Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring
Tóm tắt
Prenatal infection during pregnancy is a risk factor for schizophrenia, as well as for other developmental psychiatric disorders, such as autism and bipolar disorder. Schizophrenia patients were reported to have altered brain metabolism and neuroinflammation. However, the link between prenatal infection, altered brain inflammation and metabolism, and schizophrenia remains unclear. In this project, we aimed to evaluate whether there are changes in brain glucose consumption and microglia activation in the offspring of pregnant rats exposed to maternal immune activation (MIA), and if so, whether these changes occur before or after the initiation of schizophrenia-like behaviour. Pregnant rats were treated with the viral mimic polyinosinic-polycytidylic acid (MIA group) or saline (control group) on gestational day 15. Static PET scans of the male offspring were acquired on postnatal day (PND) 21, 60, and 90, using [11C]-PK11195 and deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) as tracers to measure TSPO expression in activated microglia and brain glucose consumption, respectively. On PND60 and PND90, anxiety-like behaviour, recognition memory, and sensorimotor gating were measured using the open field test (OFT), novel object recognition test (NOR), and prepulse inhibition test (PPI). [18F]-FDG PET demonstrated that MIA offspring displayed higher brain glucose consumption in the whole brain after weaning (p = 0.017), and in the frontal cortex during late adolescence (p = 0.001) and adulthood (p = 0.037) than control rats. [11C]-PK11195 PET did not reveal any changes in TSPO expression in MIA offspring. Prenatal infection induced age-related behavioural alterations. Adolescent MIA offspring displayed a more anxious state in the OFT than controls (p = 0.042). Adult MIA offspring showed recognition memory deficits in the NOR (p = 0.003). Our study did not show any PPI deficits. Our results suggest that prenatal immune activation changed neurodevelopment, resulting in increased brain glucose consumption, but not in microglia activation. The increased brain glucose consumption in the frontal cortex of MIA offspring remained until adulthood and was associated with increased anxiety-like behaviour during adolescence and recognition memory deficits in adulthood.
Tài liệu tham khảo
Kneeland RE, Fatemi SH (2013) Viral infection, inflammation and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 42:35–48
Modai S, Shomron N (2016) Molecular Risk Factors for Schizophrenia. Trends Mol Med 22:242–253
Van Os J, Rutten BPF, Poulton R (2008) Gene-environment interactions in schizophrenia: Review of epidemiological findings and future directions. Schizophr Bull 34:1066–1082
Patterson PH (2009) Immune involvement in schizophrenia and autism: Etiology, pathology and animal models. Behav Brain Res 204:313–321
Avramopoulos D, Pearce BD, McGrath J et al (2015) Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation. PLoS ONE 10:e0116696–e0116696
Lee BK, Magnusson C, Gardner RM et al (2015) Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders. Brain Behav Immun 44:100–105
Seethalakshmi R, Parkar S, Nair N et al (2006) Regional brain metabolism in schizophrenia: An FDG-PET study. Indian J Psychiatry Indian J Psychiatry 48(3):149–153
Soyka M, Koch W, Möller HJ et al (2005) Hypermetabolic pattern in frontal cortex and other brain regions in unmedicated schizophrenia patients: Results from a FDG-PET study. Eur Arch Psychiatry Clin Neurosci 255:308–312
Radewicz K, Garey LJ, Gentleman SM, Reynolds R (2000) Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J Neuropathol Exp Neurol 59(2):137–50
Doorduin J, de Vries EFJ, Willemsen ATM et al (2009) Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 50:1801–1807
Marques TR, Ashok AH, Pillinger T et al (2019) Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies. Psychol Med 49:2186–2196
Fillman SG, Weickert TW, Lenroot RK et al (2016) Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume. Mol Psychiatry 21:1090–1098
Fillman SG, Cloonan N, Catts VS et al (2013) Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry 18:206–214
Brown AS (2018) Meyer U (2018) Maternal immune activation and neuropsychiatric illness: A translational research perspective. Am J Psychiatry 175(11):1073–1083
Hadar R, Soto-Montenegro ML, Götz T et al (2015) Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course. Schizophr Res Schizophrenia Research 166(1–3):238–247
