The orbitofrontal cortex (oPFC) sends substantial projections to the ventrolateral striatum and aspects of the nucleus accumbens that are—functionally—poorly understood. This is despite probable cortico-striatal involvement in multiple diseases such as addiction and obsessive-compulsive disorder. Here we surgically disconnected the oPFC from the ventrolateral striatum using unilateral asymmetric lesions in mice and classified instrumental decision-making strategies. Mice with symmetric lesions that spared one oPFC-striatal network served as controls. As a complementary approach, we selectively knocked down Brain-derived neurotrophic factor (Bdnf) bilaterally in the oPFC and ascertained behavioral and neurobiological consequences within the downstream striatum. oPFC-striatal disconnection and oPFC Bdnf knockdown blocked sensitivity to outcome-predictive relationships in both food-reinforced and cocaine-associated settings. Bdnf knockdown simultaneously regulated striatal BDNF expression, and striatal c-Fos predicted sensitivity to action-outcome associative contingencies. Prior evidence strongly implicates the dorsolateral striatum in stimulus-response habit formation. Our findings thus provide novel evidence for functional compartmentalization within the lateral striatum, with the dorsal compartment subserving classical stimulus-response habit systems and a ventral compartment coordinating outcome-based decision-making via oPFC interactions. This compartmentalization may apply to both ‘natural’—as in the case of food-reinforced behavior—and ‘pathological’—as in the case of cocaine-seeking—contexts.

Background Distinguishing between actions that are more, or less, likely to be rewarded is a critical aspect of goal-directed decision-making. However, neuroanatomical and molecular mechanisms are not fully understood. Methods We used anterograde tracing, viral-mediated gene silencing, functional disconnection strategies, pharmacological rescue, and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to determine the anatomical and functional connectivity between the orbitofrontal cortex (oPFC) and the amygdala in mice. In particular, we knocked down Brain-derived neurotrophic factor (Bdnf) bilaterally in the oPFC, or generated an oPFC-amygdala “disconnection” by pairing unilateral oPFC Bdnf knockdown with lesions of the contralateral amygdala. We characterized decision-making strategies using a task wherein mice select actions based on the likelihood that they will be reinforced. Additionally, we assessed the effects of DREADD-mediated oPFC inhibition on the consolidation of action-outcome conditioning. Results As in other species, the oPFC projects to the basolateral amygdala and dorsal striatum in mice. Bilateral Bdnf knockdown within the ventrolateral oPFC, and unilateral Bdnf knockdown accompanied by lesions of the contralateral amygdala, impede goal-directed response selection, implicating BDNF-expressing oPFC projection neurons in selecting actions based on their consequences. The TrkB agonist 7,8-dihydroxyflavone rescues action selection and increases dendritic spine density on excitatory neurons in the oPFC. Rho-kinase inhibition also rescues goal-directed response strategies, linking neural remodeling with outcome-based decision-making. Finally, DREADD-mediated oPFC inhibition weakens new action-outcome conditioning. Conclusions Activity- and BDNF-dependent neuroplasticity within the oPFC coordinate outcome-based decision-making through interactions with the amygdala. These interactions brake reward-seeking habits, a putative factor in multiple psychopathologies.

An essential component of goal-directed decision-making is the ability to maintain flexible responding based on the value of a given reward, or "reinforcer." The medial orbitofrontal cortex (mOFC), a subregion of the ventromedial prefrontal cortex, is uniquely positioned to regulate this process. We trained mice to nose poke for food reinforcers and then stimulated this region using CaMKII-driven G s -coupled designer receptors exclusively activated by designer drugs (DREADDs). In other mice, we silenced the neuroplasticityassociated neurotrophin brain-derived neurotrophic factor (BDNF). Activation of G s -DREADDs increased behavioral sensitivity to reinforcer devaluation, whereas Bdnf knockdown blocked sensitivity. These changes were accompanied by modifications in breakpoint ratios in a progressive ratio task, and they were recapitulated in Bdnf ϩ/Ϫ mice. Replacement of BDNF selectively in the mOFC in Bdnf ϩ/Ϫ mice rescued behavioral deficiencies, as well as phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2). Thus, BDNF expression in the mOFC is both necessary and sufficient for the expression of typical effort allocation relative to an anticipated reinforcer. Additional experiments indicated that expression of the immediate-early gene c-fos was aberrantly elevated in the Bdnf ϩ/Ϫ dorsal striatum, and BDNF replacement in the mOFC normalized expression. Also, systemic administration of an MAP kinase kinase inhibitor increased breakpoint ratios, whereas the addition of discrete cues bridging the response-outcome contingency rescued breakpoints in Bdnf ϩ/Ϫ mice. We argue that BDNF-ERK1/2 in the mOFC is a key regulator of "online" goal-directed action selection.

Anxiety disorders that develop in adolescence represent a significant burden and are particularly challenging to treat, due in no small part to the high occurrence of relapse in this age group following exposure therapy. This pattern of persistent fear is preserved across species; relative to those younger and older, adolescents consistently show poorer extinction, a key process underpinning exposure therapy. This suggests that the neural processes underlying fear extinction are temporarily but profoundly compromised during adolescence. The formation, retrieval, and modification of fear- and extinction-associated memories are regulated by a forebrain network consisting of the prefrontal cortex (PFC), the amygdala, and the hippocampus. These regions undergo robust maturational changes in early life, with unique alterations in structure and function occurring throughout adolescence. In this review, we focus primarily on two of these regions—the PFC and the amygdala—and discuss how changes in plasticity, synaptic transmission, inhibition/excitation, and connectivity (including modulation by hippocampal afferents to the PFC) may contribute to transient deficits in extinction retention. We end with a brief consideration of how exposure to stress during this adolescent window of vulnerability can permanently disrupt neurodevelopment, leading to lasting impairments in pathways of emotional regulation.

In humans and rodents, stress promotes habit-based behaviors that can interfere with action–outcome decision-making. Further, developmental stressor exposure confers long-term habit biases across rodent–primate species. Despite these homologies, mechanisms remain unclear. We first report that exposure to the primary glucocorticoid corticosterone (CORT) in adolescent mice recapitulates multiple neurobehavioral consequences of stressor exposure, including long-lasting biases towards habit-based responding in a food-reinforced operant conditioning task. In both adolescents and adults, CORT also caused a shift in the balance between full-length tyrosine kinase receptor B (trkB) and a truncated form of this neurotrophin receptor, favoring the inactive form throughout multiple corticolimbic brain regions. In adolescents, phosphorylation of the trkB substrate extracellular signal-regulated kinase 42/44 (ERK42/44) in the ventral hippocampus was also diminished, a long-term effect that persisted for at least 12 wk. Administration of the trkB agonist 7,8-dihydroxyflavone (7,8-DHF) during adolescence at doses that stimulated ERK42/44 corrected long-lasting corticosterone-induced behavioral abnormalities. Meanwhile, viral-mediated overexpression of truncated trkB in the ventral hippocampus reduced local ERK42/44 phosphorylation and was sufficient to induce habit-based and depression-like behaviors. Together, our findings indicate that ventral hippocampal trkB is essential to goal-directed action selection, countering habit-based behavior otherwise facilitated by developmental stress hormone exposure. They also reveal an early-life sensitive period during which trkB–ERK42/44 tone determines long-term behavioral outcomes.