Microglia, Sex and Autism: The Stress Perspective

At IMFAR this year it sounded as if there were some outstanding presentations about the involvement of microglia in autism. Microglia were once thought to be merely the “glue” that kept neurons together. We now know that they are rather complex communication network for neurons.  They are the first line defense of our immune reactions and one of our most primitive abilities to respond and adapt to stress.

What’s really cool about microglia are that they are also very plastic. They can adjust quite rapidly to accommodate environmental changes or our own resource needs (wiki).  Microglia also have phenotypes, meaning they have a distinct character of actions and reactions based on the needs of the larger organisms (us) and their experience with us. This may suggest that microglia networks have distinct personality types. Which may also suggest, consistent with the “Theory of Peripheral Minds”, that our microglia personality may also reflect our own personality. A Personality-Immune connection has been suggested for quite some time and is demonstrable in both human (HowardD’Acquisto, Capitanio) and animal studies (Jacques-Hamilton, Wolf)

This new study described by Donna Werling at IMFAR, as described here on Spectrum News by Jessica Wright, discusses microglia as a reason for the difference in autism expression in males and females. Males in the study have a higher number and greater immune reactivity and are therefore more susceptible to autism perturbations in neonatal development.

Jessica Wright in article “Brain’s immune cells may explain sex bias in autism“:

A boost in the activity of microglia, the brain’s immune cells, during gestation may predispose boys to autism. The unpublished results were presented yesterday at the 2017 International Meeting for Autism Research in San Francisco, California.

Roughly four times as many boys as girls are diagnosed with autism. This may be because girls are somehow protected from autism — a popular theory — or because boys are predisposed to it.

Although the exact mechanism is still unclear, the new data suggest one way that male brains may become more susceptible to autism, says Donna Werling, who presented the findings. Werling is a postdoctoral associate in Stephan Sanders’ lab at the University of California, San Francisco.

A subset of genes in microglia are expressed at higher levels in male brains than in female brains during mid-fetal development, the researchers found. This is thought to be a key developmental period in autism.

For far too long fields of science have not talked to one another.  Each was its own speciality and stayed within their own field. Today we are challenging that dogma and universities across the globe are implementing multi-disciplinary approaches to disease modelling. Because as we know, diseases cross over from immunology, to neurology, from digestion to cognition. These aren’t separated as we long assumed.

The study of microglia is a large part of breaking down that barrier. Microglia communication is a large discovery shedding light on how all of these different systems speak and adjust to each other. It may also give us greater insight into a “Stress Perspective of Autism” or vice versa, a stress perspective can give us insight into how microglia activation creates the autism spectrum. Since male and female stress susceptibility has been known for a long time in stress research.

And we also know from personality research that our temperaments and personalities could be starting points for understanding how we handle stress differently.

A stress perspective and the theory of peripheral minds could suggest autism as an early life stress adaptation that leads to the various symptoms and spectrum of autism.

Word and Pattern Thinking to replace Male to Female Susceptibility

—->What are Pattern and Word Thinkers?: Definition by Temple Grandin

Men typically have more diversity when it comes to personalities than women (Yanna). Women tend to have a higher ratio of socially-oriented or Word-Thinking brains. We also know from stress studies that timing matters. Susceptibility to stress, males are more susceptible to stress during the third trimester of pregnancy (but this doesn’t mean they are always more susceptible, nor that this is the only time this could happen). This study shows us the role microglia may play in this cross-talk of stress to behavior modification by the immune cells in the brain.

If microglia turn out to be the key to male prevalence in autism, microglia could be representing merely a more common cognitive-type in males.  This testosterone temperament could represent Pattern-Thinkers on the spectrum. This would be a subtle but significant shift.

From stress and personality research, what we know is that “male and female” brains are likely an arbitrary construct (males can have female brains and vice versa) . This would be a HUGE shift in our understanding of “sex-related disorders”.  If we changed this simple idea that brains can be intersexed; males can have female brains and females can have male brains we change the conversation about susceptibility. Instead of a disease susceptibility by Gender,  the susceptibility would be first by Cognitive-Type (or Temperament described by Helen Fisher).  And if a cognitive-type creates the susceptibility which could then interact with the sex, we would not lead with sex susceptibility (which we are currently doing).

