# Neurotrophic and ontogenic factors in medial orbitofrontal cortical function

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $424,673

## Abstract

SUMMARY
In day-to-day life, we often must select actions by envisioning the likely outcomes of our behaviors, and we adjust
our behavior if prospective outcomes become more or less valuable. This capacity for prospective decision
making can be imperiled by addictive drugs, such that individuals suffering from substance use disorders may
seek addictive drugs despite threats to social ties, employment, etc.
 The ability to select actions that will result in valued rewards requires the medial orbitofrontal cortex (MO),
particularly when those rewards are not immediately delivered (are unobservable) and must be anticipated.
Addictive drugs like cocaine cause MO atrophy and impede MO function in both rodents and humans,
emphasizing the need to fully understand the manner by which the MO coordinates prospective action selection.
 The neurotrophic factor, Brain-Derived Neurotrophic Factor (BDNF), and its high-affinity receptor
tropomyosin receptor kinase B (TrkB) control MO function. BDNF presence in the MO is necessary and sufficient
for mice to appropriately direct behaviors towards rewards of higher value relative to low-value options. Further,
locally overexpressing a truncated isoform of TrkB (TrkB.t1), which acts as a dominant negative, or locally
ablating TrkB occludes value-based action, particularly when potential rewards are unobservable. We
hypothesize that neurotrophin signaling stabilizes neural connections essential to adaptive choice.
 Which neural connections are necessary for choice behavior? We recently discovered that ventral
hippocampal (vHC) inputs to the MO are necessary for value memory updating – and particularly, the integration
of new value information into instrumental response strategies. Meanwhile, projections from the MO to the
basolateral amygdala (BLA) are necessary for value memory retrieval (and not updating). Thus, vHC inputs to
the MO appear to update value memory, while outputs retrieve new memories to execute adaptive action.
 The goals of this proposal are to: (1) determine whether functional vHC-to-MO and MO-to-BLA connections
require TrkB-mediated signal propagation on excitatory MO neurons.
 (2) We will next determine whether MO neurons form stable value memory traces necessary for adaptive
choice, and whether trace formation requires i.) vHC inputs, ii.) TrkB, and iii.) local dendritic spine plasticity.
 (3) The capacity for prospective goal-directed action improves throughout adolescence. Because of this,
mechanistic insights can be gained by studying adolescent development. We will delineate the adolescent
development of vHC-to-MO projections, the morphological maturation of projection-defined layer V MO neurons,
and the stimulation of TrkB+ MO neurons during decision-making tasks in mice. We will test the hypotheses that
TrkB controls typical development, and that TrkB+ MO neurons are increasingly stimulated during tests of
behavioral flexibility as mice mature, ultimately forming stable memory traces attune...

## Key facts

- **NIH application ID:** 10652720
- **Project number:** 2R01DA044297-06A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Shannon Leigh Gourley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $424,673
- **Award type:** 2
- **Project period:** 2018-03-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652720

## Citation

> US National Institutes of Health, RePORTER application 10652720, Neurotrophic and ontogenic factors in medial orbitofrontal cortical function (2R01DA044297-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10652720. Licensed CC0.

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