Maternal Immune Activation during Pregnancy Alters Postnatal Brain Growth and Cognitive Development in Nonhuman Primate Offspring.

Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys (Macaca mulatta) born to MIA-treated dams (n = 14) injected with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the same gestational time points (n = 10) or were untreated (n = 4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal MRI revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.SIGNIFICANCE STATEMENT Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical maternal immune activation (MIA) models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are conducted in rodents, the nonhuman primate provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a nonhuman primate MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.

Tumor necrosis factor superfamily member APRIL contributes to fibrotic scar formation after spinal cord injury.

BACKGROUND: Fibrotic scar formation contributes to the axon growth-inhibitory environment that forms following spinal cord injury (SCI). We recently demonstrated that depletion of hematogenous macrophages led to a reduction in fibrotic scar formation and increased axon growth after SCI. These changes were associated with decreased TNFSF13 (a proliferation inducing ligand (APRIL)) expression, but the role of APRIL in fibrotic scar formation after SCI has not been directly investigated. Thus, the goal of this study was to determine the role of APRIL in fibrotic scar formation after SCI. METHODS: APRIL knockout and wild-type mice received contusive SCI and were assessed for inflammatory cytokine/chemokine expression, leukocyte infiltration, fibrotic scar formation, axon growth, and cell proliferation. RESULTS: Expression of APRIL and its receptor BCMA is increased following SCI, and genetic deletion of APRIL led to reduced fibrotic scar formation and increased axon growth. However, the fibrotic scar reduction in APRIL KO mice was not a result of changes in fibroblast or astrocyte proliferation. Rather, APRIL knockout mice displayed reduced TNFα and CCL2 expression and less macrophage and B cell infiltration at the injury site. CONCLUSIONS: Our data indicate that APRIL contributes to fibrotic scar formation after SCI by mediating the inflammatory response.

Impact of Maternal Immune Activation on Nonhuman Primate Prefrontal Cortex Development: Insights for Schizophrenia.

Late adolescence is a period of dynamic change in the brain as humans learn to navigate increasingly complex environments. In particular, prefrontal cortical (PFC) regions undergo extensive remodeling as the brain is fine-tuned to orchestrate cognitive control over attention, reasoning, and emotions. Late adolescence also presents a uniquely vulnerable period as neurodevelopmental illnesses, such as schizophrenia, become evident and worsen into young adulthood. Challenges in early development, including prenatal exposure to infection, may set the stage for a cascade of maladaptive events that ultimately result in aberrant PFC connectivity and function before symptoms emerge. A growing body of research suggests that activation of the mother's immune system during pregnancy may act as a disease primer, in combination with other environmental and genetic factors, contributing to an increased risk of neurodevelopmental disorders, including schizophrenia. Animal models provide an invaluable opportunity to examine the course of brain and behavioral changes in offspring exposed to maternal immune activation (MIA). Although the vast majority of MIA research has been carried out in rodents, here we highlight the translational utility of the nonhuman primate (NHP) as a model species more closely related to humans in PFC structure and function. In this review, we consider the protracted period of brain and behavioral maturation in the NHP, describe emerging findings from MIA NHP offspring in the context of rodent preclinical models, and lastly explore the translational relevance of the NHP MIA model to expand understanding of the etiology and developmental course of PFC pathology in schizophrenia.

Macrophage depletion and Schwann cell transplantation reduce cyst size after rat contusive spinal cord injury.

Schwann cell transplantation is a promising therapy for the treatment of spinal cord injury (SCI) and is currently in clinical trials. In our continuing efforts to improve Schwann cell transplantation strategies, we sought to determine the combined effects of Schwann cell transplantation with macrophage depletion. Since macrophages are major inflammatory contributors to the acute spinal cord injury, and are the major phagocytic cells, we hypothesized that transplanting Schwann cells after macrophage depletion will improve cell survival and integration with host tissue after SCI. To test this hypothesis, rat models of contusive SCI at thoracic level 8 were randomly subjected to macrophage depletion or not. In rat subjected to macrophage depletion, liposomes filled with clodronate were intraperitoneally injected at 1, 3, 6, 11, and 18 days post injury. Rats not subjected to macrophage depletion were intraperitoneally injected with liposomes filled with phosphate buffered saline. Schwann cells were transplanted 1 week post injury in all rats. Biotinylated dextran amine (BDA) was injected at thoracic level 5 to evalute axon regeneration. The Basso, Beattie, and Bresnahan locomotor test, Gridwalk test, and sensory test using von Frey filaments were performed to assess functional recovery. Immunohistochemistry was used to detect glial fibrillary acidic protein, neurofilament, and green fluorescent protein (GFP), and also to visulize BDA-labelled axons. The GFP labeled Schwann cell and cyst and lesion volumes were quantified using stained slides. The numbers of BDA-positive axons were also quantified. At 8 weeks after Schwann cell transplantation, there was a significant reduction in cyst and lesion volumes in the combined treatment group compared to Schwann cell transplantation alone. These changes were not associated, however, with improved Schwann cell survival, axon growth, or locomotor recovery. Although combining Schwann cell transplantation with macrophage depletion does improve histopathology of the injury site, the effect on axon growth and behavioral recovery appears no better than what can be achieved with Schwann cell transplants alone.