Buck, T. G. | bioRxiv Science

bioRxiv2024

PRENATAL STRESS MODIFIES SPATIAL COGNITION IN MICE: EFFECTS OF AGE AND SEX.

Prenatal stress is linked with neuropathology of the cortical-hippocampal circuit, due to abnormal brain development that leads to long term neurological deficits in offspring, in both rodents and in humans with psychiatric disorders. Conflicting reports exist of the effects of prenatal stress in C57BL/6J mice, which is an inbred strain that is the most frequently used for neurobehavioral research. We now present comprehensive analyses of the effects of prenatal stress on spatial cognition and related behaviors in this inbred strain, in males and females at young adult and aged adult stages. The prenatal stress exposure was conducted by exposing pregnant mice to restraint stress three times daily from day 7 to day 18 of gestation. We tested the effects of prenatal stress on cognitive behavior using a battery of behavioral assays including the open-field test, the light-dark box, Morris water maze spatial acquisition and spatial reversal testing, in addition to assays of social interaction and social memory. We compared the behavioral phenotype of male and female offspring in young adult (10-20 weeks) and older adult ages (60- 70 weeks). Data reveal that male but not female mice had reduced body weight throughout the lifespan after exposure to prenatal stress. Young prenatally stressed adult females showed greater organization of tracking behavior in spatial acquisition tests than other groups. Prenatal stress improved reversal learning in aged females relative to non-stressed aged females. We detected decreased extinction of the spatial acquisition memory in prenatally stressed young adult mice of both sexes. Overall results indicate that prenatal stress may protect females from detrimental effects of age on function of the hippocampus. Our data support the finding that C57BL/6J are a relatively resilient strain of mouse that may be useful for investigating the differences between resilience and susceptibility to stress. Genomic differences between the C57BL/6J strain relative to Swiss Webster strain, which is more susceptible to prenatal stress are discussed. Future studies of prenatal stress in the C57BL/6J mouse strain should focus on the identification of molecular pathways that underlie resilience to prenatal stress, to identify novel targets for drug development.

neuroscience↗

bioRxiv2024

Prenatal Stress Alters Transcription of NMDA-Type Glutamate Receptors in the Hippocampus.

Prenatal stress damages the development of the cortico-hippocampal circuit in the brain and increases the risk for neurological disorders associated with deficits of social behavior, including schizophrenia. Accumulating evidence indicates that the NMDA-type glutamate receptor plays an important role in social cognition and stress-induced pathology in the hippocampus. In this study we have tested the hypothesis that transcription of NMDAR subunits is modified in the frontal cortex and hippocampus of prenatally stressed mice. Prenatal stress exposure was conducted by exposing pregnant mice to restraint stress three times daily during gestational weeks 2 and 3. We treated the adult offspring with haloperidol (1mg/kg), clozapine (5mg/kg) or vehicle (saline) twice daily for 5 days, after which we measured social interaction behavior (SI) and locomotor activity. After euthanasia, we measured the transcription of NMDAR subunits in the hippocampus and frontal cortex. We observed that saline-treated prenatally stressed (PRS-Sal) mice had reduced social interaction (SI) behavior compared to controls (NS-Sal) (P<0.01). This deficit was recovered in PRS mice treated with clozapine (PRS-Clz) but not the haloperidol-treated PRS group (PRS-Hal). These changes were not due to suppressed locomotion as neither PRS nor antipsychotic treatment reduced locomotor activity. These effects of prenatal stress were associated with increased transcription of NMDAR subunits (GRIN genes) in the hippocampus but not the frontal cortex. We observed positive correlation between GRIN transcription and social behavior in the frontal cortex, and conversely, negative correlation between GRIN transcription and social behavior in the hippocampus. Studies indicate that transcription of NMDARs is activity dependent, therefore altering the transcription levels of different NMDAR subunits would have a significant impact on the excitatory transmission in the corticolimbic circuit. The results suggest a molecular pathway by which prenatal stress in mice leads to life-long deficits in social behavior. Its worth noting that while these associations have been observed in mice, the direct translation to human prenatal stress and NMDA receptor alterations requires further investigation. Nevertheless, these findings contribute to our understanding of the impact of prenatal stress on pathology in the hippocampus and downstream effects on social behavior and may have implications for understanding neuropsychiatric disorders related to prenatal stress exposure.

pharmacology and toxicology↗