Altered resting-state brain activity in a postnatally developing valproic acid mouse model of autism
Open Access
- Author:
- Lovell, Trevor Thomas
- Area of Honors:
- Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Yongsoo Kim, Thesis Supervisor
Sairam V Rudrabhatla, Thesis Honors Advisor - Keywords:
- Autism
Mouse
Resting-State
Brain Activation
c-Fos
Valproic Acid
Serial Two-Photon
Immunohistochemistry - Abstract:
- Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder characterized by difficulties with social communication, coinciding with restricted or repetitive interests or behaviors. The symptoms of ASD are heterogeneous between those clinically diagnosed, however these symptoms consistently emerge early in childhood. Previous research has identified significant neuroanatomical and neurophysiological alterations in ASD brains, but the underlying neural mechanisms behind these changes are poorly understood. One of the most widely-researched theories of ASD is the imbalance of excitatory and inhibitory (E/I) neurons within the brain. Despite its significance, E/I balance in early postnatally developing brains has not been examined. In order to test the potential imbalance, we analyzed the neural activation levels in early postnatal mouse brains that were prenatally exposed to valproic acid, an environmental animal model of ASD. We measured endogenous c-Fos, a transcription factor and marker for activated neurons, in mice at postnatal (P) days 7 and 14 using serial two-photon tomography, a novel fluorescence microscopy method that enables us to achieve brain-wide imaging at cellular resolution. Furthermore, we quantified total brain-cell, neuronal and inhibitory neuron-density in the prefrontal cortex to examine altered neuronal composition at P14. The preliminary results of this study show a trend towards overall hyperactivation at P7, followed by hypoactivation at P14. Furthermore, we found the total number of brain cells at P14 decreased, the number of neurons decreased, and the number of inhibitory cells increased. This has led us to propose that excitatory neurons more vulnerable to VPA treatment. Conversely, the relative greater density of inhibitory neurons compared to excitatory neurons can be linked with the hypoactivation at P14. This early postnatal hypoactivation of the brain could result in developmental delays, which is one of the core symptoms of ASD in humans.