# Abnormal Prefrontal Network Structure Underlying Anxiety in Autism

> **NIH NIH K08** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $200,178

## Abstract

Project Summary
Autism is a pervasive developmental disorder caused by heterogeneous insults at the cellular or molecular level
affecting the function of distributed brain regions. Co-morbid anxiety and other psychiatric disorders are common,
likely due to underlying mechanisms shared with core features of autism. Loss of the postsynaptic density protein
Shank3 is associated with deficits in synapses at the molecular level, as well as autism and intellectual disability.
Autism is associated with changes in prefrontal circuit function which likely impede the spatial and temporal
patterning of neuronal ensemble activity, degrading the precision with which the prefrontal cortex responds to
input. I propose to test the hypothesis that abnormal recruitment of prefrontal activity in response to vHPC input
during anxiety contributes to abnormal anxiety in the Shank3 knockout (KO) mouse.
I will first define the specificity with which ensemble activation occurs in response to vHPC input within prefrontal
microcircuits, and determine the degree to which ensemble recruitment is altered in mice lacking Shank3. These
mice are abnormally anxious and have abnormal social interaction. I have demonstrated that network
organization in prefrontal slices from KO mice is abnormal; individual neurons are more active, and the
organization of ensemble activity also abnormal. Specifically, pairwise correlations are abnormally high and the
KO generates abnormal patterns of activity. I quantified the patterns of activity sampled by the network by
counting the number of specific n-neuron motifs consisting of combinations of 2,3,4, or 5 neurons. This revealed
that the KO samples a greater number of patterns, but patterns sampled are less likely to occur more frequently
than in shuffled data. This suggests that while the KO samples more diverse modes of activity, it does so in a
disorganized manner. This may increase noise or decrease the precision of ensemble recruitment during
behavior. I propose to test how these changes in network activity affect how the PFC responds to anxiogenic
input using optogenetic stimulation of defined inputs from the ventral hippocampus to examine neuronal
ensembles recruited in response to specified input (Aim 1). I will then use implanted microendoscopes to explore
the precision with which distinct ensembles of neurons are recruited during anxiety-related behavior (Aim 2) in
the intact animal, and the precision with which anxiogenic input from the ventral hippocampus results in activation
of PFC projections to the amygdala (Aim 3).
These studies are of immediate relevance to autism, as despite a dramatic increase in our knowledge of genetic
and cellular pathology underlying autism there remains a paucity of therapeutic options. This mentored award
will provide the opportunity to develop technical skills and quantitative methods needed for the analysis of large,
dynamic populations of neurons. I will be mentored by Dr. Vikaas Sohal, a clinician-...

## Key facts

- **NIH application ID:** 10452527
- **Project number:** 5K08NS105938-06
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Nicholas Alonzo Frost
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $200,178
- **Award type:** 5
- **Project period:** 2021-09-26 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452527

## Citation

> US National Institutes of Health, RePORTER application 10452527, Abnormal Prefrontal Network Structure Underlying Anxiety in Autism (5K08NS105938-06). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10452527. Licensed CC0.

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