediated mechanisms contribute to these long-term effects. These data suggest that early life injury may predispose individuals to enhanced sensitivity to painful events.
One of the primal drivers of behavior in any animal, pain, can be persistently modified at a molecular level! Have you ever known someone that seemed to have a higher pain tolerance than you? Maybe they did, and the training of their microglia (or yours) in early life might be why. The most basic physiologic responses can be organized through the crucible of early life events sensitizing microglia to the future environment. Multi hit wow!
The effect that befalls us all, getting older, has a ton of studies on the effect of aging on glial priming, with greatest, err, ‘hits’ including Immune and behavioral consequences of microglial reactivity in the aged brain, Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system (full),Immune and behavioral consequences of microglial reactivity in the aged brain (full), and the autism implication heavy Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation, and others. Broadly, these studies spoke of the same pattern, a primed neuroimmune response, except in this instance, the “hits” that predisposed towards altered microglial reactivity weren’t a vigorous insult during development, but just the hum drum activity of growing older. It wasn’t a hit so much, more like a then gentle force of a relentless tide, but the functional effect on microglia response was largely similar, responses to stimuli were changed and programming was observed. I do not believe that the underlying instrument of change in age related priming is understood, but the thought occurs to me that it could simply be an exhaustion effect; a lifetime of exposure to inflammatory cytokines gradually changes the microglial phenotype.
So what about autism?
First and foremost, it provides us a line of insight into the likelyhood of a causal relationship between an altered neuroimmune milieu and autism (or nearly any other neurological disorder); that is, the question of whether or not our continued and repeated findings of altered neuroimmune parameters in the autism population represent a participating force in autism, as opposed to an artifact, a function of something else, which is also causing autism, or perhaps a result of having autism. While these are still possible explanations, the findings of glial priming provide additional detail on available mechanisms to affect brain activity and behavior through neuroimmune modifications alone.
If nothing else, we now know that we need not rely on models with no underlying substrate except the lamentations of ‘correlation does not equal causation’ and the brash faith of another, as of yet undefined, explanation. These models tell us that immune mediated pathologies can be created (and removed!) in very well established animal models of behavioral disturbances with corollaries to autism findings.
For more direct links to autism, we can look at the autism immune biomarker data set and find evidence of primed peripheral (i.e., outside the CNS) programming, literal examples where the autism population responds with a different pattern than the control group including an increased response to some pathogen type agonists, increased immune response following exposure to pollutants, of even dietary proteins.
The pattern we see of an altered microglial phenotype in the autism population, a state of chronic activity, is certainly consistent with disturbed developmental programming; it does not seem unlikely to me that a priming effect is also present, the initial prime seems to be responsible for the programming. As far as I know, there are no studies that have directly attempted to evaluate for a primed phenotype in the microglia of the autism population; I’d be happy to be corrected on this point.
Thinking about the possibility of increased microglial responsiveness and possible cognitive effects of a sustained neuroimmune toggling got me wondering if this is one of the mechanisms of a change in behavior following sickness? Or, alternatively, for some of us, “Is This Why My Child Goes Goddamn Insane And Stims Like Crazy For A Week After He Gets Sick?”
If we look to a lot of the studies that have shown a priming effect, they share a common causative pathway as some cases of autism, an early life immune insult. For some examples, the interested reader could check out Neonatal programming of the rat neuroimmune response: stimulus specifc changes elicited by bacterial and viral mimetics (full paper), Modulation of immune cell function by an early life experience, or the often mentioned Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats (full paper). If there are some cases of autism that have an early life immune insult as a participating input, it is very likely a primed microglia phenotype is also present.
The studies on aging are bothering me, not only am I getting older, but the findings suggest that a priming need not necessarily mandate a distinct ‘hit’, it can be more like a persistent nudge. Our fetuses and infants develop in an environment with an unprecedented number of different nudges in the past few decades as we have replaced infection with inflammation. Acknowledging this reality, however, raises the troubling thought that our embrace of lifestyles associated with increased inflammation has reached a tipping point that we are literally training the microglia of our children to act and react differently; we aren’t waiting a lifetime to expose our fetuses and infants to environments of increased inflammation, we are getting started from the get go.