This is why a Stress Perspective Approach is so important. If we just say “males are more susceptible” to autism, we miss all the variations in both males and females and why, when, where and how they are imposed upon by stress. (‘Stress’ may be defined as any situation which tends to disturb the equilibrium between a living organism and its environment. A ‘stress response’ aimed at promoting adaptation and improving survival (Musazzi)). From this stress perspective we see the variation of outcomes on the autism spectrum; males, females and everything beyond and in-between that we observe.

Currently the axis in which we split differences is between Man vs Woman. However, because of personality disparity between men and women, the question remains if a better split for susceptibility would be between Pattern vs Word Thinkers.

While research on personality theory and the battle of the sexes is far from over. What we do know is that the consensus view on such topics needs to be re-evaluated.  There are aspects of the male vs female that present differently in autism. But the big split, the major split of opposites, wouldn’t be the line of Male/Female.  A better split, from a stress perspective, would be that of Pattern/WordPattern Thinkers (Asperger’s) present differently in men and women.  And Word Thinkers too present differently in men and women. For Patter Thinkers (Asperger’s or high functioning autism) women are slightly less severely impacted.  Their symptoms are more hidden than in their male counterparts. One reason why autism is so often misdiagnosed  or we miss the diagnosis in females. And for Word Thinkers (Classic Autism), females are actually found to be more severely impacted.  This could have to do with relationship of estrogen and brain function/protection (Gillies).  So men and women aren’t so much different as their presentation in the opposite sides of the spectrum– Pattern vs Word Thinkers.

A stress perspective, a Theory of Peripheral Minds perspective, helps makes sense of these contradictions. Because we currently split the difference between boys/girls which doesn’t completely makes sense, when we should be splitting the difference between pattern/word and then boys/girls. When we see it from a stress perspective the data, numbers and patterns make more sense.

For the purposes here on this site, these studies are exciting.  I strongly believe we need to remove the “male” label and replace it with “Pattern Thinkers” (testosterone brain and temperament) and males themselves can present with any thinking type on the spectrum.  If we can remove the assumption that this is a male disorder and rather that it is a disorder on Peripheral Minds, then we can more clearly see that when they have an early or before life stress adaptation, this creates the disorders we know as autism spectrum condition and disorders.



REFERENCES for Microglia, Stress, Adaptations, Sex and Personality:

Brain’s immune cells may explain sex bias in autism. by Jessica Wright  /  11 May 2017

Autism—It’s Different in Girls: New research suggests the disorder often looks different in females, many of whom are being misdiagnosed and missing out on the support they need. By Maia Szalavitz on March 1, 2016 أعرض هذا باللغة العربيةhttps://www.scientificamerican.com/article/autism-it-s-different-in-girls/

Gender Differences in Personality across the Ten Aspects of the Big Five. Frontiers in Psychology. 2011;2:178. Weisberg YJ, DeYoung CG, Hirsh JB. doi:10.3389/fpsyg.2011.00178. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149680/

The Link Between Personality and Immunity
Eric Jaffe https://www.psychologicalscience.org/observer/the-link-between-personality-and-immunity#.WT_J_saQzIV

A system in our body might actually be what controls our personality
Fiona MacDonald Jul. 22, 2016, 12:34 PM Researchers have shown that by switching off just one immune molecule in mice, they can change the way the animals behave and interact with each other – which suggests the immune system may play a role in conditions such as autism-spectrum disorder or schizophrenia. LINK


Are microglia minding us? Digging up the unconscious mind-brain relationship from a neuropsychoanalytic approach

Functions of microglia in the central nervous system–beyond the immune response.
Wake H1, Moorhouse AJ, Nabekura J.Neuron Glia Biol. 2011 Feb;7(1):47-53. doi: 10.1017/S1740925X12000063. Epub 2012 May 22. LINK

Sex differences in microglial appetites during development: Inferences and implications. Staci D. Bilbo

“Most if not all neurological disorders exhibit some degree of sex bias in their incidence, presentation, or pathologic progression. For instance, autism spectrum disorder (ASD), learning disabilities, attention deficit disorder, and early-onset schizophrenia are more common in males, whereas depression, anxiety, anorexia, and Alzheimer’s disease are more common in females. At first glance the clustering of disorders within each sex appear to have little in common; however, upon closer inspection it is clear they segregate by timing – that is, disorders that emerge early in life are more common in males, whereas disorders that emerge later in life (at adolescence or beyond) are more common in females. This pattern is a compelling clue into the origin and pathophysiology of neurological disorders that has been relatively ignored in scientific research and in clinical practice. We ignore this clue at our peril, given that in heterogeneous disorders such as ASD, the sex of the individual is perhaps the most predictive variable of all, which strongly suggests the sex of an individual is critical in the neurobiology underlying the disorder.” (LINK)

