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Imbalanced Activity in the Orbitofrontal Cortex and Nucleus Accumbens Impairs Behavioral Inhibition.

ABSTRACT: Contemporary models of behavioral regulation maintain that balanced activity between cognitive control areas (prefrontal cortex, PFC) and subcortical reward-related regions (nucleus accumbens, NAC) mediates the selection of appropriate behavioral responses, whereas imbalanced activity (PFC < NAC) results in maladaptive behavior [1-6]. Imbalance can arise from reduced engagement of PFC (via fatigue or stress [7]) or from excessive activity in NAC [8]. Additionally, a concept far less researched is that an imbalance can result from simultaneously low PFC activity and high NAC activity. This occurs during adolescence, when the maturation of PFC lags behind that of NAC and NAC is more functionally active compared to adulthood or pre-adolescence [2, 5, 9, 10]. Accordingly, activity is disproportionately higher in NAC than in PFC, which may contribute to impulsivity and risk-taking exhibited by adolescents [5, 6, 10-12]. Despite having explanatory value, support for this notion has been solely correlational. Here, we causally tested this using chemogenetics to simultaneously decrease neural activity in the orbitofrontal cortex (OFC) and increase activity in NAC in adult rats, mimicking the imbalance during adolescence. We tested the effects on negative occasion setting, an important yet understudied form of inhibitory learning that may be particularly relevant during adolescence. Rats with combined manipulation of OFC and NAC were impaired in learning to use environmental cues to withhold a response, an effect that was greater than that of either manipulation alone. These findings provide direct evidence that simultaneous underactivity in OFC and overactivity in NAC can negatively impact behavioral control and provide insight into the neural systems that underlie inhibitory learning.

SUBMITTER: Meyer HC

PROVIDER: S-EPMC5117684 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Imbalanced Activity in the Orbitofrontal Cortex and Nucleus Accumbens Impairs Behavioral Inhibition.

Meyer Heidi C HC Bucci David J DJ

Current biology : CB 20160929 20

Contemporary models of behavioral regulation maintain that balanced activity between cognitive control areas (prefrontal cortex, PFC) and subcortical reward-related regions (nucleus accumbens, NAC) mediates the selection of appropriate behavioral responses, whereas imbalanced activity (PFC < NAC) results in maladaptive behavior [1-6]. Imbalance can arise from reduced engagement of PFC (via fatigue or stress [7]) or from excessive activity in NAC [8]. Additionally, a concept far less researched i ...[more]

PMID: 27693139

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Project description:Cues that predict the availability of food rewards influence motivational states and elicit food-seeking behaviors. If a cue no longer predicts food availability, then animals may adapt accordingly by inhibiting food-seeking responses. Sparsely activated sets of neurons, coined "neuronal ensembles," have been shown to encode the strength of reward-cue associations. Although alterations in intrinsic excitability have been shown to underlie many learning and memory processes, little is known about these properties specifically on cue-activated neuronal ensembles. We examined the activation patterns of cue-activated orbitofrontal cortex (OFC) and nucleus accumbens (NAc) shell ensembles using wild-type and Fos-GFP mice, which express green fluorescent protein (GFP) in activated neurons, after appetitive conditioning with sucrose and extinction learning. We also investigated the neuronal excitability of recently activated, GFP+ neurons in these brain areas using whole-cell electrophysiology in brain slices. Exposure to a sucrose cue elicited activation of neurons in both the NAc shell and OFC. In the NAc shell, but not the OFC, these activated GFP+ neurons were more excitable than surrounding GFP- neurons. After extinction, the number of neurons activated in both areas was reduced and activated ensembles in neither area exhibited altered excitability. These data suggest that learning-induced alterations in the intrinsic excitability of neuronal ensembles is regulated dynamically across different brain areas. Furthermore, we show that changes in associative strength modulate the excitability profile of activated ensembles in the NAc shell.SIGNIFICANCE STATEMENT Sparsely distributed sets of neurons called "neuronal ensembles" encode learned associations about food and cues predictive of its availability. Widespread changes in neuronal excitability have been observed in limbic brain areas after associative learning, but little is known about the excitability changes that occur specifically on neuronal ensembles that encode appetitive associations. Here, we reveal that sucrose cue exposure recruited a more excitable ensemble in the nucleus accumbens, but not orbitofrontal cortex, compared with their surrounding neurons. This excitability difference was not observed when the cue's salience was diminished after extinction learning. These novel data provide evidence that the intrinsic excitability of appetitive memory-encoding ensembles is regulated differentially across brain areas and adapts dynamically to changes in associative strength.

Dataset Information

Imbalanced Activity in the Orbitofrontal Cortex and Nucleus Accumbens Impairs Behavioral Inhibition.

Publications

Imbalanced Activity in the Orbitofrontal Cortex and Nucleus Accumbens Impairs Behavioral Inhibition.

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