Even with all of that, however, there is a genuinely microscopic Google footprint if you search for “autism ‘glial priming’”. So, either I’m seeing phantoms (very possible), or the rest of the autism research community hasn’t caught on yet, at least in such a way that Google is notified.
Even if I am chasing phantoms, there is evidence of a widespread lack of understanding of the depth of the neuroimmune/behavioral crosstalk literature, even by the people who should be paying the most attention. This was brought to my attention by a post at Paul Patterson’s blog, where Tom Insel was quoted as finding the recent Patterson and Derecki findings ‘unexpected’.
A bone marrow transplant, which replaces the immune system, corrected both the immune response and the behavior. This finding, which was unexpected, is surprisingly similar to another recent paper reporting disappearance of the symptoms of Rett syndrome in mice following a bone marrow transplant.
Keep in mind, this is from the guy who is the head of the IACC! I can tell you one thing; while the studies were impressive, I don’t think that the findings were especially unexpected. The researchers took the time to give mice bone marrow transplants, and in Wild-type microglia arrest pathology in a mouse model of Rett syndrome, the authors utilized a variety of knockout mice and even partial body irradiation to illuminate the question of neuroimmune participation in disorder. This work was not initiated in a vacuum, they did not throw a dart at a barn door sized diagram of study methodologies and land on ‘bone marrow transplants with subsequent analysis of microglia population properties and behaviors, accounting for different exposure timeframes, radiation techniques, and genotypes’. These were efforts that had a lot of supporting literature in place to justify the expense and researcher time. [I really want to find time to blog both of those papers in detail, but for the record, I did feel the rescue effects are particularly nice touches.]
So given that the head of the IAAC was surprised to find that immune system replacement having an effect on behavior was ‘surprising’, I’m not all together shocked at the relative lack of links on ‘glial priming’ and autism, but I don’t think it will stay that way for too much longer. As more experiments demonstrating a primed phenotype start stacking up, we are going to have to find a way to understand if generation autism exhibits a primed glial phenotype. I don’t think we are going to like the answer to that question very much, and the questions that come afterwards are going to get very, very inconvenient.
Spelling it out a bit more, with bonus speculation, we should remember our recent findings of the critical role microglia are playing in shaping the neural network; our microglia are supposed to be helping form the physical contours of the brain, a once in a lifetime optimization of synaptic structures that has heavy investment from fetushood to toddlerhood. Unfortunately, it appears that microglia perform this maintenance while in a resting state, i.e., not when they have been alerted of an immune response and taken on a morphology consistent with an ‘activated state’. An altered microglia morphology can be instigated during infection, or perceived infection and consequent immune response. For examples of peripheral immune challenges changing microglial morphology, the neuroimmune environment and behavior some examples include: Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice, Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system, or Long-term changes of spine dynamics and microglia after transient peripheral immune response triggered by LPS in vivo.
But what if we have a susceptible population, a population sensitized such that the effects of an immune challenge would result in an exaggerated and extended microglial response, effectively increasing the length of time the microglia would be ‘not resting’. What might be the changes in this population in response to a series of ‘hits’?
It does not seem to be a large logical leap to assume that if some of the altered brain physiology in autism is due to abnormal microglia function during the period of robust synaptic pruning, triggering the microglia to leave their resting state for an extended period in response could be a reasonable participant. Think of it as an exaggerated loss of opportunity effect, essentially a longer timeframe during which the microglia are not performing synaptic upkeep when compared to the microglia in an individual that is not sensitized. While our brains do show a lot of ability to ‘heal’, that does not mean that all things or times are created equally; there are some very distinct examples of time and spatially dependent neurochemical environments during early synapse development, environments that change as time goes on; i.e., Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain (full paper), or A new synaptic player leading to autism risk: Met receptor tyrosine kinase. In other words, recovering from a delay in microglial participation in synaptic pruning during development may not be as simple as ‘catching up’; if the right chemical environment isn’t available when the microglia get done responding, you might not be able to restart like a game of solitaire. The Met levels might be different, the neurexin levels might be different, a thousand other chemical rally points could be set that much of a nudge differently; in a system dependent on so many moving variables being just so, an opportunity missed is an opportunity lost. For good.