A starring role for microglia in brain sex differences.
Lenz KM1, McCarthy MM2. Neuroscientist. 2015 Jun;21(3):306-21. doi: 10.1177/1073858414536468. Epub 2014 May 28. https://www.ncbi.nlm.nih.gov/pubmed/24871624

Minocycline Modulates Human Social Decision-Making: Possible Impact of Microglia on Personality-Oriented Social Behaviors. Takahiro A. Kato et al. 2012 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040461


Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease. Deak T, Quinn M, Cidlowski JA, Victoria NC, Murphy AZ, Sheridan JF. Stress (Amsterdam, Netherlands). 2015;18(4):367-380. doi:10.3109/10253890.2015.1053451. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813310/

Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult CNS in male and female mice.Crain JM, Nikodemova M, Watters JJ. Journal of neuroscience research. 2013;91(9):1143-1151. doi:10.1002/jnr.23242. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715560/

In conclusion, age- and sex-specific variances in basal gene expression may enable differential microglial responses to the same stimulus at different ages, perhaps contributing to altered CNS vulnerabilities and/or disease courses.

Microglial activation in young adults with autism spectrum disorder.
Suzuki K1. JAMA Psychiatry. 2013 Jan;70(1):49-58. doi: 10.1001/jamapsychiatry.2013.272. LINK

Our results indicate excessive microglial activation in multiple brain regions in young adult subjects with ASD. The similar distribution pattern of regional microglial activity in the ASD and control groups may indicate augmented but not altered microglial activation in the brain in the subjects with ASD.

A Non-inflammatory Role for Microglia in Autism Spectrum Disorders. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734207/

Affective immunology: where emotions and the immune response converge. D’Acquisto F. Dialogues in Clinical Neuroscience. 2017;19(1):9-19. LINK

Sex differences in microglial appetites during development: Inferences and implications. Staci D. Bilbo. Lurie Center for Autism, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, United States.Brain, Behavior, and Immunity 12 May 2017 http://www.sciencedirect.com/science/article/pii/S0889159117301563

Personality, coping style, and constitutional neuroimmunology. Zozulya AA1, Gabaeva MV, Sokolov OY, Surkina ID, Kost NV. J Immunotoxicol. 2008 Apr;5(2):221-5. doi: 10.1080/15476910802131444. (LINK)

Molecules in pain and sex: a developing story. https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-017-0289-8 Front. Synaptic Neurosci., 10 May 2017 | https://doi.org/10.3389/fnsyn.2017.00009

Function and Dysfunction of Microglia during Brain Development: Consequences for Synapses and Neural Circuits.  Rosa C. Paolicelli1,2*† and Maria T. Ferretti1,2*† http://journal.frontiersin.org/article/10.3389/fnsyn.2017.00009/full

Many diverse factors, ranging from stress to infections, can perturb brain homeostasis and alter the physiological activity of microglia, the immune cells of the central nervous system. Microglia play critical roles in the process of synaptic maturation and brain wiring during development. Any perturbation affecting microglial physiological function during critical developmental periods could result in defective maturation of synaptic circuits. In this review, we critically appraise the recent literature on the alterations of microglial activity induced by environmental and genetic factors occurring at pre- and early post-natal stages. Furthermore, we discuss the long-lasting consequences of early-life microglial perturbation on synaptic function and on vulnerability to neurodevelopmental and psychiatric disorders.

