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J Neurosci. 2019 Jun 5;39(23):4595-4605. doi: 10.1523/JNEUROSCI.2031-18.2019. Epub 2019 Apr 2.

Reward-Related Expectations Trigger Dendritic Spine Plasticity in the Mouse Ventrolateral Orbitofrontal Cortex.

Whyte AJ1,2,3, Kietzman HW2,3,4, Swanson AM2,3,4, Butkovich LM2,3,4, Barbee BR2,3,5, Bassell GJ1,4, Gross C6,7, Gourley SL8,3,4,5.

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Departments of Cell Biology.
Pediatrics, Emory School of Medicine.
Yerkes National Primate Research Center.
Graduate Program in Neuroscience.
Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, Georgia 30329.
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, and.
Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267.
Pediatrics, Emory School of Medicine,


An essential aspect of goal-directed decision-making is selecting actions based on anticipated consequences, a process that involves the orbitofrontal cortex (OFC) and potentially, the plasticity of dendritic spines in this region. To investigate this possibility, we trained male and female mice to nose poke for food reinforcers, or we delivered the same number of food reinforcers non-contingently to separate mice. We then decreased the likelihood of reinforcement for trained mice, requiring them to modify action-outcome expectations. In a separate experiment, we blocked action-outcome updating via chemogenetic inactivation of the OFC. In both cases, successfully selecting actions based on their likely consequences was associated with fewer immature, thin-shaped dendritic spines and a greater proportion of mature, mushroom-shaped spines in the ventrolateral OFC. This pattern was distinct from spine loss associated with aging, and we identified no effects on hippocampal CA1 neurons. Given that the OFC is involved in prospective calculations of likely outcomes, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for solidifying durable expectations. To investigate causal relationships, we inhibited the RNA-binding protein fragile X mental retardation protein (encoded by Fmr1), which constrains dendritic spine turnover. Ventrolateral OFC-selective Fmr1 knockdown recapitulated the behavioral effects of inducible OFC inactivation (and lesions; also shown here), impairing action-outcome conditioning, and caused dendritic spine excess. Our findings suggest that a proper balance of dendritic spine plasticity within the OFC is necessary for one's ability to select actions based on anticipated consequences.SIGNIFICANCE STATEMENT Navigating a changing environment requires associating actions with their likely outcomes and updating these associations when they change. Dendritic spine plasticity is likely involved, yet relationships are unconfirmed. Using behavioral, chemogenetic, and viral-mediated gene silencing strategies and high-resolution microscopy, we find that modifying action-outcome expectations is associated with fewer immature spines and a greater proportion of mature spines in the ventrolateral orbitofrontal cortex (OFC). Given that the OFC is involved in prospectively calculating the likely outcomes of one's behavior, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for maintaining durable expectations.


Fragile X syndrome; habit; orbital; prefrontal; response–outcome; stimulus–response

[Available on 2019-12-05]

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