Table 1.
Preclinical studies investigating the impact of perinatal compromise on the hippocampus.
| Species and model | Manipulation | Age at study | Hippocampal morphology | Hippocampal function | Reference |
|---|---|---|---|---|---|
| Baboon (Prematurity) | Preterm baboons born 125, 140 and 160dGA (term 185dGA). | Tissue collected after delivery at 125, 140 and 160dGA. | Cell loss was observed in the CA2/3 region of the hippocampus, and reactive astrogliosis was observed. | NA | Inder et al.37 |
| Rabbits (Prematurity) | Preterm rabbits were born on embryonic day 28.5 (term 32 days). | Preterm rabbits were assessed at day 28–30, and tissue collected at day 30. | ↓ dendritic arborisation and spine density in hippocampal CA1. |
↓ social and object novelty ↓ recognition and memory ↑ anxiety behaviour |
Klebe et al.22 |
| Rabbits (Prematurity) | Preterm rabbits born postconceptional age 28 days (term 32 days). | Behavioural assessments at postconceptional age 32 days, brain tissue collected at 32 days. |
↓ neuron density, oligodendrocyte pre-cursor proportion in the hippocampus. ↑ pyknotic and apoptotic cells, evidence of astrogliosis |
Significant motor deficit, less pain responsive. | van der Merwe et al.38 |
| Guinea Pigs (Prematurity) | Preterm pups born 62dGA (term 69dGA) were treated with ganaxolone. | Ganaxolone 2.5 mg/kg twice daily until term equivalence. Behavioural testing at day 25, and tissue collected at day 28. | ↓ myelination in the CA1 region of the hippocampus in premature non-treated animals. | ↑ activity in premature non-treated animals and disinhibited social response. | Shaw et al.39 |
| Sheep (FGR) | Chronic placental insufficiency induced by umbilicoplacental embolization | Surgery at 115dGA, tissue collected at 140dGA (term ~147 days). | ↓ BDNF protein expression in the hippocampus. | NA | Duncan et al.16 |
| Rabbits (FGR) | Ligation of 40–50% of uteroplacental vessels. | Surgery at 25dGA, born at 30 days (term ~31 days). A neurobehavioural assessment was completed then tissue was collected on postnatal day 1. | ↓ fractional anisotropy in FGR hippocampus. Correlations between hippocampus and neurobehavioural domains. | ↓ neurobehavioural performance (motor activity and olfactory function—social interaction) | Eixarch et al.52 |
| Guinea Pigs (FGR) | FGR surgery and prenatal stress (PS). | Stress protocol commenced at 40dGA. Tissue taken at 69dGA (term ~71 days). | ↓ myelin basic protein coverage in the hippocampus in FGR and FGR + PS males. | NA | Cumberland et al.2 |
| Guinea Pigs (FGR) | Chronic placental insufficiency induced by unilateral uterine artery ligation. | Surgery was at 28–30dGA, fetus was collected for tissue analysis at 60dGA (term ~71 days). | ↓ dendritic complexity of CA1 neurons in growth-restricted fetuses | NA | Dieni et al.14 |
| Guinea Pigs (FGR) | Chronic placental insufficiency induced by unilateral uterine artery ligation. | Surgery was at 28–30dGA, fetus was collected for tissue analysis at 60dGA (term ~71 days). |
↓ BDNF protein expression in hippocampus ↑ TrkB protein expression |
NA | Dieni et al.15 |
| Guinea Pigs (FGR) | Maternal nutrient restriction | Guinea pigs are fed 70% of the control diet before pregnancy up to mid-pregnancy. Tissue collected from near-term fetuses | ↑ hypoxia (HP-1) and oxidative stress markers in the hippocampus | NA | Maki et al.86 |
| Rats (FGR) | L-NAME induced FGR (50 mg/kg/d), control FGR and glutathione-treated FGR. | L-NAME intervention 9–19dGA. Glutathione was administered either postnatal day 4–9 or 25–31. | ↓ corrected total cell fluorescence VGLUT1 in the hippocampus in FGR, treatment of glutathione caused ↑ | ↓ in spontaneous alternation percentage (SAP), early treatment with glutathione increased SAP. | Shallie et al.30 |
| Mice (FGR) | Mice inserted with micro-osmotic pump infusion of thromboxane A2-analogue (TXA) to induce FGR | Pump inserted at embryonic day 12. Tissue collected at embryonic day 15.5 or 19, or on postnatal day 18 or 40 |
↓ hippocampal volumes in IUGR mice Accelerated embryonic DG neurogenesis and Sox2+ neural stem cell depletion |
↓ short-term adult learning and memory deficits (novel object recognition and fear conditioning) | Brown et al.28 |
| Mice (FGR) | Dexamethasone-induced FGR and protein restriction-influenced FGR mouse models. | Behavioural experiments were conducted at 8 to 12 weeks of age. |
↓ hippocampal neurogenesis with FGR. ↓ proliferations of neuronal stem cells. ↓ Tet1 protein expression. |
Impaired learning and memory in FGR offspring (novel object recognition and Morris water maze) | Chen et al.13 |
| Mice (FGR) | Mice inserted with micro-osmotic pump infusion of thromboxane A2-analogue (TXA) to induce FGR | Pump inserted at embryonic day 12. Tissue was collected at postnatal day 10, 18 and 40. | Hippocampal synaptic plasticity disturbed with FGR balance between excitatory and inhibitory neuronal development impaired. | NA | St. Pierre et al.29 |
