# Prenatal striatal morphogenesis: maternal and placental contributions and behavioral consequences

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $386,250

## Abstract

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 addres...

## Key facts

- **NIH application ID:** 10764797
- **Project number:** 5R01MH122485-05
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** HANNA E STEVENS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764797

## Citation

> US National Institutes of Health, RePORTER application 10764797, Prenatal striatal morphogenesis: maternal and placental contributions and behavioral consequences (5R01MH122485-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10764797. Licensed CC0.

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