Djani_Sci_Vet_Med_Presentation_10_8_15
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Djani_Sci_Vet_Med_Presentation_10_8_15
- 1. Dylan M. Djani Mentor: Nikolay M. Filipov Department of Physiology and Pharmacology College of Veterinary Medicine University of Georgia
- 2. Presentation Outline • Obesity and Autism Spectrum Disorder (ASD) – Prevalence, key features • ASD Etiology – Maternal environment • Early Brain Monoamines – Our Experiment What are monoamines? (Bear et. al., 2015)
- 3. Obesity Trends in the U.S. National Health and Nutrition Examination Survey (NHANES) • Obesity Prevalence in U.S. Adults ≥ 25 years [2007 – 2012] – Men: 35.04% Data published June 22, 2015 (Yang and Colditz, 2015) – Women: 36.84% Prevalence consistently high [2003 – 2010] Data published February 26, 2014 (Ogden et. al., 2014) Obesity – chronic inflammatory condition: risk mortality, physical, emotional, and mental conditions OVER 1 in 3 AMERICANS Regardless of sex or race (Monteiro and Azevedo, 2010; Nijhuis et. al., 2009)
- 4. Maternal Obesity Adversely Impacts Offspring Rivera et. al., 2015 BMI: Body mass index GWG: Gestational weight gain HFD: High-fat diet Rivera et. al., 2015 Human research studies Animal model research studies Increased risk in offspring for: • ASD • Anxiety/Depression • Schizophrenia
- 5. Maternal Obesity Trends in the U.S. Schlaff et. al., 2014 *Gestational weight gain; 1Archive for Research on Child Health Overweight and obese women are more likely to gain excess weight during pregnancy. Over 50% women gained excess weight during gestation. (2009 Institute of Medicine)
- 6. Maternal Obesity in the Perinatal Period Maternal obesity (Rivera et. al., 2015; Sullivan et. al., 2015; Mehta et. al., 2014; Bolton and Bilbo, 2014) Immunologic dysregulation Altered placental function Maternal circulation Pro-inflammatory cytokines Glucose and triglycerides Hormones (i.e. leptin) Serotonin (5-HT) Altered fetal exposure during perinatal period Altered brain connectivity and neurotransmitter systems Epigenetic, metabolic, neurobehavioral programming
- 7. Autism-Spectrum Disorder: Overview DSM-V: Neurodevelopmental Disorder Early onset and lifelong impact (APA, 2013) Core symptoms: deficits in communication, social interaction, behavior http://www.autismspeaks.org/ Last updated January 6, 2015 Prevalence Facts: *1 in 68 children in the U.S. *Male bias (M/F Sex Ratio 4:1) *Positive correlation with obesity 123% increase in ASD prevalence since 2002. Analysis of 2010 data; published in 2014; studies ongoing (ADDM) CDC Autism and Developmental Disabilities Monitoring Network
- 8. Key Features: ASD Comorbidities Chen et. al., 2015 Zerbo et. al., 2015 Increased odds ratios for psychiatric and immune-mediated comorbidities.
- 9. Synaptic dysregulation leads to altered brain connectivity. Gastrointestinal and innate immune alterations – pro-inflammatory. GENETICS: h2 = 52% (common variation ~48.4%) Neuroimmunologic Cell Adhesion Cellular Function EPIGENETICS: Environmental factors impact epigenetic load in utero. ENVIRONMENT: Prenatal, perinatal, postnatal factors. Environmental toxicants. Maternal infection/inflammation, maternal obesity. Etiological Insights into ASD Animal Models & Epidemiological Studies: Key Findings (Banerjee et. al., 2014; Kana et. al., 2014; Hahamy et. al., 2015; Jaiswal et. al., 2015; Gaugler et. al., 2014; Loki et. al., 2015; Tamashiro and Moran, 2010)
- 10. Monoaminergic Involvement in ASD: Serotonin Jaiswal et. al., 2015 Neuroimmunologic dysregulation in ASD involves serotonin.