Acute and Chronic Stress-Induced Disturbances of Microglial Plasticity, Phenotype and Function.  Walkera FR, Nilsson M, Jones K. Current Drug Targets. 2013;14:1262-1276. doi:10.2174/13894501113149990208. LINK

Traditionally, microglia have been considered to act as macrophages of the central nervous system. While this concept still remains true it is also becoming increasingly apparent that microglia are involved in a host of non-immunological activities, such as monitoring synaptic function and maintaining synaptic integrity. It has also become apparent that microglia are exquisitely sensitive to perturbation by environmental challenges. The aim of the current review is to critically examine the now substantial literature that has developed around the ability of acute, sub-chronic and chronic stressors to alter microglial structure and function. The vast majority of studies have demonstrated that stress promotes significant structural remodelling of microglia, and can enhance the release of pro-inflammatory cytokines from microglia. Mechanistically, many of these effects appear to be driven by traditional stress-linked signalling molecules, namely corticosterone and norepinephrine. The specific effects of these signalling molecules are, however, complex as they can exert both inhibitory and suppressive effects on microglia depending upon the duration and intensity of exposure. Importantly, research has now shown that these stress-induced microglial alterations, rather than being epiphenomena, have broader behavioural implications, with the available evidence implicating microglia in directly regulating certain aspects of cognitive function and emotional regulation.

Responses of glial cells to stress and glucocorticoids

NeuroWiki: Sexual Dimorphism http://neurowiki2013.wikidot.com/individual:sexual-dimorphisms#toc6

Sex Differences in the Brain: The Scientist How male and female brains diverge is a hotly debated topic, but the study of model organisms points to differences that cannot be ignored. By Margaret M. McCarthy | October 1, 2015 http://www.the-scientist.com/?articles.view/articleNo/44096/title/Sex-Differences-in-the-Brain/

Your Brain Is a Mosaic of Male and Female. By Stephanie Pappas, Live Science Contributor | December 1, 2015 07:47am E http://www.livescience.com/52941-brain-is-mix-male-and-female.html

There is no such thing as a “male brain” or a “female brain,” new research finds. Instead, men and women’s brains are an unpredictable mishmash of malelike and femalelike features, the study concludes. Even in brain regions previously thought to show differences based on sex, variability is more common than consistency. “Our study demonstrates that although there are sex/gender differences in brain structure, brains do not fall into two classes, one typical of males and the other typical of females, nor are they aligned along a ‘male brain–female brain’ continuum,” the study researchers wrote today (Nov. 30) in the journal Proceedings of the National Academy of Sciences. “Rather, even when considering only the small group of brain features that show the largest sex/gender differences, each brain is a unique mosaic of features, some of which may be more common in females compared with males, others may be more common in males compared with females, and still others may be common in both females and males.” [10 Surprising Facts About a Woman’s Brain]

Hormones, Sexual Dimorphism, and the Brain—A Primer by Kayt Sukel. February 1, 2012 http://dana.org/News/Details.aspx?id=43520

Sexually dimorphic stress and pro-inflammatory cytokine responses to an intravenous corticotropin-releasing hormone challenge of Brahman cattle following transportation.Lindsey E Hulbert, Jeffery A Carroll, Michael A Ballou, Nicole C Burdick, Jeffery W Dailey, Lisa C Caldwell, Andrea N Loyd, Rhonda C Vann, Thomas H Welsh, Ronald D Randel http://journals.sagepub.com/doi/abs/10.1177/1753425912462752

Sexually dimorphic neuronal responses to social isolation. Laura Senst Dinara Baimoukhametova Toni-Lee Sterley Jaideep Singh Bains University of Calgary, CanadaDOI: http://dx.doi.org/10.7554/eLife.18726 eLife 2016;5:e18726 https://elifesciences.org/content/5/e18726

Sexual dimorphism in the mast cell transcriptome and the pathophysiological responses to immunological and psychological stress. Emily Mackey, Saravanan Ayyadurai, Calvin S. Pohl, Susan D’ Costa, Yihang Li and Adam J. Moeser Biology of Sex Differences20167:60DOI: 10.1186/s13293-016-0113-7

Corazonin Neurons Function in Sexually Dimorphic Circuitry That Shape Behavioral Responses to Stress in Drosophila. Yan Zhao, Colin A. Bretz, Shane A. Hawksworth, Jay Hirsh, Erik C. Johnson. PLOS. February 10, 2010    https://doi.org/10.1371/journal.pone.0009141

Sex differences in microglial colonization of the developing rat brain. Schwarz JM, Sholar PW, Bilbo SD. Journal of Neurochemistry. 2012;120(6):948-963. doi:10.1111/j.1471-4159.2011.07630.x. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296888/