| Rats (FGR) | FGR induced by a low-protein diet or bilateral uterine ligation. | 18 dGA surgery performed. Assessed at postnatal day 1, 12 and 180. | mTOR signalling in the hippocampus dysregulated with FGR | NA | Schömig et al.49 |
| Sheep (Hypoxia) | Umbilical cord occlusion (UCO) until MAP decreased to 18–20mmHG—severe asphyxia | Lambs delivered at 139–141dGA, UCO, with clamp-on delivery. Lambs were resuscitated and maintained for 72 h. |
Neuronal degeneration in hippocampus ↑ astrogliosis in CA1 of the hippocampus |
NA | Aridas et al.61 |
| Sheep (Hypoxia) | UCO for 25 min—severe asphyxia | Instrumentation surgery on 98–100dGA fetal sheep, experimentation 4–6 days after. Fetuses recovered for 3-, 7-, 14- and 21-days post UCO, before post-mortem. |
↓ hippocampal total area with UCO ↓ neuronal density ↑ microglia and astrocyte activation in the hippocampus |
NA | Lear et al.54 |
| Sheep (Hypoxia) | UCO for 10 min—severe asphyxia. | Instrumentation surgery on 120–127dGA fetal sheep, experimentation 72 h after. | Neuronal loss in the hippocampus of the experimental group, more neurons were lost in the dorsal horn than ventral. | NA | Mallard et al.55 |
| Sheep (Hypoxia) | Transient hypoxia-ischaemia (HI) and hypoxia (Hx) in a preterm fetal sheep model. | 88–92dGA (0.65 gestation) surgery performed, HI studies 3 days later. |
↓ hippocampal volume in HI and Hx. ↓ complexity, CA1 maturation augmented. |
Long-term synaptic potentiation is impaired following short-term hypoxia. | McClendon et al.1 |
| Sheep (Hypoxia | UCO for 10 min—severe asphyxia. | Instrumentation surgery on 126dGA fetal sheep, UCO at 130dGA, post-mortem conducted 48 h after. |
↑ pyknotic cells in the CA1 region of hippocampus ↑ astrocytes in the CA1 region of hippocampus ↑ cellular lipid peroxidation |
NA | Yawno et al.56 |
| Rats (Hypoxia) | Intermittent asphyxia at 9 and 5% O2 at postnatal day 11 rat pups. | Asphyxia at postnatal day 11. Behavioural tests from age 3–14 months. | Neurodegeneration in hippocampus and thalamus in post-asphyxia rats. | Impaired spatial learning and memory and increased anxiety. | Gailus et al.64 |
| Mice (Hypoxia) | Chronic sublethal hypoxia (CSH). | Hypoxia from postnatal day 3 to day 11. DTI at days 15, 17, 38, 45 and 51. | ↓ connectivity in CSH mice, damage to axons and disturbance to development. | Hyperactivity observed in CSH mice, impaired performance on spatial memory tasks. | Chahboune et al.3 |
| Chicken Embryos (Hypoxia) | Hypoxic insult for 24 h followed by reoxygenation period and growth hormone treatment. | Chicken embryos at 15 days embryogenesis. | Growth hormone can cross the BBB and provide hippocampal neuroprotection to hypoxia. | NA | Baltazar-Lara et al.76 |
| Sheep (Inflammation) | Preterm fetal sheep model exposed to LPS | Intra-amniotic injection of LPS at 117 days gestation | ↑ cell death in the hippocampus | NA | Yawno et al.25 |
| Sheep (Inflammation) | Preterm fetal sheep model exposed to LPS | LPS IV injection on days 109, 110 and 111 of gestation | ↑ activated microglia in the hippocampus | NA | Yawno et al.68 |
| Rats (Inflammation) | Fetal rats exposed to intra-amniotic LPS. | LPS administered 2 days before birth, and tissue was taken at postnatal day 7. | Activation of microglia in the hippocampus of LPS rats. | NA | Gisslen et al.27 |
| Mice (Inflammation) | Intraperitoneal LPS injections. | Postnatal day 14, behavioural testing was conducted at 8–9 weeks old. | ↓ hippocampal volume in the LPS group. | Memory deficits in LPS mice, impaired retrieval and retention of hippocampus-dependent learning. | Malaeb et al.67 |
| Mice (Inflammation) | Intraperitoneal IL-1β injections | IL-1β administered twice daily from postnatal day 1–4. Tissue was collected at postnatal days 2, 5 and 10, and the long-term cohort conducted behavioural testing up to postnatal day 76. |
↑ pro-inflammatory cytokines and chemokines in the hippocampus ↓ growth of hippocampal neural progenitors |
↑ anxiety-like behaviours (elevated plus maze and open field test) ↓ spatial memory function (Barnes maze task) |
Veerasammy et al.26 |
CSH chronic sublethal hypoxia, dGA days gestational age, DTI diffusion tensor imaging, FGR fetal growth restriction, GA gestational age, GM-IVH germinal matrix-intraventricular haemorrhage, HP-1 hypoxyprobe-1, IL-1β interleukin-1 beta, IVH intraventricular haemorrhage, L-NAM Nω-nitro-l-arginine methyl, LPS lipopolysaccharide, MAP mean arterial pressure, MRI magnetic resonance imaging, mTOR mammalian target of rapamycin, NA not assessed, Tet1 ten–eleven translocation methylcytosine dioxygenase 1, TrkB Tropomyosin receptor kinase B, UCB-MSCs umbilical cord blood-mesenchymal stem cells, UCO umbilical cord occlusion, VLBW very low birth weight, VPT very preterm.