While the effects of a series of challenges and consequent obstructions of synaptic maintenance might not be acutely clear, I am becoming less and less convinced of the ‘safety’ of an observed lack of immediately obvious effects. I think that an intellectually honest evaluation of our recent ‘discoveries’ in many areas of early life disturbances (i.e., antibiotics and IDB risk, C-section and obesity risk, birth weight and cardiovascular risk) tell us that subtle changes are still changes, and many rise to the level of a low penetrant, environmentally induced effect once we get clever enough to ask the right question. And boy are we a bunch of dummies.
Taking all of this into consideration, all I can think is thank goodness we haven’t been artificially triggering the immune system of our infants for the past two decades while we were blissfully unaware of the realities of microglial maintenance of the brain and glial priming! What a relief that we did not rely on an assumption of lack of effect as a primary reason not to study the effect of an immune challenge. If we had done those things, we might start kicking ourselves when we realized out that our actions could be affecting susceptible subsets of children who were predisposed to reacting in difficult to measure but real ways that could literally affect the physical structure of their brains.
Oops.
– pD
Intriguing Findings – Maternal Obesity, Inflammation, and Consequent Priming of Microglia, Immune Alterations, and Spatial Processing in Offspring (!)
Posted May 4, 2010
on:Hello friends –
I’ve been forced to modify my pubmed alerts so that I don’t miss abstracts like this:
Enduring consequences of maternal obesity for brain inflammation and behavior of offspring
Obesity is well characterized as a systemic inflammatory condition, and is also associated with cognitive disruption, suggesting a link between the two. We assessed whether peripheral inflammation in maternal obesity may be transferred to the offspring brain, in particular, the hippocampus, and thereby result in cognitive dysfunction. Rat dams were fed a high-saturated-fat diet (SFD), a high-trans-fat diet (TFD), or a low-fat diet (LFD) for 4 wk prior to mating, and remained on the diet throughout pregnancy and lactation. SFD/TFD exposure significantly increased body weight in both dams and pups compared to controls. Microglial activation markers were increased in the hippocampus of SFD/TFD pups at birth. At weaning and in adulthood, proinflammatory cytokine expression was strikingly increased in the periphery and hippocampus following a bacterial challenge [lipopolysaccharide (LPS)] in the SFD/TFD groups compared to controls. Microglial activation within the hippocampus was also increased basally in SFD rats, suggesting a chronic priming of the cells. Finally, there were marked changes in anxiety and spatial learning in SFD/TFD groups. These effects were all observed in adulthood, even after the pups were placed on standard chow at weaning, suggesting these outcomes were programmed early in life.
WOW. [All emphasis is mine]
You may note that there isn’t any mention of autism per se here, but we do seem to hit a lot of sweet spots that immediately grabbed my attention for a couple of reasons. While my primary persona as Some Jerk On The Internet is a self appointed autism investigator, somewhere along the line in real life I’ve been trying some relatively strange (for the US) dietary practices; a ‘veganesque’ ingredient selection and the move to a diet based on whole foods, organic when possible. What I’ve noticed during this timeframe is just how fat so many Americans are. The obesity epidemic is real, folks, and doesn’t have the fuzzy nature of ‘increased awareness’ to allow us to (pretend) hope that there isn’t something real happening; we have been getting fatter and fatter for the past few decades. And here we have evidence that obesity can create physiological and behavioral changes in offspring through our mediator de jour, inflammation.
So, why am I blogging about this paper on an autism blog? Creepily enough, a lot of the differences listed here (well, all of them, actually), have similarities to findings in the autism realm.