Differential Effects of Stress on Microglial Cell Activation in Male and Female Medial Prefrontal Cortex. Bollinger JL, Bergeon Burns CM, Wellman CL.  Brain, behavior, and immunity. 2016;52:88-97. doi:10.1016/j.bbi.2015.10.003. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909118/

Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease. Deak T, Quinn M, Cidlowski JA, Victoria NC, Murphy AZ, Sheridan JF. Stress (Amsterdam, Netherlands). 2015;18(4):367-380. doi:10.3109/10253890.2015https://www.ncbi.nlm.nih.gov/pubmed/27240659.1053451. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813310/

Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice Mauricio D. Dorfman, Jordan E. Krull, John D. Douglass, Nature Communications 8, Article number: 14556 (2017) doi:10.1038/ncomms14556 https://www.nature.com/articles/ncomms14556

Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. https://www.nature.com/articles/ncomms10717

This suggests that it is not sex-differential regulation of ASD risk genes, but rather naturally occurring sexually dimorphic processes, potentially including neuron–glial interactions, that modulate the impact of risk variants and contribute to the sex-skewed prevalence of ASD.

Prenatal stress programs neuroendocrine stress responses and affective behaviors in second generation rats in a sex-dependent manner. Grundwald NJ, Brunton PJ. Psychoneuroendocrinology. 2015;62:204-216. doi:10.1016/j.psyneuen.2015.08.010.  LINK

Individual differences in the effects of prenatal stress exposure in rodents. https://psychology.as.uky.edu/individual-differences-immunity-and-cancer-lessons-personality-psychology

Meta-analysis reveals a lack of sexual dimorphism in human amygdala volume. Dhruv Marwha, Meha Halari, Lise Eliot. NeuroImage, 2017; 147: 282 DOI: 10.1016/j.neuroimage.2016.12.021

Study finds differences in male, female brain activity when it comes to cooperation https://med.stanford.edu/news/all-news/2016/06/brain-activity-during-cooperation-differs-by-sex.html

Do Men Vary More than Women in Personality? A Study in 51 Cultures. Borkenau P, McCrae RR, Terracciano A. Journal of research in personality. 2013;47(2):135-144. doi:10.1016/j.jrp.2012.12.001. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612964/

Do Men and Women Really have Different Personalities. By Christian JarrettBBC Psychology 12 October 2016 http://www.bbc.com/future/story/20161011-do-men-and-women-really-have-different-personalities

Sex Differences in the Brain: The Estrogen Quandary
The Estrogen Quandary. by Brenda PatoineJanuary, 2005 LINK

Gender differences in personality across the ten aspects of the Big Five.  Yanna J. Weisberg1, Colin G. DeYoung2* and Jacob B. Hirsh3 Front. Psychol., 01 August 2011 | https://doi.org/10.3389/fpsyg.2011.00178 http://journal.frontiersin.org/article/10.3389/fpsyg.2011.00178/full

The Gender Similarities Hypothesis. Hyde, Janet Shibley American Psychologist, Vol 60(6), Sep 2005, 581-592. http://dx.doi.org/10.1037/0003-066X.60.6.581 http://psycnet.apa.org/psycinfo/2005-11115-001

The Distance Between Mars and Venus: Measuring Global Sex Differences in Personality. Marco Del Giudice ,Tom Booth, Paul Irwing PLOS Published: January 4, 2012 https://doi.org/10.1371/journal.pone.0029265


How age, sex and genotype shape the stress response Ashley Novais et al.  Neurobiology of Stress,Volume 6, February 2017, Pages 44–56 http://www.sciencedirect.com/science/article/pii/S2352289516300303

Gender differences in stress response: Role of developmental and biological determinants.Verma R, Balhara YPS, Gupta CS. Industrial Psychiatry Journal. 2011;20(1):4-10. doi:10.4103/0972-6748.98407. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425245/ Stress response is associated with manifestations of various psychosomatic and psychiatric disorders. Hence, it is important to understand the underlying mechanisms that influence this association. Moreover, men and women tend to react differently with stress–both psychologically and biologically.

