# (9) Biophysical Description of Age and Dose Dependent Changes to Dendritic Morphology that Impact Cognition following Radiation Cancer Therapy

> **NIH NIH R01** · UNIVERSITY OF NEVADA LAS VEGAS · 2020 · $472,047

## Abstract

Abstract/Summary
The National Cancer Institute, Provocative Question Initiative considers specific high impact questions in
cancer research, including what are the molecular and/or cellular mechanisms that underlie the development of
cancer therapy induced severe adverse sequelae? Cognitive decrements including impaired learning and
memory are common occurrences for the nearly one-half a million Americans of varying ages undergoing
radiation therapy for brain cancers each year. Recently, changes to dendritic morphology have been observed
in the hippocampus and medial pre-frontal cortex following low to moderate doses of x-rays and charged
particles (protons and heavier ions) that are representative of patient doses at the tumor margins (1 to 10 Gy).
The resultant morphological deficits have been shown to be temporally coincident with impaired behavioral
performance using a variety of cognitive tests in multiple rodent models. Traditionally biophysics models have
played a key role in understanding dose delivery and the minimization of normal tissue effects in radiation
therapy; however such models have not been considered for the complex structures that comprise various
types of neurons in the brain. Our proposal brings together the modeling skills at the University of Nevada, Las
Vegas and the laboratory at the University of California, Irvine to develop a predictive stochastic
microdosimetric model of radiation induced changes to dendritic morphology in dentate granule cell layer
(GCL) and pyramidal cell (PYC) neurons in the hippocampal and medial pre-frontal cortex of transgenic mice
using a highly innovative combined computational-experimental approach. Our primary hypothesis is that
ionizing radiation (IR) will alter dendritic morphology in neurons of the hippocampus, medial pre-frontal cortex
(mPFC), and likely neurons in other brain areas and that biophysics models based on a stochastic
microdosimetry can lead to accurate predictions of these changes for different radiation doses, modalities
(radiation type) and delivery paradigms (acute vs fractionated). Furthermore, we hypothesize that age related
susceptibility will influence the dose and time-dependent radiation response of the CNS, and that these
changes will be responsive (i.e. ameliorated) after dose fractionation. Our mechanistic model will provide a
quantitative description of changes to dendritic morphology and spine dynamics as dependent on dose and
dose fractionation paradigms using x-rays, protons, and carbon beams, the preferred radiation modalities used
for the clinical management of brain cancer. In addition, biophysical models will incorporate age, time and
dose-dependent radio-dendritic morphology parameters that will be directly tested experimentally, by
subjecting young (1 month) and adult (6 month) mice to carefully selected irradiation paradigms, while studying
the resulting morphologic changes over time (30 days or longer).

## Key facts

- **NIH application ID:** 9982044
- **Project number:** 5R01CA208526-05
- **Recipient organization:** UNIVERSITY OF NEVADA LAS VEGAS
- **Principal Investigator:** Francis A Cucinotta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $472,047
- **Award type:** 5
- **Project period:** 2016-08-17 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982044

## Citation

> US National Institutes of Health, RePORTER application 9982044, (9) Biophysical Description of Age and Dose Dependent Changes to Dendritic Morphology that Impact Cognition following Radiation Cancer Therapy (5R01CA208526-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9982044. Licensed CC0.

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