Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor

doi:10.1016/j.biopsych.2015.10.026

Biological Psychiatry

Volume 81, Issue 4, 15 February 2017, Pages 366-377

https://doi.org/10.1016/j.biopsych.2015.10.026 Get rights and content

Abstract

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.

Section snippets

Methods and Materials

For additional details, see Supplemental Methods and Materials.

The Mouse OFC Innervates the Dorsal Striatum and Amygdala

We first compared projection patterns between the well-studied dorsolateral OFC/agranular insula (AI) and the adjacent ventrolateral OFC. Infusion of BDA into the ventrolateral OFC (Figure 1A) revealed innervation of both the dorsal striatum and the amygdala to be overwhelmingly ipsilateral. The central aspect of the dorsal striatum received heavy innervation broadly along the rostrocaudal axis (Figure 1B). By contrast, only light labeling was present in the ventral striatum. Fibers entered the

Discussion

Considerable evidence indicates that the OFC encodes salient information regarding desirable outcomes, such as external cues signaling reinforcement as well as the value of rewards (2). The OFC may also guide outcome-based decision making based on other reinforcement-related information, such as the likelihood that a given behavior will be reinforced, but to date, relatively few investigations into OFC function have focused on action-outcome associative learning and memory. We addressed this

Acknowledgments and Disclosures

This work was supported by Grant Nos. T32DA015040, P51OD011132, P30NS055077, DA034808, DA036737 (National Institutes of Health), Children’s Healthcare of Atlanta, Brain and Behavior Research Foundation Katherine Deschner Family Investigator award (SLG), and National Institute of Mental Health Biobehavioral Research Awards for Innovative New Scientists Grant No. MH101477 (SLG).

We thank Ms. Amanda Allen, Dr. R. Jude Samulski, and Mr. Zach Liang for their contributions and Ms. Lauren Shapiro, Dr.

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^☆: We thank Ms. Amanda Allen and Mr. Zach Liang for their contributions and Ms. Lauren Shapiro, Dr. Geoffrey Schoenbaum, and Dr. Christopher Muly for guidance and valuable feedback.

^☆☆: The authors report no biomedical financial interests or potential conflicts of interest.

View full text

Archival ReportConnections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor☆,☆☆

Abstract

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

The Mouse OFC Innervates the Dorsal Striatum and Amygdala

Discussion

Acknowledgments and Disclosures

Neurobiol Learn Mem

Neuroscience

Neuron

Neurosci Lett

Brain Res

Neurosci Lett

Behav Brain Res

Neurobiol Learn Mem

Neuron

Prog Brain Res

Brain Res Bull

Curr Opin Neurobiol

Neuron

Neuroscience

Differential effects of amygdala, orbital prefrontal cortex, and prelimbic cortex lesions on goal-directed behavior in rhesus macaques

J Neurosci

Neurobiology of economic choice: A good-based model

Annu Rev Neurosci

A new perspective on the role of the orbitofrontal cortex in adaptive behaviour

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Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions

Nat Commun

Repeated cortico-striatal stimulation generates persistent OCD-like behavior

Science

The orbitofrontal cortex regulates outcome-based decision-making via the lateral striatum

Eur J Neurosci

The effect of lesions of the basolateral amygdala on instrumental conditioning

J Neurosci

Consolidation and reconsolidation of incentive learning in the amygdala

J Neurosci

At the limbic-motor interface: Disconnection of basolateral amygdala from nucleus accumbens core and shell reveals dissociable components of incentive motivation

Eur J Neurosci

The role of the amygdala-striatal pathway in the acquisition and performance of goal-directed instrumental actions

J Neurosci

The rat prefrontostriatal system analyzed in 3D: Evidence for multiple interacting functional units

J Neurosci

Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity

Mol Endocrinol

The Mouse Brain in Stereotaxic Coordinates

The effect of the instrumental training contingency on susceptibility to reinforcer devaluation. Q J

Exp Psychol A

Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding

Proc Natl Acad Sci U S A

Glucocorticoid receptor regulation of action selection and prefrontal cortical dendritic spines

Commun Integr Biol

Archival Report
Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor☆,☆☆