Incorporating Sex As a Biological Variable in Neuropsychiatric Research: Where Are We Now and Where Should We Be? Joel D1, McCarthy MM2. Neuropsychopharmacology. 2017 Jan;42(2):379-385. doi: 10.1038/npp.2016.79. Epub 2016 https://www.ncbi.nlm.nih.gov/pubmed/27240659

Developmental neurogenetics and multimodal neuroimaging of sex differences in autism. Chen C1, Van Horn JD2; GENDAAR Research Consortium. Brain Imaging Behav. 2017 Feb;11(1):38-61. doi: 10.1007/s11682-015-9504-3.  https://www.ncbi.nlm.nih.gov/pubmed/26781567

Differential Susceptibility to Environmental Influences. Belsky, J. ICEP (2013) 7: 15. doi:10.1007/2288-6729-7-2-15 http://link.springer.com/article/10.1007/2288-6729-7-2-15

Estrogens regulate neuroinflammatory genes via estrogen receptors α and β in the frontal cortex of middle-aged female rats. Miklós Sárvári et al. Journal of Neuroinflammation20118:82 DOI: 10.1186/1742-2094-8-82


Germs, Fats and Sunlight

An enhanced susceptibility from our environment because of crucial missing stress foundation resources. This is evidence for the larger part of the Stress Theoretical Model that linear decisions that get rid of “stressors” instead of a systematic approach of making us more resilient created a more stressful environment for us. Hence a constant connection of these three factors with model of stress adaptation disorders.

Communicating systems in the body: how microbiota and microglia cooperate. Erny D1, Hrabě de Angelis AL1, Prinz M1Immunology. 2017 Jan;150(1):7-15. doi: 10.1111/imm.12645. Epub 2016 Aug 24.

Host microbiota constantly control maturation and function of microglia in the CNS. Erny D1, Hrabě de Angelis AL1, Jaitin D2, Nat Neurosci. 2015 Jul;18(7):965-77. doi: 10.1038/nn.4030. Epub 2015 Jun 1. LINK

The microbiome: A key regulator of stress and neuroinflammation
Kieran Rea. et al. https://doi.org/10.1016/j.ynstr.2016.03.001

There is a growing emphasis on the relationship between the complexity and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiota) and health/disease, including brain health and disorders of the central nervous system. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the brain, glands, gut, immune cells and gastrointestinal microbiota that communicate in a complex multidirectional manner to maintain homeostasis. Changes in this environment can lead to a broad spectrum of physiological and behavioural effects including hypothalamic-pituitary-adrenal (HPA) axis activation, and altered activity of neurotransmitter systems and immune function. While an appropriate, co-ordinated physiological response, such as an immune or stress response are necessary for survival, a dysfunctional response can be detrimental to the host contributing to the development of a number of CNS disorders.

Host microbiota constantly control maturation and function of microglia in the CNS. http://www.nature.com/neuro/journal/v18/n7/full/nn.4030.html

As the tissue macrophages of the CNS, microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. We observed substantial contributions of the host microbiota to microglia homeostasis, as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype, leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings suggest that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be rectified to some extent by complex microbiota.

Vitamin D Deficiency Reduces the Immune Response, Phagocytosis Rate, and Intracellular Killing Rate of Microglial Cells. Bäumler AJ, Djukic M, Onken ML, Schütze S, et al. ed. Infection and Immunity. 2014;82(6):2585-2594. doi:10.1128/IAI.01814-14. LINK

Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism. Boontanrart M1, Hall SD1, Spanier JA2 J Neuroimmunol. 2016 Mar 15;292:126-36. doi: 10.1016/j.jneuroim.2016.01.015. Epub 2016 Jan 27. LINK

Vitamin-D Deficiency As a Potential Environmental Risk Factor in Multiple Sclerosis, Schizophrenia, and Autism. Kočovská E1, Gaughran F2, Krivoy A2, Meier UC3 Front Psychiatry. 2017 Mar 27;8:47. doi: 10.3389/fpsyt.2017.00047. eCollection 2017. LINK

Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function. Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK. Cell reports. 2014;9(6):2124-2138. doi:10.1016/j.celrep.2014.11.018. LINK

Sexually dimorphic brain fatty acid composition in low and high fat diet-fed mice

Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms. Bolton JL, Bilbo SD. Dialogues in Clinical Neuroscience. 2014;16(3):307-320. LINK

Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity. Shuai Hao, Aditi Dey, Xiaolin Yu, Alexis M. Stranahan. Brain, Behavior, and Immunity, 2015; DOI: 10.1016/j.bbi.2015.08.023

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