# Neural Basis of Individual Differences in Fear Extinction

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

ABSTRACT
While most of the general population, and particularly combat veterans, experience traumatic events, only a
relatively small proportion go on to develop post-traumatic stress disorder (PTSD), suggesting there are
individual differences in susceptibility to the long-term consequences of traumatic stress. PTSD patients also
show impairments in fear extinction, extinction recall, and safety learning, so extinction learning processes
form the basis of exposure-based therapies. We have observed individual variation in the behavioral (freezing)
and cardiovascular responses during the extinction of cued fear memories in outbred rats, providing a model to
study PTSD-like resistance to fear extinction. Our overarching goal is to define the mechanistic role of
cholinergic system, and specifically muscarinic receptors (mACHRs), in differentially regulating the cortico-
amygdalar circuit to induce individual differences in extinguishing fear memories. Cholinergic inputs from the
basal forebrain (BF) provide strong inputs to the prefrontal (PFC)-amygdalar circuit which is important for fear
extinction. Preliminary data in our rat model suggests that individual differences in cued fear extinction are
related to differences in cholinergic neurotransmission and function, but particularly mACHR regulation in the
basolateral amygdala (BLA). Our hypothesis is that muscarinic receptor activation in the amygdala decreases
excitatory inputs from the PFC to diminish fear extinction learning in the resistant (high freezing) phenotype,
and thus extinction learning can be enhanced specifically in this extinction resistant population with mACHR
antagonists. All experiments compare individual differences in male and female rats with distinct extinction
phenotypes. Using a multidisciplinary approach, three Aims explore the ability of pharmacological approaches
to enhance extinction learning or recall in the extinction resistant phenotype, and provide a mechanistic view of
the neurobiological effects underlying these effects. Aim 1 tests the therapeutic potential of mACHR
antagonists, agonists, and positive allosteric modulators in shifting fear extinction, with a focus on M1 and M4
selective compounds. We will examine extinction of conditioned freezing, ultrasonic vocalizations, and
cardiovascular responses during extinction learning and recall with both systemic and intra-amygdalar
injections of mACHR compounds. Aim 2 examines if the differential release of acetylcholine from the basal
forebrain and/or acetylcholinesterase activity mediates differences in fear extinction. In vivo microdialysis will
be used to assess acetylcholine and glutamate efflux, and a transgenic rat model will be used for
optogenetically stimulating or inhibiting basal forebrain cholinergic inputs to examine effects in our extinction
phenotypes. Aim 3 examines muscarinic modulation of excitatory responses and synaptic plasticity evoked by
stimulation of PFC inputs using optogenetic and electr...

## Key facts

- **NIH application ID:** 9824457
- **Project number:** 5I01BX001374-06
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Marlene A. Wilson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9824457

## Citation

> US National Institutes of Health, RePORTER application 9824457, Neural Basis of Individual Differences in Fear Extinction (5I01BX001374-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9824457. Licensed CC0.

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