Casquero-Veiga M, García-García D, MacDowell KS et al (2019) Risperidone administered during adolescence induced metabolic, anatomical and inflammatory/oxidative changes in adult brain: A PET and MRI study in the maternal immune stimulation animal model. Eur Neuropsychopharmacol 29(7):880–896
Garay PA, Hsiao EY, Patterson PH, McAllister AK (2013) Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav Immun 31:54–68
Yee N, Ribic A, de Roo CC, Fuchs E (2011) Differential effects of maternal immune activation and juvenile stress on anxiety-like behaviour and physiology in adult rats: No evidence for the “double-hit hypothesis.” Behav Brain Res 224:180–188
Guma E, Bordignon P, Devenyi GA et al (2020) Early or late gestational exposure to maternal immune activation alters neurodevelopmental trajectories in mice: An integrated neuroimaging, behavioural, and transcriptional study. Biol Psychiatry S0006–3223(21):01176–01178
Ibi D, Nakasai G, Koide N et al (2020) Reelin Supplementation Into the Hippocampus Rescues Abnormal Behavior in a Mouse Model of Neurodevelopmental Disorders. Front Cell Neurosci 14:285
Gray A, Tattoli R, Dunn A et al (2019) Maternal immune activation in mid-late gestation alters amphetamine sensitivity and object recognition, but not other schizophrenia-related behaviours in adult rats. Behav Brain Res 356:358–364
Guerrin CGJ, Doorduin J, Sommer IE, de Vries EFJ (2021) The dual hit hypothesis of schizophrenia: Evidence from animal models. Neurosci Biobehav Rev 131:1150–1168
Mattei D, Ivanov A, Ferrai C et al (2017) (2017) Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment. Transl Psychiatry 7(5):e1120
Ibi D, Nagai T, Kitahara Y et al (2009) Neonatal polyI: C treatment in mice results in schizophrenia-like behavioral and neurochemical abnormalities in adulthood. Neurosci Res 64:297–305
Ozawa K, Hashimoto K, Kishimoto T et al (2006) Immune Activation During Pregnancy in Mice Leads to Dopaminergic Hyperfunction and Cognitive Impairment in the Offspring: A Neurodevelopmental Animal Model of Schizophrenia. Biol Psychiatry 59:546–554
Sijbesma J, van Waarde A, Vállez García D, Boersma H, Slart R, Dierckx R, Doorduin J (2017) Gender differences in the cerebral uptake of [18F]FDG. Eur J Nucl Med Mol Imaging 44(Suppl. 2):S316–S317
Murray KN, Edye ME, Manca M et al (2019) Evolution of a maternal immune activation (mIA) model in rats: Early developmental effects. Brain Behav Immun 75:48–59
Sarkar T, Patro N, Patro IK (2019) Cumulative multiple early life hits- a potent threat leading to neurological disorders. Brain Res Bull 147:58–68
Kentner AC, Bilbo SD, Brown AS et al (2019) Maternal immune activation: reporting guidelines to improve the rigor, reproducibility, and transparency of the model. Neuropsychopharmacology 44:245–258
Garcia DV, Casteels C, Schwarz AJ et al (2015) A standardized method for the construction of tracer specific PET and SPECT rat brain templates: Validation and implementation of a toolbox. PLoS ONE 10:1–21
Schwarz AJ, Danckaert A, Reese T et al (2006) A stereotaxic MRI template set for the rat brain with tissue class distribution maps and co-registered anatomical atlas: Application to pharmacological MRI. Neuroimage 32:538–550
Marx C, Lex B, Calaminus C et al (2012) Conflict Processing in the Rat Brain: Behavioral Analysis and Functional μPET Imaging Using [18F]Fluorodeoxyglucose. Front Behav Neurosci 6:1–12
Lehnert W, Gregoire MC, Reilhac A, Meikle SR (2012) Characterisation of partial volume effect and region-based correction in small animal positron emission tomography (PET) of the rat brain. Neuroimage 60:2144–2157
Radonjic M, Cappaert NLM, de Vries EFJ et al (2013) Delay and impairment in brain development and function in rat offspring after maternal exposure to methylmercury. Toxicol Sci 133:112–124
Kim M, Haney JR, Zhang P et al (2021) Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia. Nat Neurosci 24:799–809
Andoh M, Shibata K, Okamoto K et al (2019) Exercise Reverses Behavioral and Synaptic Abnormalities after Maternal Inflammation. Cell Rep 27:2817-2825.e5
Temmingh H, Stein DJ (2015) Anxiety in Patients with Schizophrenia: Epidemiology and Management. CNS Drugs 29(819–832):7
Harvey P-O, Lee J, Horan WP et al (2011) Do patients with schizophrenia benefit from a self-referential memory bias? Schizophr Res 127:171–177
Williams DL, Goldstein G, Minshew NJ (2005) Impaired memory for faces and social scenes in autism: clinical implications of memory dysfunction. Arch Clin Neuropsychol 20:1–15