At weaning and in adulthood, proinflammatory cytokine expression was strikingly increased in the periphery and hippocampus following a bacterial challenge [lipopolysaccharide (LPS)] in the SFD/TFD groups compared to controls.
With human subjects, it is a bit problematic to determine if there are ‘striking increases’ in proinflammatory cytokine expression in the hippocampus following bacterial challenge, but in vitro, we have scads of evidence that the autism population creates an exaggerated innate immune response when compared to ‘normal’. The most recent example of this is, Differential monocyte responses to TLR ligands in children with autism spectrum disorders, by Enstrom, which I also blogged about. We also have Ashwood, and several by Jyonouchi showing similar findings; increased production of proinflammatory cytokines TNF-alpha, IL-6, and IL1-B to some TLR agonists, including TLR4.
Microglial activation within the hippocampus was also increased basally in SFD rats, suggesting a chronic priming of the cells.
Of course, the seminal paper in this regard was Vargas, Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism, which found increased levels of microglial activation in an autism cohort; their focus seemed to be areas other than the hippocampus. Similar findings of an ongoing immune response within the CNS in autism population can be found in Elevated immune response in the brain of autistic patients, and Immune transcriptome alterations in the temporal cortex of subjects with autism. The concept of ‘primed microglia’ is touched on in another paper by Bilbo, Early-life programming of later-life brain and behavior: a critical role for the immune system, which I’d like to get to eventually, but haven’t had the time for yet, but essentially suggests that there are time critical periods during which the microglia are vulnerable to persistent immunological modification, changing their resting state and response to future immune challenges.
Finally, there were marked changes in anxiety and spatial learning in SFD/TFD groups.
Oh yeah. Everyone has heard the story about the kid with autism who can paint New York City after a helicopter ride, or seeing colors in sound, or whatever, but there does also seem to be a lot of applied research involving specific kinds of visual tests that people with autism seem to do better at than people without. Curiously, we even have a knock out model in rodents that show superior spatial processing skills. Anyone who knows a couple of kids with autism knows one that has anxiety problems; there are some evaluations of this, but honestly, this type of thing suffers a bit from my mind because in order to ask the right question, ‘Are you anxious?’, you’ve eliminated a chunk of the autism population. If we break down to the chemical level and start looking at known biomarkers for the stress response, the HPA-Axis, we’ve got tons of evidence that something is amiss.
Here are some of the juicier parts of the paper. From the introduction:
Obesity and insulin resistance are also strongly linked to cognitive dysfunction, including Alzheimer’s disease (13, 14). Neuroinflammation is independently linked to cognitive disruption (15); brain IL-1 expression, in particular, is implicated in Alzheimer’s disease pathogenesis (16). However, a direct mechanism linking these diverse factors is lacking; that is, whether peripheral inflammation in obesity contributes directly to inflammation/ cytokine production in cognitive regions of the brain, and thus cognitive disruption, remains unclear. Moreover, whether maternal obesity may program inflammation within the brains of offspring long term, particularly in regions important for cognition, such as the hippocampus, is virtually unknown. Tozuka et al. (17) recently reported long-term impairments in neurogenesis within the dentate gyrus as a consequence of being born to obese mouse dams, although the researchers did not explore a potential role for inflammation. Notably, White et al. (18) reported increased glial activation and oxidative stress in the cortex of high-fat-diet-fed rats that were also born to high-fat dams. Glia are the primary immunocompetent cells of brain; thus, long-term changes in their activity as a consequence of diet could be critical in long-term programming of neural function.
The whole ‘long term programming of neural function’ theory is beautiful and terrifying. From the discussion section:
A central question in this study was to identify whether systemic inflammation is transferred to cognitive regions of the brain. The answer to that question is clearly yes, especially in the SFD rats. These animals exhibited increased peripheral cytokines (in liver, fat,and serum) and hippocampal IL-1 responses to an LPS challenge. At P20 and in adults, rats from SFD dams exhibited a very large increase in hippocampal IL-1 following a moderate dose of LPS (Fig. 4). Males exhibited a larger response than females in adulthood, although the diet effect was significant in both sexes. The exaggerated response in adults was particularly striking, given that these animals had been fed a low-fat diet since weaning, a period of time longer in duration (9 wk) than the total time they were exposed to the high-fat diets during development (6 wk). Notable as well was the increase in basal levels of IL-1 in high-fat diet groups in adulthood. These data indicate a basal shift in the expression of this cytokine.
