Objective
Hypoxic-ischemic (HI) brain injury in the human perinatal period often leads to significant long-term neurobehavioral dysfunction in the cognitive and sensory-motor domains. Using a neonatal HI injury model (unilateral carotid ligation followed by hypoxia) in postnatal day seven rats, the present study investigated the long-term effects of HI and potential behavioral protective effect of pentoxifylline.
Methods
Seven-day-old rats underwent right carotid ligation, followed by hypoxia (F
i
O
2
= 0.08). Rats received pentoxifylline immediately after and again 2 hours after hypoxia (two doses, 60–100 mg/kg/dose), or serum physiologic. Another set of seven-day-old rats was included to sham group exposed to surgical stress but not ligated. These rats were tested for spatial learning and memory on the simple place task in the Morris water maze from postnatal days 77 to 85.
Results
HI rats displayed significant tissue loss in the right hippocampus, as well as severe spatial memory deficits. Low-dose treatment with pentoxifylline resulted in significant protection against both HI-induced hippocampus tissue losses and spatial memory impairments. Beneficial effects are, however, negated if pentoxifylline is administered at high dose.
Conclusion
These findings indicate that unilateral HI brain injury in a neonatal rodent model is associated with cognitive deficits, and that low dose pentoxifylline treatment is protective against spatial memory impairment.
Long-term potentiation and long-term depression (LTD) are cellular mechanisms of learning and memory in the mammalian brain. We have previously shown that adult hyperthyroid rats showed a delay in the acquisition of a place learning task and attenuated long-term potentiation. However, changes in LTD in hyperthyroidism remain unclear. Rats were administered 0.2 mg/kg/day of L-thyroxine for 21 days starting at postnatal day 40 to induce hyperthyroidism. LTD was induced in the dentate gyrus using low-frequency stimulation (LFS) of the perforant pathway. The mRNA expressions of p38 mitogen-activated protein kinase (p38-MAPK) and protein phosphatase 1 (PP1) were evaluated using a quantitative reverse transcriptase PCR. In control rats, a standard LFS protocol induced a slight depression of the population spike (PS) amplitude during the induction phase of LTD (76±13% vs. baseline), but a small potentiation of the PS amplitude was observed in the early (107±18%) and late (111±20%) phases of LTD. Interestingly, in the hyperthyroid rats, the same LFS protocol induced a reliable LTD in the dentate gyrus of the hippocampus as evidenced by a marked depression in the PS amplitude during the induction (54±6% vs. baseline) and the early phases (56±8%) of LTD. Elevated mRNA levels of p38-MAPK and PP1 were observed in the hippocampus of the LFS-treated hyperthyroid rats compared with the hippocampus of the vehicle-treated hyperthyroid rats. No significant change in p38-MAPK or PP1 mRNA expression was observed in the euthyroid rats. The present study shows that a standard LFS protocol can induce a durable depression of synaptic strength and an upregulation of PP1 and p38-MAPK mRNA in hyperthyroid rats. We conclude that hyperthyroidism can induce molecular changes associated with degeneration of the hippocampus. The relationship between the levels of thyroid hormone and dementia requires further investigation.
The present study investigated the differences in the activation of c‐Jun NH2‐terminal kinases (JNK), p38 mitogen‐activated protein kinases (p38MAPK), and extracellular signal‐regulated kinases 1/2 (Erk1/2) 1 hr after the induction of long‐term potentiation (LTP) between rats with hyperthyroidism that was produced at two different stages of development. Hyperthyroidism was produced in rats by daily injections of L‐thyroxine (T4, ip., 0.2 mg/kg) to their dams for lactation period or to the rats itself during the young adult period. LTP was induced by application of high‐frequency stimulation protocol. Five‐min averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes at the end of recording were averaged to measure the magnitude of LTP. Total and phosphorylated levels of Erk1/2, JNK, and P38‐MAPK were assessed via western blotting in these hippocampi. LTP was found to be impaired in both groups of hyperthyroidisms, but this impairment observed together with increased expression and phosphorylation of ERK1/2, and increased phosphorylation of JNK in rats treated maternally with T4 compared to those treated adultly. These results suggest that excessiveness of thyroid hormone has longstanding effects on hippocampal function and may account for failed LTP in both early and relatively late stage of development depending on various molecular pathways, such as ERK1/2 and JNK.
Background: Numerous studies have suggested that sexual dimorphism may exist in learning and memory. Herein, we associated sex differences in the long-term potentiation (LTP) and the long-term depression (LTD) with the N-methyl-D-aspartate (NMDA) receptor subunits, given their well-known roles in the establishment of longterm memory.Methods: After a 15-min baseline recording, LTP and LTD were induced by application of high-and low-frequency stimulation protocols, respectively. The averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes between 70-75 minutes were used as a measure of the LTP/LTD. The mRNA level of GluN1, GluN2A and GluN2B subunits were evaluated using real-time quantitative polymerase chain reaction (RT-qPCR) analysis.Results: Male and female rats showed no differences in a pre-LTP and pre-LTD I/O curves. Although the magnitude of LTP was similar between sexes, female animals exhibited LTD in much more easily than their male counterparts in the absence of the difference in I/O curves. Concomitantly, none of transcript significantly differed between sexes for baseline gene expression, while the decreasing NR2A/NR2B ratio in female rats throughout LTP and LTD time courses was only observed after LTP in male rats. In addition, NR1 mRNA expression was increased in male rats compared to female rats 60min after LTP induction.
Conclusion:The capacity for LTD expression is higher in female rats compared to male rats in young adult ages, and this sex difference is paralleled by a sex difference in GluN2B subunit generated by perforant path LFS. The present study suggests that sex differences in hippocampus-dependant learning tasks may be result of sexually dimorphic hippocampal LTD, but not LTP.
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