Hollocks MJ, Lerh JW, Magiati I et al (2019) Anxiety and depression in adults with autism spectrum disorder: a systematic review and meta-analysis. Psychol Med 49:559–572
Young AH, Gallagher P, Watson S et al (2004) Improvements in Neurocognitive Function and Mood Following Adjunctive Treatment with Mifepristone (RU-486) in Bipolar Disorder. Neuropsychopharmacology 29:1538–1545
Spoorthy MS, Chakrabarti S, Grover S (2019) Comorbidity of bipolar and anxiety disorders: An overview of trends in research. World J psychiatry 9:7–29
Hare BD, Duman RS (2020) Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions. Mol Psychiatry 25:2742–2758
Padilla-Coreano N, Bolkan SS, Pierce GM et al (2016) Direct Ventral Hippocampal-Prefrontal Input Is Required for Anxiety-Related Neural Activity and Behavior. Neuron 89:857–866
Felix-Ortiz AC, Burgos-Robles A, Bhagat ND et al (2016) Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex. Neuroscience 321:197–209
Reincke SAJ, Hanganu-Opatz IL (2017) Early-life stress impairs recognition memory and perturbs the functional maturation of prefrontal-hippocampal-perirhinal networks. Sci Rep 7:1–16
Barker GRI, Bird F, Alexander V, Warburton EC (2007) Recognition memory for objects, place, and temporal order: A disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex. J Neurosci 27:2948–2957
Sangha S, Greba Q, Robinson PD et al (2014) Heightened fear in response to a safety cue and extinguished fear cue in a rat model of maternal immune activation. Front Behav Neurosci 8:168
Murray BG, Davies DA, Molder JJ, Howland JG (2017) Maternal immune activation during pregnancy in rats impairs working memory capacity of the offspring. Neurobiol Learn Mem 141:150–156
Kentner AC, Khoury A, Lima Queiroz E, MacRae M (2016) Environmental enrichment rescues the effects of early life inflammation on markers of synaptic transmission and plasticity. Brain Behav Immun 57:151–160
Zhao X, Rondón-Ortiz AN, Lima EP et al (2020) Therapeutic efficacy of environmental enrichment on behavioral, endocrine, and synaptic alterations in an animal model of maternal immune activation. Brain, Behav Immun - Heal 3:100043
Park J, Moghaddam B (2017) Impact of anxiety on prefrontal cortex encoding of cognitive flexibility. Neuroscience 345:193–202
Mena A, Ruiz-Salas JC, Puentes A et al (2016) (2016) Reduced Prepulse Inhibition as a Biomarker of Schizophrenia. Front Behav Neurosci 10:202
Perry W, Minassian A, Feifel D, Braff DL (2001) Sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania. Biol Psychiatry 50:418–424
Perry W, Minassian A, Lopez B et al (2007) Sensorimotor Gating Deficits in Adults with Autism. Biol Psychiatry 61:482–486
Swanepoel T, Möller M, Harvey BH (2018) N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges. Psychopharmacology 235:351–368
Giovanoli S, Engler H, Engler A et al (2013) Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science 339(6123):1095–1099
Missault S, Van den Eynde K, Vanden Berghe W et al (2014) The risk for behavioural deficits is determined by the maternal immune response to prenatal immune challenge in a neurodevelopmental model. Brain Behav Immun 42:138–146
Babri S, Doosti MH, Salari AA (2014) Strain-dependent effects of prenatal maternal immune activation on anxiety- and depression-like behaviors in offspring. Brain Behav Immun 37:164–176
Silbersweig DA, Stern E, Frith C et al (1995) A functional neuroanatomy of hallucinations in schizophrenia. Nature. https://doi.org/10.1038/378176a0
Vollenweider F (1997) Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Neuropsychopharmacol 7(1):9–24
Vollenweider (1997) Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacol 16(5):357–72
Potkin SG, Alva G, Fleming K et al (2002) A PET study of the pathophysiology of negative symptoms in schizophrenia. Am J Psychiatry 159:227–237
Fujimoto T, Takeuch K, Matsumoto T et al (2007) Abnormal glucose metabolism in the anterior cingulate cortex in patients with schizophrenia. Psychiatry Res 154(1):49–58
Na KS, Jung HY, Kim YK (2014) The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 48:277–286
Mattei D, Djodari-Irani A, Hadar R et al (2014) Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia. Brain Behav Immun 38:175–184
Li X, Tian X, Lv L et al (2018) Microglia activation in the offspring of prenatal Poly I: C exposed rats: A PET imaging and immunohistochemistry study. Gen Psychiatry 31:29–36