It is almost as if being male provides risks every time they bother to look. Oh well. This would seem to be an illustration of ‘long term programming’, what happened during development was more important than what happened afterwards. There were some differences found in the transfat group compared to the saturated fat group, primarily observed in differences in neural and peripheral response to LPS; the authors theorize that this is related to the deposition locations of the different kinds of fats; i.e., saturated fats make it into the brain more easily than trans fats, which are stored in the liver (where they measured perfipheral inflammation).
We explored the influence of a trans-fat-rich vs. saturated-fat-rich diet independently in this study. This comparison yielded surprising findings as well, as the SFD appeared to be much more deleterious for body weight, leptin, and IL-1 compared to the TFD, especially in males. Conversely, CRP expression in the liver, a reliable risk factor for heart disease in humans, was significantly increased in the TFD groups following LPS compared to the SFD and LFD groups. It should be noted, however, that the dams consumed less of the TFD than of the SFD, suggesting it may have been less palatable, and therefore, induced fewer changes. Furthermore, the role of CRP as an acute-phase protein in rodents is controversial (52); support for this idea is the lack of increase in response to LPS in every diet group. Thus, the role of CRP in this experimental model, if any, remains to be further explored.
Remarkably, the authors found that low fat diet rats performed better in some tasks, and the authors speculate that a high fat diet may produce some cognitive gains.
A very intriguing possibility as well is that increased basal IL-1 in the high-fat-diet groups facilitated cognition. A growing body of evidence suggests a role for IL-1 in normal, nonpathological, synaptic plasticity mechanisms within the brain, including memory (44). IL-1 is critical for long-term potentiation (LTP) maintenance during learning (45, 46). However, exaggerated IL-1 within the brain is also strongly associated with memory impairment, providing support for an inverted-U function for optimal IL-1 and cognition(46, 47).
The inveterd U function is, I believe, similar to the concept of hormesis, wherein exposure to an agent and physiological response does not necessarily follow a straight linear response. A good example of this that may be the Pessah studies, which found that for some types of PCBs, low level exposure caused more problems than high levels of exposure. [Note: Beware of anyone who wants to use the ‘poison is in the dose’ cannard, which might be meaningful if the measurement endpoints are mortality, but increasingly less worthwhile if you want to measure subtle effects.]
Here is the closing paragraph:
In closing, it is clear that maternal high-fat diet has a profound influence on the innate immune response of the offspring, in both the periphery and the brain, and that this has enduring consequences for cognition and affect in both males and females. Future studies are needed to assess whether peripheral signals such as leptin vs. central targets such as microglia may be driving the responses in brain, and whether immune targeting (e.g., TLR4 signaling) may be sufficient to prevent exaggerated CNS inflammation in high-fatdiet-exposed pups.
Great idea at the end! I’d love to see a paper where they replicated these groups, but one group of rats also got fish oil or other anti-inflammatories to see if the effect of the inflammation was attenuated. TLR4 knockout mice might also be neat to see. This is a cool study that tells us just how much we still have to learn about how our choices can have very difficult to predict effects.
One of the authors of this paper, Staci Bilbo, has been on a bit of a tear lately regarding the effect of early life immune challenges and subsequent immune and behavioral differences in the treatment animals, including recent hits like Early-life infection is a vulnerability factor for aging-related glial alterations and cognitive decline, Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain, and Early-life programming of later-life brain and behavior: a critical role for the immune system, all of which may have implications for everyone’s favorite environmental agent. I’ll be tackling those papers, and several others that have come out with similar methodologies soon enough, but the entire Frontline debacle has left me a little exhausted on the issue.
– pD