- 11. Monoaminergic Involvement in ASD Dopaminergic System Noradrenergic System ASD Psychiatric comorbidities Cross-talk between DA and NE Brainstem (VTA, LC) Dorsal hippocampus (Hara et. al., 2015; Kriete and Noelle, 2015) (Jellinger, 2011; Guiard et. al., 2008) Prefrontal Cortex Valproic-acid mouse model: PND21 Computerized developmental modeling Rivera et. al., 2015
- 12. Experimental Objectives Evaluate the effects of maternal obesity and sex on monoamine systems in the early post-natal life of mice. (post-natal day 10 [PND10]) Hypothesis Significant neurochemical differences will be observed in selected brain regions of post-natal day 10 mice due to maternal high fat diet and sex.
- 13. Comparative Mammalian Neurodevelopment “Translating Time” Why PND10? Assumptions: Mouse gestation length: 18.5 days Human gestation length: 270 days (~38.5 weeks) (Workman et. al., 2013) Including synaptogenesis! Mouse PND10 equivalent to late third trimester in terms of neurodevelopment.
- 14. Critical Windows – Why Post-Natal Day 10? Significantly increased rates of AXONAL GROWTH and SYNAPTOGENESIS during the late third trimester of human gestation. Vertes and Bullmore, 2015 Critical window for cortical wiring of neuronal circuitries and neurotransmitter systems. Added benefit: offspring nutritional source is maternal lactation.
- 15. Experimental Design and Timeline Brain Collection: PND10 N = 7; 1m/1f per group Brain Region Collection: 500 μm coronal sectioning; dry ice Regional micropunches obtained Animals: C57BL/6 female mice, 6-7 weeks Assigned Diet*: High fat: 60% kcal from fat HFD Low fat: 10% kcal from fat LFD PND = post-natal day; *Diets balanced for simple sugars and micronutrients. *Assigned diets maintained throughout weaning (PND21). WEEK 0 Maternal diets assigned WEEK 6 Mating with control males. PND 0 Pups born. PND 10 Pups selected for brain collection. Brain region collection Neurochemical analysis
- 16. Materials and Methods Monoamine and Metabolite Analytes: Dopaminergic System: DA, DOPAC, HVA, 3-MT Serotonergic System: 5-HT, 5-HIAA Noradrenergic System: NE, MHPG Brain regions collected: Prefrontal cortex (PFC) Striatum (STR) Dorsal Hippocampus (dHIPP) Ventral Hippocampus (vHIPP) Cerebellum (CER) Neurochemical Analysis: HPLC-ECD + Bradford Assay Data normalized per mg protein prior to statistical analysis Data Processing and Presentation: Performed with Microsoft Excel, SigmaPlot, GraphPad Prism 5 software
- 17. Sex-independent dopaminergic dysregulation Dopaminergic dysregulation. Possible behavioral consequences (i.e. hyperactivity). *Statistically significant main effect of diet. aStatistically significant effect of diet within females. #Statistical trend for main effect of diet. ^Statistical trend for effect of diet within females. Prefrontal Cortex: Dopamine LFD H FD LFD H FD 0.0 0.1 0.2 0.3 0.4 Males Females DA(ng/mgprotein) * a Dorsal Hippocampus: Dopamine LFD H FD LFD H FD 0.000 0.125 0.250 0.375 0.500 Males FemalesDA(ng/mgprotein) * ^ LFD HFD Ventral Hippocampus: Dopamine LFD H FD LFD H FD 0.00 0.75 1.50 2.25 3.00 Males Females DA(ng/mgprotein) * ^ Ventral Hippocampus: DOPAC LFD H FD LFD H FD 0.0 0.5 1.0 1.5 2.0 Males Females DOPAC(ng/mgprotein) #
- 18. Female-restricted serotonergic dysregulation Serotonergic dysregulation (female-restricted) Possible communication or social interaction deficits. *Statistically significant main effect of sex. aStatistically significant effect of diet within females. #Statistical trend for main effect of diet. ^Statistical trend for effect of diet within females. Prefrontal Cortex: 5-HT LFD H FD LFD H FD 0.000 0.375 0.750 1.125 1.500 Males Females 5-HT(ng/mgprotein) ^ * Prefrontal Cortex: 5-HIAA LFD H FD LFD H FD 0.0 0.5 1.0 1.5 2.0 Males Females 5-HIAA(ng/mgprotein) ^ Ventral Hippocampus: 5-HT LFD H FD LFD H FD 0 2 4 6 8 Males Females 5-HT(ng/mgprotein) a Cerebellum: 5-HT LFD H FD LFD H FD0 2 4 6 8 Males Females 5-HT(ng/mgprotein) * ^ LFD HFD
- 19. Sex-specific noradrenergic differences *Statistically significant main effect of sex. #Statistical trend for main effect of sex. Prefrontal Cortex: NE LFD H FD LFD H FD 0.0 0.5 1.0 1.5 2.0 Males Females NE(ng/mgprotein) # Cerebellum: NE LFD H FD LFD H FD 0 2 4 6 8 Males Females NE(ng/mgprotein) * Dorsal Hippocampus: NE LFD H FD LFD H FD 0.0 0.5 1.0 1.5 2.0 2.5 Males Females NE(ng/mgprotein) * Ventral Hippocampus: NE LFD H FD LFD H FD 0 1 2 3 Males Females NE(ng/mgprotein) * Female: NE PFC, vHIPP, CER NE dHIPP Positive correlation between female-restricted maternal HFD effects on 5-HT and female- specific NE differences.
