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

ABSTRACT: 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.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.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.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.

SUBMITTER: Zimmermann KS

PROVIDER: S-EPMC4871791 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Zimmermann Kelsey S KS Yamin John A JA Rainnie Donald G DG Ressler Kerry J KJ Gourley Shannon L SL

Biological psychiatry 20151118 4

<h4>Background</h4>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.<h4>Methods</h4>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 t ...[more]

PMID: 26786312

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Project description:The prelimbic prefrontal cortex (PL) has consistently been found to be necessary for the acquisition of goal-directed actions in rodents. Nevertheless, the specific cellular processes underlying this learning remain unknown. We assessed changes in learning-related expression of mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK1/2) phosphorylation (pERK) in layers 2-3 and 5-6 of the anterior and posterior PL and in the population of neurons projecting to posterior dorsomedial striatum (pDMS), also implicated in goal-directed learning. Rats were given either a single session of training to press a lever for a pellet reward or yoked reward deliveries without instrumental training and assessed 5 or 60 min after training for pERK expression. Relative to yoked training, instrumental training produced an increase in pERK expression in all regions of the PL both at 5 and 60 min, and this was accompanied by an increase in nuclear pERK expression in the posterior PL in rats given instrumental training. pDMS-projecting neurons showed a transient increase in pERK expression in posterior layer 5-6 projection neurons after 5 min, and a delayed increase in anterior layer 2-3 neurons after 60 min, suggesting that ERK expression in the PL is necessary for the consolidation of goal-directed learning. Consistent with this claim, we found that rats trained on two lever press actions for distinct outcomes and then infused with the MEK inhibitor PD98059 into the PL immediately after training failed to acquire specific action-outcome associations, suggesting that persistent pERK signaling in the PL is necessary for goal-directed learning.Significance statementThe prelimbic cortex is implicated in goal-directed learning in rodents; however, it is unclear whether it is involved in the consolidation of this learning, and what cellular processes are involved. We used pERK as a marker of activity-related synaptic plasticity to assess learning-induced changes in distinct layers and neuronal populations of the prelimbic prefrontal cortex (PL). Training produced long-lasting upregulation of pERK throughout the PL and specifically within neurons that project to the pDMS, another region critical for goal-directed learning. Next, we demonstrated that pERK signaling in the PL was necessary for the consolidation of goal-directed learning. Together, these results indicate that instrumental training induces ERK signaling in distinct layers and populations in the PL and this signaling underlies the consolidation of goal-directed learning.

Dataset Information

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

Publications

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

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