Hippocampal neurogenesis and memory in adolescence following intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is associated with hippocampal alterations that can increase the risk of short-term memory impairments later in life. Despite the role of hippocampal neurogenesis in learning and memory, research into the long-lasting impact of IUGR on these processes is limited. We aimed to determine the effects of IUGR on neuronal proliferation, differentiation and morphology, and on memory function at adolescent equivalent age. At embryonic day (E) 18 (term ∼E22), placental insufficiency was induced in pregnant Wistar rats via bilateral uterine vessel ligation to generate IUGR offspring (n = 10); control offspring (n = 11) were generated via sham surgery. From postnatal day (P) 36-44, spontaneous location recognition (SLR), novel object location and recognition (NOL, NOR), and open field tests were performed. Brains were collected at P45 to assess neurogenesis (immunohistochemistry), dendritic morphology (Golgi staining), and brain-derived neurotrophic factor expression (BDNF; Western blot analysis). In IUGR versus control rats there was no difference in object preference in the NOL or NOR, the similar and dissimilar condition of the SLR task, or in locomotion and anxiety-like behavior in the open field. There was a significant increase in the linear density of immature neurons (DCX+) in the subgranular zone (SGZ) of the dentate gyrus (DG), but no difference in the linear density of proliferating cells (Ki67+) in the SGZ, nor in areal density of mature neurons (NeuN+) or microglia (Iba-1+) in the DG in IUGR rats compared to controls. Dendritic morphology of dentate granule cells did not differ between groups. Protein expression of the BDNF precursor (pro-BDNF), but not mature BDNF, was increased in the hippocampus of IUGR compared with control rats. These findings highlight that while the long-lasting prenatal hypoxic environment may impact brain development, it may not impact hippocampal-dependent learning and memory in adolescence.

Use of immunodampening to overcome diversity in the malarial vaccine candidate apical membrane antigen 1.

Apical membrane antigen 1 (AMA1) is a leading malarial vaccine candidate; however, its polymorphic nature may limit its success in the field. This study aimed to circumvent AMA1 diversity by dampening the antibody response to the highly polymorphic loop Id, previously identified as a major target of strain-specific, invasion-inhibitory antibodies. To achieve this, five polymorphic residues within this loop were mutated to alanine, glycine, or serine in AMA1 of the 3D7 and FVO Plasmodium falciparum strains. Initially, the corresponding antigens were displayed on the surface of bacteriophage, where the alanine and serine but not glycine mutants folded correctly. The alanine and serine AMA1 mutants were expressed in Escherichia coli, refolded in vitro, and used to immunize rabbits. Serological analyses indicated that immunization with a single mutated form of 3D7 AMA1 was sufficient to increase the cross-reactive antibody response. Targeting the corresponding residues in an FVO backbone did not achieve this outcome. The inclusion of at least one engineered form of AMA1 in a biallelic formulation resulted in an antibody response with broader reactivity against different AMA1 alleles than combining the wild-type forms of 3D7 and FVO AMA1 alleles. For one combination, this extended to an enhanced relative growth inhibition of a heterologous parasite line, although this was at the cost of reduced overall inhibitory activity. These results suggest that targeted mutagenesis of AMA1 is a promising strategy for overcoming antigenic diversity in AMA1 and reducing the number of variants required to induce an antibody response that protects against a broad range of Plasmodium falciparum AMA1 genotypes. However, optimization of the immunization regime and mutation strategy will be required for this potential to be realized.

Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury.

Midkine (MK) is a small secreted heparin-binding protein highly expressed during embryonic/fetal development which, through interactions with multiple cell surface receptors promotes growth through effects on cell proliferation, migration, and differentiation. MK is upregulated in the adult central nervous system (CNS) after multiple types of experimental injury and has neuroprotective and neuroregenerative properties. The potential for MK as a therapy for developmental brain injury is largely unknown. This review discusses what is known of MK's expression and actions in the developing brain, areas for future research, and the potential for using MK as a therapeutic agent to ameliorate the effects of brain damage caused by insults such as birth-related hypoxia and inflammation.

Impact of high sucrose diets on the discrimination of spatial and object memories with overlapping features.

High sucrose diets (HSDs) have been shown to have detrimental effects on hippocampal dependent memory in rats, including the performance of spatial tasks reliant on pattern separation, a cognitive process involved in minimising interference during memory encoding. As such we sought to investigate the impact of HSDs on object and spatial recognition tasks that varied the cognitive load placed on pattern separation processes. Young male and female rats were 4 weeks old at the start of diet manipulations. Rats in the HSD condition were provided with daily access to 10% sucrose solution for 2 h per day across a 28 d period, during which they were assessed on their performance of memory tasks that varied the similarity of spatial arrangements (Spontaneous Location Recognition, SLR) and object features (Novel Object Recognition, NOR) to determine the effect of HSD on memory encoding processes. Both female and male rats that consumed HSDs were impaired at NOR when objects shared multiple features (s-NOR), however when objects were distinct, novel object recognition was not impacted by HSD consumption. Male rats in the control condition generally outperformed female rats in the SLR task when there were small spatial separations (s-SLR) but not when there were large spatial separations (d-SLR). HSD consumption disrupted performance of d-SLR in female rats, but not male rats. Specific HSD deficits were observed in HSD consuming male rats in the s-SLR task. However, the volume of sucrose consumed differed between sexes, and may have impacted memory differentially. These findings indicate that HSD-induced memory deficits may extend to pattern separation dependent recognition memory mechanisms when objects share overlapping features, and impairments in spatial tasks may be more pronounced in female rats.