- 20. Conclusion Maternal HFD disrupts monoamine systems at PND10 in mice in a sex-specific manner, consistent with altered brain neurochemistry and connectivity. Data suggests maternal HFD may put offspring on a trajectory towards ASD. Future Research: Monoamine turnover rate analysis via NT/metabolite ratios. Biomarker analysis of dopaminergic dysfunction in PFC, dHIPP, vHIPP Western Blot + qPCR (qPCR samples obtained for HIPP) Integration with neurochemical data at other time points. Integration with behavioral data and immunologic assessment.
- 21. General and Funding Acknowledgements Department of Physiology and Pharmacology Saritha Krishna John J. Wagner Sadie E. Nennig Nikolay M. Filipov Department of Infectious Diseases Donald A. Harn Department of Foods and Nutrition Claire B. de La Serre Miscellaneous Annika Carter The project described was supported by Grant Number 05 T35 OD010433-09 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Funding was also provided by through a grant from the University of Georgia’s Obesity Initiative (http://obesity.ovpr.uga.edu).
Notes de l'éditeur
- Neurochemical deficits in offspring of dams (mothers) fed high-fat diets. In particular, we will focus on the effects on brain monoamines.
- “Biogenic amines” – AA neurotransmitters Synaptic transmission – form brain circuits. Diffuse projections throughout forebrain/striatum Focus on DA, 5-HT, NE M. F. Bear, B. W. Connors, M. A. Paradiso, Neuroscience : exploring the brain. (Lippincott Williams & Wilkins, ed. 4, 2015).
- Chronic inflammatory condition: multifactorial, mechanisms include adipocyte-sourced pro-inflammatory cytokines, involvement of other pro-inflammatory mediators, and cell rupture and ensuing inflammation. Yang L, Colditz GA. Prevalence of overweight and obesity in the united states, 2007-2012. JAMA Internal Medicine. 2015. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the united states, 2011-2012. JAMA. 2014;311(8):806-14. R. Monteiro, I. Azevedo, Chronic Inflammation in Obesity and the Metabolic Syndrome. Mediators of Inflammation 2010, 289645 (2010). J. Nijhuis et al., Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity (Silver Spring) 17, 2014-2018 (2009). Guidelines (2013) for managing overweight and obesity in adults. Preface to the Expert Panel Report (comprehensive version which includes systematic evidence review, evidence statements, and recommendations). Obesity (Silver Spring) 22 Suppl 2, S40 (2014). Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults--The Evidence Report. National Institutes of Health. Obes Res 6 Suppl 2, 51S-209S (1998).
- According to several human and animal model research studies, maternal obesity due to high-fat diet consumption and increased gestational weight gain are both risk factors for neuropsychiatric disease in the offspring, including ASD, anxiety, depression, and schizophrenia. 2015 publication describing neuropsychiatric risk and maternal obesity factors. Increased risk of ASD, anxiety/depression, and schizophrenia were associated with increased gestational weight gain. H. M. Rivera, K. J. Christiansen, E. L. Sullivan, The role of maternal obesity in the risk of neuropsychiatric disorders. Frontiers in Neuroscience 9, 194 (2015).
