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Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived
Kelsey S Zimmermann1, John A Yamin2, Donald G Rainnie3
1Department of Pediatrics, Emory University, Atlanta, Georgia; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia; Department of Yerkes National Primate Research Center, Emory University, Atlanta, Georgia; Department of Graduate Program in Neuroscience, Emory University, Atlanta, Georgia.
Background:
Distinguishing between actions that are more likely or less likely to be rewarded is a critical aspect of goal-directed decision making. However, neuroanatomic and molecular mechanisms are not fully understood.
Methods:
We used anterograde tracing, viral-mediated gene silencing, functional disconnection strategies, pharmacologic rescue, and designer receptors exclusively activated by designer drugs (DREADDs) to determine the anatomic and functional connectivity between the orbitofrontal cortex (OFC) and the amygdala in mice. In particular, we knocked down brain-derived neurotrophic factor (Bdnf) bilaterally in the OFC or generated an OFC-amygdala "disconnection" by pairing unilateral OFC Bdnf knockdown with lesions of the contralateral amygdala. We characterized decision-making strategies using a task in which mice selected actions based on the likelihood that they would be reinforced. Additionally, we assessed the effects of DREADD-mediated OFC inhibition on the consolidation of action-outcome conditioning.
Results:
As in other species, the OFC projects to the basolateral amygdala and dorsal striatum in mice. Bilateral Bdnf knockdown within the ventrolateral OFC and unilateral Bdnf knockdown accompanied by lesions of the contralateral amygdala impede goal-directed response selection, implicating BDNF-expressing OFC projection neurons in selecting actions based on their consequences. The tyrosine receptor kinase B agonist 7,8-dihydroxyflavone rescues action selection and increases dendritic spine density on excitatory neurons in the OFC. Rho-kinase inhibition also rescues goal-directed response strategies, linking neural remodeling with outcome-based decision making. Finally, DREADD-mediated OFC inhibition weakens new action-outcome memory.
Conclusions:
Activity-dependent and BDNF-dependent neuroplasticity within the OFC coordinate outcome-based decision making through interactions with the amygdala. These interactions break reward-seeking habits, a putative factor in multiple psychopathologies.
Insights
Brain-derived neurotrophic factor (BDNF) in the orbitofrontal cortex (OFC) and its amygdala connections are crucial for goal-directed decision-making. Neuroplasticity in the OFC guides action selection based on reward likelihood.
Area of Science:
- Neuroscience
- Decision Science
- Molecular Biology
Background:
- Goal-directed decision-making relies on distinguishing actions based on reward probability.
- The underlying neuroanatomic and molecular mechanisms require further elucidation.
Purpose of the Study:
- To investigate the functional connectivity between the orbitofrontal cortex (OFC) and amygdala in mice.
- To determine the role of brain-derived neurotrophic factor (BDNF) in OFC-amygdala circuits for decision-making.
Main Methods:
- Utilized anterograde tracing, viral-mediated gene silencing (Bdnf knockdown), and functional disconnection strategies.
- Employed pharmacologic rescue and designer receptors exclusively activated by designer drugs (DREADDs) for OFC inhibition.
- Assessed decision-making strategies in a reinforcement-based task and action-outcome conditioning.
Main Results:
- Bilateral OFC Bdnf knockdown and OFC-amygdala disconnection impaired goal-directed response selection.
- BDNF-expressing OFC projection neurons are critical for selecting actions based on consequences.
- Pharmacologic rescue (7,8-dihydroxyflavone, Rho-kinase inhibition) restored decision-making strategies and neural plasticity.
Conclusions:
- Activity-dependent and BDNF-dependent neuroplasticity in the OFC, via amygdala interactions, coordinate outcome-based decision-making.
- These OFC-amygdala interactions are essential for breaking reward-seeking habits, potentially impacting psychopathology.
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