Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring.

PURPOSE: 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. PROCEDURES: 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). RESULTS: [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. CONCLUSIONS: 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.

PET Imaging with S-[11C]Methyl-L-Cysteine and L-[Methyl-11C]Methionine in Rat Models of Glioma, Glioma Radiotherapy, and Neuroinflammation.

PURPOSE: S-[11C]-methyl-L-cysteine ([11C]MCYS) has been claimed to offer higher tumor selectivity than L-[methyl- 11C]methionine ([11C]MET). We examined this claim in animal models. PROCEDURES: Rats with implanted untreated (n = 10) or irradiated (n = 7, 1 × 25 Gy, on day 8) orthotopic gliomas were scanned after 6, 9, and 12 days, using positron emission tomography. Rats with striatal injections of saline (n = 9) or bacterial lipopolysaccharide (n = 9) were scanned after 3 days. RESULTS: Uptake of the two tracers in untreated gliomas was similar. [11C]MCYS was not accumulated in salivary glands, nasal epithelium, and healing wounds, in contrast to [11C]MET, but showed 40 % higher accumulation in the healthy brain. Both tracers showed a reduced tumor uptake 4 days after irradiation and minor accumulation in inflamed striatum. [11C]MCYS indicated higher lesion volumes than [11C]MET (untreated tumor + 47 %; irradiated tumor up to + 500 %; LPS-inflamed striatum + 240 %). CONCLUSIONS: [11C]MCYS was less accumulated in some non-tumor tissues than [11C]MET, but showed lower tumor-to-brain contrast.

Contribution of neuroinflammation to changes in [11C]flumazenil binding in the rat brain: Evaluation of the inflamed pons as reference tissue.

INTRODUCTION: [11C]Flumazenil is a well-known PET tracer for GABAA receptors and is mainly used as an imaging biomarker for neuronal loss. Recently, GABAA receptors on immune cells have been investigated as target for modulation of inflammation. Since neuronal loss is often accompanied by neuroinflammation, PET imaging with [11C]flumazenil is potentially affected by infiltrating immune cells. This may also compromise the validity of using the pons as reference tissue in quantitative pharmacokinetic analysis. This study aims to evaluate whether inflammatory processes in the brain can influence [11C]flumazenil uptake and affect the outcome of pharmacokinetic modeling when the pons is used as reference tissue. METHODS: The herpes simplex encephalitis (HSE) rat model is known to cause neuroinflammation in the brainstem. Dynamic [11C]flumazenil PET scans of 60-min, accompanied by arterial blood sampling and metabolite analysis, were acquired at day 6-7days post-infection of male Wistar rats (HSE, n=5 and control, n=6). Additionally, the GABAA receptor was saturated by injection of unlabeled flumazenil prior to the tracer injection in 4 rats per group. PET data were analyzed by pharmacokinetic modeling. RESULTS: No statistically significant differences were found in the volume of distribution (VT) or non-displaceable binding potential (BPND) between control and HSE rats in any of the brain regions. Pre-saturation with unlabeled flumazenil resulted in a statistically significant reduction in [11C]flumazenil VT in all brain regions. The BPND obtained from SRTM exhibited a good correlation to DVR - 1 values from the two-tissue compartment model, coupled with some level of underestimation. CONCLUSION: Reliable quantification of [11C]flumazenil binding in rats can be obtained by pharmacokinetic analysis using the pons as a pseudo-reference tissue even in the presence of strong acute neuroinflammation.

Mapping of the rat's motor area after hemispherectomy: The hemispheres as potentially independent motor brains.

PURPOSE: The remarkable motor recovery observed after hemispherectomy in patients and experimental animals has puzzled investigators, as it defies classic jacksonian neurology. Several mechanisms for this phenomenon have been considered, such as neuronal sprouting to subcortical structures, neurochemical changes, and cerebellar diaschisis. The spared hemisphere may, however, play a crucial part in this functional recovery. METHODS: In this study, seven Wistar rats were submitted to right hemisphere motor area mapping. In the same anesthetic time, a left microsurgical hemispherectomy was performed, and the animal allowed to recover for 2 weeks. After then, the right hemisphere was again stimulated for its motor area. RESULTS: Four rats had, after 2 weeks of observation, bilateral body movements with stimulation of only the right hemisphere. The same segments on both sides had symmetric and simultaneous movements. CONCLUSIONS: The results suggest that each motor area has the latent capacity to control motricity bilaterally, and that such capacity is brought into function after removal of the opposite hemisphere. The same neuronal population that gives afference to one segment contralaterally seems to give afference to the same segment ipsilaterally.