- This epi study assessed GWG via two methods – the ARCH method was more robust. Obese trend slightly less strong than overweight trend – suggests threshold of sort. 2014 cohort study re: pre-pregnancy BMI, body size, GWG, and physical activity. Data collected 2008-2012 via women participating in ARCH1 study in Michigan. ARCH calculations more robust than birth certificate calculations. Schlaff RA, Holzman C, Maier KS, Pfeiffer KA, Pivarnik JM. Associations among gestational weight gain, physical activity, and pre-pregnancy body size with varying estimates of pre-pregnancy weight. Midwifery. 2014 11//;30(11):1124-31. ARCH = Archive for Research on Child Health – study to collect and store record information re: pregnancy, perinatal urine/blood/placenta samples, etc. Birth certificate information depends on weight from records and hospital variation in such procedures makes it less robust (self-reporting vs. actually weighing etc.) ARCH calculated BMI from information collected systematically (kg weight / m^2 height upon patient reporting) as well as using weight recorded on birth certificates
- Loke YJ, Hannan AJ, Craig JM. The Role of Epigenetic Change in Autism Spectrum Disorders. Frontiers in Neurology. 2015 05/26. 02/28/received. 04/28/accepted;6:107. Tamashiro KL, Moran TH. Perinatal environment and its influences on metabolic programming of offspring. Physiol Behav. 2010 Jul 14;100(5):560-6. Schwartzer JJ, Careaga M, Onore CE, Rushakoff JA, Berman RF, Ashwood P. Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Transl Psychiatry. 2013;3:e240. Mehta SH, Kerver JM, Sokol RJ, Keating DP, Paneth N. The Association between Maternal Obesity and Neurodevelopmental Outcomes of Offspring. The Journal of Pediatrics. 2014 11//;165(5):891-6. Sullivan EL, Riper KM, Lockard R, Valleau JC. Maternal high-fat diet programming of the neuroendocrine system and behavior. Horm Behav. 2015 Apr 24. Bolton JL, Bilbo SD. Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms. Dialogues in Clinical Neuroscience. 2014;16(3):307-20.
- American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ. 2014 Mar 28;63(2):1-21. https://www.autismspeaks.org/science/science-news/can-rise-autism-be-explained-broadened-diagnosis Accessed June 25, 2015.
- Curiously enough, co-morbidities associated with ASD include psychiatric disorders and immune-mediated conditions, as shown by the increased odds ratios in these 2015 studies of ASD populations. Chen M-H, Wei H-T, Chen L-C, et al. Autistic spectrum disorder, attention deficit hyperactivity disorder, and psychiatric comorbidities: A nationwide study. Research in Autism Spectrum Disorders. 2015 2//;10(0):1-6. Zerbo O, Leong A, Barcellos L, Bernal P, Fireman B, Croen LA. Immune mediated conditions in autism spectrum disorders. Brain, Behavior, and Immunity. 2015 5//;46(0):232-6.
- OUR EXPERIMENTAL DESIGN INTENDS TO FOCUS IN ON PERINATAL MONOAMINERGIC EFFECTS OF MATERNAL OBESITY using mice models in a controlled experiment. Tying together information from animal models and epidemiological studies, two key characteristics of autism include altered brain connectivity, ultimately from dysregulation at the level of the synapse, as well as alterations in the innate immune system particularly of a pro-inflammatory nature. Teasing apart etiological factors for ASD involves identifying genetic and environmental contributions, as well as how their interactions contribute to ASD etiology. Here we see the narrow-sense heritability for ASD is estimated around 52%, thus environmental factors and gene-environment interactions play roughly an equally important role in ASD. Furthermore, the largest contribution to this 52% is from common genetic variation in the population, with only ~2.6% coming from rare mutations in genes involved with synaptic regulation, among other fundamental intracellular processes (cytoskeletal function, cell adhesion/growth) The maternal environment, in