GABAAα1-Mediated Plasticity in the Orbitofrontal Cortex Regulates Context-Dependent Action Selection

Abstract

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 GABA A a1 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 GABA A a1 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 GABA A a1 deficiency enhanced sensitivity to action-outcome relationships. Behavioral abnormalities following oPFC GABA A a1 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 GABA A a1 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 exacerbateneuropsychiatric illness.

Strain commonalities and differences in response-outcome decision making in mice

“…Similarly, BALB/c mice here clearly acquired new outcome-based information as a result of contingency degradation training, even if they initially failed to inhibit responding relative to a session when responding was reinforced. By contrast, C57BL/6 mice readily inhibited responding when the only available response strategy was unlikely to be rewarded, as shown in figure 2 and previously demonstrated in other reports (Wiltgen et al, 2007;Gourley et al, 2012;Gourley et al, 2013b;Butkovich et al, 2015;Parnaudeau et al, 2015;Swanson et al, 2015). …”

“…During this session, reinforcers were delivered into the magazine, independent of animals’ responding, for 25 min at a rate that was yoked to each animal's individual reinforcement rate from the previous session (Gourley et al, 2012;Barker et al, 2013;Gourley et al, 2013a;Gourley et al, 2013b;Swanson et al, 2013;Barker et al, 2014;Hinton et al, 2014;Gross et al, 2015;Swanson et al, 2015;Zimmermann et al, 2015). In another session, only the opposite aperture was available, and responding was reinforced using a variable ratio 2 (VR2) schedule of reinforcement for 25 min (Baldwin et al, 2002).…”

“…Over the course of several experiments, we have observed that healthy mice bred on C57BL/6 and BALB/c strain backgrounds can preferentially engage a response that is highly predictive of reinforcement during a probe test following response-outcome contingency degradation (Gourley et al, 2012;Gourley et al, 2013a;Swanson et al, 2013;Swanson et al, 2015;Zimmermann et al, 2015). Only mice bred on a C57BL/6 background, however, consistently inhibit responding during our typical 25-minute contingency degradation training session, relative to a session in which responding is reinforced.…”

Prefrontal cortical BDNF: A regulatory key in cocaine- and food-reinforced behaviors

“…In the same year, the present authors reported that oPFC-selective knockdown of Bdnf and lesions disconnecting the oPFC from the dorsal striatum also induce habits (Gourley et al, 2013a). We additionally find that habit biases can be attributed to failures in consolidating or retaining action-outcome memory (Zimmermann et al, 2015), and we have reported that viral-mediated knockdown of Gabra1 and Fmr1 in the oPFC also induce habit-based responding (Swanson et al, 2015; Gross et al, 2015). These findings suggest that the healthy oPFC is important for goal-directed (action-outcome) response selection.…”

“…These same mice can, however, ultimately develop sensitivity to changes in instrumental contingencies with repeated training, suggesting that oPFC insult delays, but does not fully block, learning or retaining new information about action-outcome contingencies. This may also account for instances in which mice with oPFC damage fail to develop sensitivity to instrumental contingency degradation, but when tested in a reinforcer devaluation task following additional training, responding is intact (Gourley et al, 2013a; Swanson et al, 2015). Additional experiments would, however, be required to explicitly test this model.…”