A method for the selective depletion of microglia in the dorsal hippocampus in the juvenile rat brain.

BACKGROUND: To understand the role of microglia in brain function and development, methods have emerged to deplete microglia throughout the brain. Liposome-encapsulated clodronate (LEC) can be infused into the brain to deplete microglia in a brain-region and time-specific manner. NEW METHOD: This study validates methodology to deplete microglia in the rat dorsal hippocampus (dHP) during a specific period of juvenile development. Stereotaxic surgery was performed to infuse LEC at postnatal day (P) 16 or 19 into dHP. Rat brains were harvested at various ages to determine specificity of infusion and duration of depletion. RESULTS: P19 infusion of LEC into dHP with a 27G syringe depleted microglia in dHP subregions CA1, dentate gyrus (DG), and CA3 from P24-P30. There was also evidence of depletion in parietal cortex above the infusion site. P16 infusion of LEC with a 32 G syringe depleted microglia only in dHP subregions CA1 and DG from P21-P40. COMPARISON WITH EXISTING METHOD(S): Previous methods have infused LEC intra-hippocampally in adult rats or intra-cerebroventricularly in neonatal rats. This study is the first to publish methodology to deplete microglia in a brain-region specific manner during juvenile rat development. CONCLUSIONS: The timing of LEC infusion during the juvenile period can be adjusted to achieve maximal microglia depletion by a specific postnatal day. A 27G needle results in LEC backflow during the infusion, but also allows LEC to reach all subregions of dHP. Infusion with a 32 G needle prevents backflow during infusion, but results in a more local spread of LEC within dHP.

An Examination of the Long-Term Neurodevelopmental Impact of Prenatal Zika Virus Infection in a Rat Model Using a High Resolution, Longitudinal MRI Approach.

Since Zika virus (ZIKV) first emerged as a public health concern in 2015, our ability to identify and track the long-term neurological sequelae of prenatal Zika virus (ZIKV) infection in humans has been limited. Our lab has developed a rat model of maternal ZIKV infection with associated vertical transmission to the fetus that results in significant brain malformations in the neonatal offspring. Here, we use this model in conjunction with longitudinal magnetic resonance imaging (MRI) to expand our understanding of the long-term neurological consequences of prenatal ZIKV infection in order to identify characteristic neurodevelopmental changes and track them across time. We exploited both manual and automated atlas-based segmentation of MR images in order to identify long-term structural changes within the developing rat brain following inoculation. The paradigm involved scanning three cohorts of male and female rats that were prenatally inoculated with 107 PFU ZIKV, 107 UV-inactivated ZIKV (iZIKV), or diluent medium (mock), at 4 different postnatal day (P) age points: P2, P16, P24, and P60. Analysis of tracked brain structures revealed significantly altered development in both the ZIKV and iZIKV rats. Moreover, we demonstrate that prenatal ZIKV infection alters the growth of brain regions throughout the neonatal and juvenile ages. Our findings also suggest that maternal immune activation caused by inactive viral proteins may play a role in altered brain growth throughout development. For the very first time, we introduce manual and automated atlas-based segmentation of neonatal and juvenile rat brains longitudinally. Experimental results demonstrate the effectiveness of our novel approach for detecting significant changes in neurodevelopment in models of early-life infections.

An IL-6 receptor antagonist attenuates postpartum anhedonia, but has no effect on anhedonia precipitated by subchronic stress in female rats.

RATIONALE: Nearly 60-80% of women experience some form of sadness, anxiety, or anhedonia in the weeks following the birth of a child (Patel et al. 23(2):534-42, 2012; Degner 10: 359;j4692, 2017); however, the exact mechanisms that precipitate these changes in mood postpartum are still unknown. It is well-known that the function of the peripheral immune system is significantly altered during pregnancy in order to protect the developing fetus from being rejected by the maternal immune system (Fallon et al. 17(1):7-17, 2002), and we have recently found a dramatic change in the central immune system during and just after pregnancy in female rats (Sherer et al. 66:201-209, 2017). We observed anhedonia in Sprague-Dawley rat dams on the day of birth that is associated with an increase in interleukin (IL)-6 expression in the brain on the day of birth (Posillico and Schwarz 298(Pt B):218-28, 2016). OBJECTIVES: The goal of the current experiments was to determine whether inhibiting the IL-6 receptor could prevent onset of this postpartum anhedonia, or anhedonia precipitated by subchronic stress in non-pregnant females. RESULTS: Treatment with an IL-6 receptor antibody attenuated postpartum anhedonia as characterized by a decrease in sucrose preference. In contrast, this antibody had no effect on the decrease in sucrose preference induced following a week of forced swim stress in non-pregnant female rats. CONCLUSIONS: The results of these studies suggest that the molecular mechanisms that underlie the onset of anhedonia following birth or mild stress in female rats may be distinct.