particular the perinatal intrauterine environment, has emerged as a key environmental factor impacting offspring development and behavior. Furthermore, the role of epigenetics in synaptic and immunologic regulation has also emerged as a key factor through mediating gene-environment interactions. What this means is that an individual’s epigenetic make-up is influenced by the maternal environment and affects neurodevelopment. What about maternal obesity in particular? Genes involved include those that directly and epigenetically regulate several aspects of synaptic homeostasis and immune pathways, as well as other basic intracellular processes. Some studies suggest involvement of genes involved in toxicant excretion from the CNS, though these overlap with immune pathways. (Rusu et. al., 2015; Medzhitov, 2008). C. Rusu, C. Preda, A. Sireteanu, C. Vulpoi, RISK FACTORS IN AUTISM SPECTRUM DISORDERS: THE ROLE OF GENETIC, EPIGENETIC, IMMUNE AND ENVIRONMENTAL INTERACTIONS. Environmental Engineering & Management Journal (EEMJ) 14, 901-917 (2015). R. Medzhitov, Origin and physiological roles of inflammation. Nature 454, 428-435 (2008). Environmental toxicants Disruption of perinatal uterine environment leads to programming of offspring metabolically and neurobehaviorally. Banerjee S, Riordan M, Bhat MA. Genetic aspects of autism spectrum disorders: insights from animal models. Frontiers in Cellular Neuroscience. 2014 02/24. 01/02/received. Kana RK, Uddin LQ, Kenet T, Chugani D, Müller R-A. Brain connectivity in autism. Frontiers in Human Neuroscience. 2014 06/02. 03/05/received. 05/08/accepted;8:349. Hahamy A, Behrmann M, Malach R. The idiosyncratic brain: distortion of spontaneous connectivity patterns in autism spectrum disorder. Nat Neurosci. 2015 02//print;18(2):302-9. Jaiswal P, Mohanakumar KP, Rajamma U. Serotonin mediated immunoregulation and neural functions: Complicity in the aetiology of autism spectrum disorders. Neuroscience & Biobehavioral Reviews. 2015 8//;55(0):413-31. Gaugler T, Klei L, Sanders SJ, et al. Most genetic risk for autism resides with common variation. Nat Genet. 2014 08//print;46(8):881-5. Tamashiro KL, Moran TH. Perinatal environment and its influences on metabolic programming of offspring. Physiol Behav. 2010 Jul 14;100(5):560-6.
- Serotonin is a critical player in coordinating the development of the entire serotonergic system, and how neuroimmunologic dysregulation associated with ASD involves serotonin. Note how pro-inflammatory cytokines affect the expression of serotonin-reuptake proteins, and the involvement of down-stream immunologic dysregulation. Serotonin and the enteric nervous system may also help explain gastrointestinal alterations in ASD. Jaiswal P, Mohanakumar KP, Rajamma U. Serotonin mediated immunoregulation and neural functions: Complicity in the aetiology of autism spectrum disorders. Neuroscience & Biobehavioral Reviews. 2015 8//;55(0):413-31.
- Dopaminergic dysregulation Meth-induced DA release Meth-induced hyperactivity D1 and D2 mRNA levels PND21 mice showed no changes in monoamine levels after maternal valproic acid administration on post-conception day 12.5 Hara Y, Takuma K, Takano E, et al. Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model. Behavioural Brain Research. 2015 8/1/;289(0):39-47. Kriete T, Noelle DC. Dopamine and the development of executive dysfunction in autism spectrum disorders. PLoS One. 2015;10(3):e0121605. Jellinger KA. The Neurochemical Basis of Autism: From Molecules to Minicolumns. European Journal of Neurology. 2011;18(1):e9-e. Guiard BP, El Mansari M, Blier P. Cross-talk between dopaminergic and noradrenergic systems in the rat ventral tegmental area, locus ceruleus, and dorsal hippocampus. Mol Pharmacol. 2008 Nov;74(5):1463-75.
- Workman AD, Charvet CJ, Clancy B, Darlington RB, Finlay BL. Modeling transformations of neurodevelopmental sequences across mammalian species. J Neurosci. 2013 Apr 24;33(17):7368-83.
