Consequences of excessive plasticity in the hippocampus induced by perinatal asphyxia.

Perinatal asphyxia (PA) is one of the most frequent risk factors for several neurodevelopmental disorders (NDDs) of presumed multifactorial etiology. Dysfunction of neuronal connectivity is thought to play a central role in the pathophysiology of NDDs. Because underlying causes of some NDDs begin before/during birth, we asked whether this clinical condition might affect accurate establishment of neural circuits in the hippocampus as a consequence of disturbed brain plasticity. We used a murine model that mimics the pathophysiological processes of perinatal asphyxia. Histological analyses of neurons (NeuN), dendrites (MAP-2), neurofilaments (NF-M/Hp) and correlative electron microscopy studies of dendritic spines were performed in Stratum radiatum of the hippocampal CA1 area after postnatal ontogenesis. Protein and mRNA analyses were achieved by Western blot and RT-qPCR. Behavioral tests were also carried out. NeuN abnormal staining and spine density were increased. RT-qPCR assays revealed a ß-actin mRNA over-expression, while Western blot analysis showed higher ß-actin protein levels in synaptosomal fractions in experimental group. M6a expression, protein involved in filopodium formation and synaptogenesis, was also increased. Furthermore, we found that PI3K/Akt/GSK3 pathway signaling, which is involved in synaptogenesis, was activated. Moreover, asphyctic animals showed habituation memory changes in the open field test. Our results suggest that abnormal synaptogenesis induced by PA as a consequence of excessive brain plasticity during brain development may contribute to the etiology of the NDDs. Consequences of this altered synaptic maturation can underlie some of the later behavioral deficits observed in NDDs.

Pharmacological alterations that could underlie radiation-induced changes in associative memory and anxiety.

It is widely known that ionizing radiation is a physical agent broadly used to kill tumor cells during human cancer therapy. Unfortunately, adjacent normal tissues can concurrently undergo undesirable cell injury. Previous data of our laboratory demonstrated that exposure of developing rats to ionizing radiations induced a variety of behavioral differences respect to controls, including changes in associative memory and in anxiety state. However, there is a lack of data concerning modifications in different related pharmacological intermediaries. Therefore, the aim of the present study was to investigate whether the behavioral differences observed in young animals irradiated at birth might be underlain by early changes in PKCß1 levels which, in turn, could lead to changes in hippocampal GABAergic neurotransmission. Male Wistar rats were irradiated with 5Gy of X rays between 24 and 48 h after birth. Different pharmacological markers related to the affected behavioral tasks were assessed in control and irradiated hippocampus at 15 and 30 days, namely GABAA receptor, GAD65-67, ROS and PKCß1. Results showed that all measured parameters were increased in the hippocampus of 30-days-old irradiated animals. In contrast, in the hippocampus of 15-days-old irradiated animals only the levels of PKCß1 were decreased. These data suggest that PKCß1 might constitute a primary target for neonatal radiation damage on the hippocampus. Therefore, it could be hypothesized that an initial decrease in the levels of this protein can trigger a subsequent compensatory increase that, in turn, could be responsible for the plethora of biochemical changes that might underlie the previously observed behavioral alterations.

Rat hippocampal alterations could underlie behavioral abnormalities induced by exposure to moderate noise levels.

Noise exposure is known to affect auditory structures in living organisms. However, it should not be ignored that many of the effects of noise are extra-auditory. Previous findings of our laboratory demonstrated that noise was able to induce behavioral alterations that are mainly related to the cerebellum (CE) and the hippocampus (HC). Therefore, the aim of this work was to reveal new data about the vulnerability of developing rat HC to moderate noise levels through the assessment of potential histological changes and hippocampal-related behavioral alterations. Male Wistar rats were exposed to noise (95-97 dB SPL, 2h daily) either for 1 day (acute noise exposure, ANE) or between postnatal days 15 and 30 (sub-acute noise exposure, SANE). Hippocampal histological evaluation as well as short (ST) and long term (LT) habituation and recognition memory assessments were performed. Results showed a mild disruption in the different hippocampal regions after ANE and SANE schemes, along with significant behavioral abnormalities. These data suggest that exposure of developing rats to noise levels of moderate intensity is able to trigger changes in the HC, an extra-auditory structure of the Central Nervous System (CNS), that could underlie the observed behavioral effects.

Effects of loud noise on hippocampal and cerebellar-related behaviors. Role of oxidative state.

Living organisms are exposed to potentially hazardous noise levels coming from the environment. Besides the direct effect on hearing, extra-auditory noise-associated effects should be considered. Since loud noise has been suggested to induce central nervous system symptoms, the aim of the present work was to investigate the effect of acute (ANE) and chronic noise exposures (CNE) on different behavioral tasks. To understand the mechanisms involved, levels of oxidative status markers were determined in two areas related to memory processes, the hippocampus (Hip) and the cerebellum (CE). 15-day-old male Wistar rats were exposed to loud noise (95-97 dB, 2h/day), at ANE or CNE. At 30 days, rats were subjected to different CE and Hip-related behavioral tasks. Reactive oxygen species (ROS) levels and antioxidant enzyme activities (CAT and SOD) were also assessed. Results show impairments in spatial and associative memory in noise-exposed animals. Moreover, a decrease in anxiety levels and an increase in habituation memory were observed in CNE animals. While an increase in cerebellar ROS levels was found early after the first noise exposure, a decrease was found in the CE and the Hip at 30 days. The activity of hippocampal CAT was increased early and remained high in ANE rats, while it was unchanged in the CE. Finally, although SOD activity was decreased immediately after the first noise exposure, its levels were increased at 30 days in ANE rats. In summary, the present study shows that an imbalance in oxidative status induced by noise exposure could underlie behavioral changes, some of which would be long-lasting.