Autism spectrum disorder (ASD) is linked with enlargement of striatum and deficits in learning processes that depend on striatal function. We have found increased striatal volume, greater striatal neuron generation, and changes in striatal-dependent learning in mice exposed to prenatal maternal repetitive restraint stress. Prenatal disruptions including maternal stress are risk factors for negative developmental outcomes in children (e.g. ASD). There are gaps in knowledge about whether enlarged striatum is causative of ASD-related problems with learning and what maternal, placental and brain factors during prenatal development contribute to increased striatal morphogenesis. We have preliminary data showing that prenatal stress increases levels of maternal interleukin-6, a proinflammatory cytokine implicated in ASD, which independently increases striatal neuron generation. We also show that increased IGF signaling between placenta and embryonic brain is implicated in our prenatal stress model and independently increases striatal neuron generation. We hypothesize that increased striatal morphogenesis plays a central role in prenatal risk for neurodevelopmental problems and that these changes are mediated by maternal interleukin-6 and IGF signaling. Our focus on striatal morphogenesis in embryonic brain is particularly novel and significant; we will examine multiple levels of its regulation and consequences when striatal growth is increased. We also will test the same mechanisms across multiple maternal stress models?restraint, foot-shock, and chronic variable stress--to generalize these stress findings beyond a single paradigm. First in Aim 1, we will assess the necessity and sufficiency of elevated maternal interleukin-6 for increased striatal neuron generation as a component of prenatal stress effects. We will also determine the importance of exposure timing, a critical question during rapid embryonic development. Second in Aim 2, we will assess the necessity and sufficiency of increased IGF signaling for prenatal stress effects on striatal progenitors. We will also assess growth factor changes in maternal circulation and placenta across maternal stress models. Lastly in Aim 3, we will examine the sufficiency of increased striatal neuron generation in vivo for changes in animal learning and striatal physiology. We will use a novel strategy to increase striatal neuron generation in utero: intracerebroventricular injection of a selective metabotropic glutamate receptor agonist, CHPG, with specificity for increasing cell proliferation in striatal progenitors. In offspring with this exposure, we will test striatal dependent types of learning?procedural, habit, reversal, and interval timing through operant training. We will also measure striatal neuronal ramping activity during learned interval timing. With our expertise in understanding prenatal stress, embryonic brain morphogenesis, growth factors, and rodent learning, we are well-situated to address how the proposed mechanisms could be targets for prevention and treatment.

Public Health Relevance

Many children with autism spectrum disorder (ASD) have enlarged dorsal striatum and striatal-dependent learning problems, which may be central to clinically significant impairments. Prenatal stress is a risk factor for ASD; translatable targets for prevention and intervention of ASD are goals of studying prenatal stress in model systems. We will study a novel mechanism?increased striatal neuron generation?in mouse models of prenatal stress, test its importance for striatal growth and striatal-dependent learning, and examine its regulation by prenatal maternal and placental mechanisms which we and others have implicated in prenatal stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH122485-01
Application #
9942651
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tonelli, Leonardo H
Project Start
2020-04-01
Project End
2025-01-31
Budget Start
2020-04-01
Budget End
2021-01-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Iowa
Department
Psychiatry
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242