- Critical window since altered connectivity is seen in autism. Furthermore, post-natal day 10 is prior to weaning (PND21); thus, the offspring’s sole nutritional source is via maternal lactation, allowing us to better factor out environmental impacts on our study. So the question of why we chose post-natal day 10 in the mouse naturally arises. Looking at critical windows in neurodevelopment, significant increases in rates of axonal growth and synaptogenesis occur in the late third trimester of human gestation. This window is integral for physiologic “wiring” of the brain, including structural formation of cortical regions, as well as functional development, as related to levels of NTs, receptor density in post-synaptic targets, and receptor sensitivity. Vértes PE, Bullmore ET. Annual Research Review: Growth connectomics – the organization and reorganization of brain networks during normal and abnormal development. Journal of Child Psychology and Psychiatry. 2015;56(3):299-320. Zakharova LA. Cross-regulation in development of neuroendocrine and immune systems. Russ J Dev Biol. 2010 2010/11/01;41(6):347-56. Sullivan EL, Riper KM, Lockard R, Valleau JC. Maternal high-fat diet programming of the neuroendocrine system and behavior. Horm Behav. 2015 Apr 24. Herlenius E, Lagercrantz H. Development of neurotransmitter systems during critical periods. Experimental Neurology. 2004 11//;190, Supplement 1(0):8-21. Workman AD, Charvet CJ, Clancy B, Darlington RB, Finlay BL. Modeling transformations of neurodevelopmental sequences across mammalian species. J Neurosci. 2013 Apr 24;33(17):7368-83.
- Average American diet is roughly 33% kcal from fat (CDC; http://www.cdc.gov/nchs/fastats/diet.htm)
- Upon extraction, brains were rinsed with ice-cold Hank’s buffer, sliced midsagitally, and half was later frozen over dry ice and coronally sectioned into 500 micron segments in order to obtain brain regions via micropunches. DOPAC: 3,4-dihydroxyphenylacetic acid HVA: homovanillic acid 3-MT: 3-methoxytyramine 5-HT: 5-hydroxytryptamine 5-HIAA: 5-hydroxyindoleacetic acid MHPG: 3-methoxy-4-hydroxyphenylglycol
- Monoamine system most affected by maternal HFD: dopaminergic system. Brain region most affected: ventral hippocampus; least affected: striatum. Sex-independent increases in DA levels in PFC, dHIPP, vHIPP. Stat. sig in PFC, dHIPP females, trend in vHIPP fema les. Sex-independent increase in DOPAC in vHIPP – suggests increased DA vHIPP tone at PND10 due to maternal HFD. MATERNAL HFD EFFECTS: Sex-independent increased DA levels in the PFC, dHIPP, and vHIPP. Statistically significant in female PFC and vHIPP. EFFECTS OF SEX (not shown) *HVA levels lower in female PFC, higher in female dHIPP. *Striatal 3-MT levels higher in females. Both appear to be driven by maternal diet in females (interaction approaching significance). Maternal HFD leads to disrupted dopaminergic homeostasis in the PND10 mouse, which may relate to ASD-like behaviors involving behavioral dysregulation or hyperactivity.
- Female-restricted increases in 5-HT noted in PFC, vHIPP, CER, but specifically not the dHIPP. Statistical trend for increased 5-HIAA in female PFC, suggests increased serotonergic tone in PFC in female PND10 mice. MATERNAL HFD EFFECTS: (i) sex-dependent female-specific increased 5-HT levels. Statistically significant in female vHIPP, but not the dHIPP* Statistical trend in female PFC, CER. (ii) Increased 5-HIAA levels in female PFC (statistically significant). Suggests increased serotonergic tone in female PND10 PFC. EFFECTS OF SEX (not shown) – appear to be driven by maternal diet in females. *5-HT levels higher in female PFC and CER – appear to be driven by diet. *5-HT levels lower in female dHIPP – statistically and biologically significant. Maternal HFD leads to disrupted serotonergic homeostasis in the PND10 female mouse, which may relate to ASD-like behaviors involving communication or social deficits.
- There were no statistically significant effects of maternal HFD or sex on MHPG levels in PND10 mouse. Consistent with other studies. L.-J. Kepser, J. R. Homberg, The neurodevelopmental effects of serotonin: A behavioural perspective. Behavioural Brain Research 277, 3-13 (2015). Hara Y, Takuma K, Takano E, et al. Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model. Behavioural Brain Research. 2015 8/1/;289(0):39-47. Loke YJ, Hannan AJ, Craig JM. The Role of Epigenetic Change in Autism Spectrum Disorders. Frontiers in Neurology. 2015 05/26. 02/28/received. 04/28/accepted;6:107.
- Recall the valproic-acid mouse study previously mentioned, where no differences were found in monoamine levels at PND21.