Hippocampal neurogenesis and memory in adolescence following intrauterine growth restriction

Abstract

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.

An Optimized and Detailed Step-by-Step Protocol for the Analysis of Neuronal Morphology in Golgi-Stained Fetal Sheep Brain

“…Dean and colleagues [16] used Rapid-Golgi with Neurolucida to quantify neuronal morphology in a fetal sheep model of cerebral ischemia and show impaired expansion of the dendritic arbor and a significant reduction in spine density following ischemia. Preclinical models of fetal growth restriction have used the Rapid-Golgi method with Im-ageJ (with ImageJ plugins for neuronal morphological analysis) [17,34], showing altered morphology of CA1 pyramidal neurons and a significant reduction in dendritic length [17]. Interestingly, an unexpected increase in spine density was seen in a guinea pig model of fetal growth restriction [17].…”

The Vulnerability of the Developing Brain: Analysis of Highly Expressed Genes in Infant C57BL/6 Mouse Hippocampus in Relation to Phenotypic Annotation Derived From Mutational Studies

“…Previous studies have shown that fetal growth restriction (also known as intrauterine growth restriction) affects the development of hippocampus and is associated with a decreased hippocampus volume but is also associated with an overall reduced brain volume, abnormalities in the development of white matter myelination and the basal ganglia. 47 , 116 - 122 Moreover, fetal growth restriction has been shown to lead to a reduction in motor capabilities, cognition, and learning as well as behavioral issues such as poor attention and altered mood. 116 - 123 …”

“… 47 , 116 - 122 Moreover, fetal growth restriction has been shown to lead to a reduction in motor capabilities, cognition, and learning as well as behavioral issues such as poor attention and altered mood. 116 - 123 …”

Effect of electro‐acupuncture at ST 36 on maternal food restriction‐induced lung phenotype in rat offspring

“…3,4 The essence of IUGR is the adaptive protection of the fetus against insufficient nutrient supply, with the potential of long-term effects on organs such as the lung. 11,28,29 The adverse effects on lung development have been widely addressed in previous studies. 5,6,16 However, there is no specific clinical intervention to prevent MFRinduced pulmonary dysplasia in offspring.…”

“…Malnutrition is the most common cause of IUGR, with nutritional insufficiency being the most common contributor in developing countries 3,4 . The essence of IUGR is the adaptive protection of the fetus against insufficient nutrient supply, with the potential of long‐term effects on organs such as the lung 11,28,29 . The adverse effects on lung development have been widely addressed in previous studies 5,6,16 .…”