This project aims to test whether prenatal selective serotonin reuptake inhibitor (SSRI) exposure in a syndromic (monogenic) mouse model (Fmr1-KO) and idiopathic (polygenic) mouse model (BTBR) of autism spectrum disorders (ASD) exacerbates existing cognitive and synaptic plasticity phenotypes or produces new ASD-related cognitive impairments and synaptic alterations. Specific Aim 1 will determine whether prenatal SSRI exposure in Fmr1-KO and BTBR mice affects spatial learning and reversal learning under conditions in which feedback is certain (100% accurate) and under conditions in which feedback is uncertain (80% accurate for correct choice). Specific Aim 2 will determine in the same animals from Aim 1 whether prenatal SSRI exposure affects different aspects of hippocampal synaptic plasticity in adult Fmr1-KO and BTBR mice. The two aims will be integrated by determining whether there is a relationship between different learning phenomena (Aim 1) and various forms of hippocampal synaptic plasticity (Aim 2). Together, the findings from this project will advance understanding of how a prenatal risk factor interacts with genetic factors to alter synaptic and cognitive function related to ASD. Overall, this approach can provide promising new neurobehavioral endophenotypes for developing mechanistically-based neuropharmacological interventions.
Naked mole-rats have an unusual lifestyle in that they combine a fully subterranean existence, extreme sociality, and a proclivity for living in large numbers. Spending their entire lives in crowded burrows where many individuals share a limited air supply, these animals have developed an unusual resilience to the challenges of breathing exceptionally low levels of oxygen and exceptionally high levels of carbon dioxide. Initial studies have revealed numerous extraordinary features of naked mole-rat neurobiology that are hypothesized to be adaptations for living under these challenges. Some of these features protect the brain from low O2, while others promote peripheral nerve insensitivity to CO2-induced acidosis. Intriguingly, the same traits are also seen in neonatal mammals, prompting the current hypothesis that naked mole-rats employ a form of arrested development (neoteny) to protect their nervous system from chronic low O2/high CO2, a protection lost during development in other mammals. The current goals of the project are to better understand the nature of neoteny and associated phenomena, including the underlying basis of hypoxia-induced suspended animation and the molecular/ genetic basis of neonate-like hypoxia tolerance. The project will rely on a systems neurobiology approach, which will include behavioral, physiological, anatomical, and molecular experiments. The results of the studies could transform our understanding of nervous system adaptations to environmental conditions and promote a wider appreciation for evolutionary neurobiology in students and the public at large.
Stroke is one of the leading causes of both mortality and adult-acquired disability worldwide. The loss of blood supply (ischemia) to the brain induces a rapid cascade of cellular reactions to loss of energy (ATP) production that causes neuronal death within minutes. One particularly vulnerable area to such an infarct is the hippocampus: CA1 hippocampal neurons are the first to show pathology after global ischemia. Importantly, much of the “ischemic catastrophe” can be reproduced in slices of hippocampus in vitro after removal of the oxygen supply (hypoxia) to the slices. Given the unpredictability of stroke and the rapid neuronal damage that ensues, post-stroke therapy has limited effectiveness. There is, therefore, great interest in interventions that can reduce the severity of subsequent ischemic events. One promising intervention is exercise training: maintaining physical fitness can both decrease the likelihood of stroke occurrence and improve recovery from strokes when they occur. However, the mechanisms by which physical activity protects the brain from ischemic damage are unknown.
This research project uses the hippocampal slice preparation to assess the effects of exercise training in mice on neuronal responses to hypoxic injury. Groups of mice will be given either exercise training (daily access to running wheels) or no exercise training. We will measure the time to anoxic depolarization, a measure of ischemic vulnerability, in slices from the exercise and sedentary groups. We will also measure the relative recovery of neurons after a specific time (2 minutes) spent in the depolarized state as a measure of neuroprotection.