The Medial Orbitofrontal Cortex Regulates Sensitivity to Outcome Value.

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 Gs-coupled designer receptors exclusively activated by designer drugs (DREADDs). In other mice, we silenced the neuroplasticity-associated neurotrophin brain-derived neurotrophic factor (BDNF). Activation of Gs-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(+/-)mice. Replacement of BDNF selectively in the mOFC in Bdnf(+/-)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(+/-)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(+/-)mice. We argue that BDNF-ERK1/2 in the mOFC is a key regulator of "online" goal-directed action selection. SIGNIFICANCE STATEMENT: Goal-directed response selection often involves predicting the consequences of one's actions and the value of potential payoffs. Lesions or chemogenetic inactivation of the medial orbitofrontal cortex (mOFC) in rats induces failures in retrieving outcome identity memories (Bradfield et al., 2015), suggesting that the healthy mOFC serves to access outcome value information when it is not immediately observable and thereby guide goal-directed decision-making. Our findings suggest that the mOFC also bidirectionally regulates effort allocation for a given reward and that expression of the neurotrophin BDNF in the mOFC is both necessary and sufficient for mice to sustain stable representations of reinforcer value.

Adolescent-onset GABAA α1 silencing regulates reward-related decision making.

The GABAA receptor mediates fast, inhibitory signaling, and cortical expression of the α1 subunit increases during postnatal development. Certain pathological stimuli such as stressors or prenatal cocaine exposure can interfere with this process, but causal relationships between GABAA α1 deficiency and complex behavioral outcomes remain unconfirmed. We chronically reduced GABAA α1 expression selectively in the medial prefrontal cortex (prelimbic subregion) of mice using viral-mediated gene silencing of Gabra1. Adolescent-onset Gabra1 knockdown delayed the acquisition of a cocaine-reinforced instrumental response but spared cocaine seeking in extinction and in a cue-induced reinstatement procedure. To determine whether response acquisition deficits could be associated with impairments in action-outcome associative learning and memory, we next assessed behavioral sensitivity to instrumental contingency degradation. In this case, the predictive relationship between familiar actions and their outcomes is violated. Adolescent-onset knockdown, although not adult-onset knockdown, delayed the expression of goal-directed response strategies in this task, resulting instead in inflexible habit-like modes of response. Thus, the maturation of medial prefrontal cortex GABAA α1 systems during adolescence appears necessary for goal-directed reward-related decision making in adulthood. These findings are discussed in the light of evidence that prolonged Gabra1 deficiency may impair synaptic plasticity.

Selective role of the catalytic PI3K subunit p110ß in impaired higher order cognition in fragile X syndrome.

Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110ß plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110ß, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110ß in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110ß knockdown. Our results suggest that FMRP-mediated control of p110ß is crucial for neuronal protein synthesis and cognition.

GABAAα1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection.

An essential aspect of goal-directed action selection is differentiating between behaviors that are more, or less, likely to be reinforced. Habits, by contrast, are stimulus-elicited behaviors insensitive to action-outcome contingencies and are considered an etiological factor in several neuropsychiatric disorders. Thus, isolating the neuroanatomy and neurobiology of goal-directed action selection on the one hand, and habit formation on the other, is critical. Using in vivo viral-mediated gene silencing, we knocked down Gabra1 in the orbitofrontal prefrontal cortex (oPFC) in mice, decreasing oPFC GABAAα1 expression, as well as expression of the synaptic marker PSD-95. Mice expressing Green Fluorescent Protein or Gabra1 knockdown in the adjacent M2 motor cortex served as comparison groups. Using instrumental response training followed by action-outcome contingency degradation, we then found that oPFC GABAAα1 deficiency impaired animals' ability to differentiate between actions that were more or less likely to be reinforced, though sensitivity to outcome devaluation and extinction were intact. Meanwhile, M2 GABAAα1 deficiency enhanced sensitivity to action-outcome relationships. Behavioral abnormalities following oPFC GABAAα1 knockdown were rescued by testing mice in a distinct context relative to that in which they had been initially trained. Together, our findings corroborate evidence that chronic GABAAα1 deficiency remodels cortical synapses and suggest that neuroplasticity within the healthy oPFC gates the influence of reward-related contextual stimuli. These stimuli might otherwise promote maladaptive habit-based behavioral response strategies that contribute to-or exacerbate-neuropsychiatric illness.

Developmentally divergent effects of Rho-kinase inhibition on cocaine- and BDNF-induced behavioral plasticity.

Prefrontal cortical dendritic spine remodeling during adolescence may open a window of vulnerability to pathological stimuli that impact long-term behavioral outcomes, but causal mechanisms remain unclear. We administered the Rho-kinase inhibitor HA-1077 during three adolescent periods in mice to destabilize dendritic spines. In adulthood, cocaine-induced locomotor activity was exaggerated. By contrast, when administered in adulthood, HA-1077 had no psychomotor consequences and normalized food-reinforced instrumental responding after orbitofrontal-selective knockdown of Brain-derived neurotrophic factor, a potential factor in addiction. Thus, early-life Rho-kinase inhibition confers cocaine vulnerability, but may actually protect against pathological reward-seeking - particularly in cases of diminished neurotrophic support - in adulthood.