Laura A. Bradfield

The Thalamostriatal Pathway and Cholinergic Control of Goal-Directed Action: Interlacing New with Existing Learning in the Striatum

The capacity for goal-directed action depends on encoding specific action-outcome associations, a learning process mediated by the posterior dorsomedial striatum (pDMS). In a changing environment, plasticity has to remain flexible, requiring interference between new and existing learning to be minimized, yet it is not known how new and existing learning are interlaced in this way. Here we investigated the role of the thalamostriatal pathway linking the parafascicular thalamus (Pf) with cholinergic interneurons (CINs) in the pDMS in this process. Removing the excitatory input from Pf to the CINs was found to reduce the firing rate and intrinsic activity of these neurons and produced an enduring deficit in goal-directed learning after changes in the action-outcome contingency. Disconnection of the Pf-pDMS pathway produced similar behavioral effects. These data suggest that CINs reduce interference between new and existing learning, consistent with claims that the thalamostriatal pathway exerts state control over learning-related plasticity.

Medial Orbitofrontal Cortex Mediates Outcome Retrieval in Partially Observable Task Situations

Choice between actions often requires the ability to retrieve action consequences in circumstances where they are only partially observable. This capacity has recently been argued to depend on orbitofrontal cortex; however, no direct evidence for this hypothesis has been reported. Here, we examined whether activity in the medial orbitofrontal cortex (mOFC) underlies this critical determinant of decision-making in rats. First, we simulated predictions from this hypothesis for various tests of goal-directed action by removing the assumption that rats could retrieve partially observable outcomes and then tested those predictions experimentally using manipulations of the mOFC. The results closely followed predictions; consistent deficits only emerged when action consequences had to be retrieved. Finally, we put action selection based on observable and unobservable outcomes into conflict and found that whereas intact rats selected actions based on the value of retrieved outcomes, mOFC rats relied solely on the value of observable outcomes.

The role of the anterior, mediodorsal, and parafascicular thalamus in instrumental conditioning

The traditional animal model of instrumental behavior has focused almost exclusively on structures within the cortico-striatal network and ignored the contributions of various thalamic nuclei despite large and specific connections with each of these structures. One possible reason for this is that the thalamus has been conventionally viewed as a mediator of general processes, such as attention, arousal and movement, that are not easily separated from more cognitive aspects of instrumental behavior. Recent research has, however, begun to separate these roles. Here we review the role of three thalamic nuclei in instrumental conditioning: the anterior thalamic nuclei (ANT), the mediodorsal (MD), and parafascicular thalamic nuclei (PF). Early research suggested that ANT might regulate aspects of instrumental behavior but, on review, we suggest that the types of tasks used in these studies were more likely to recruit Pavlovian processes. Indeed lesions of ANT have been found to have no effect on performance in instrumental free-operant tasks. By contrast the mediodorsal thalamus (MD) has been found to play a specific and important role in the acquisition of goal-directed action. We propose this role is related to its connections with prelimbic cortex (PL) and present new data that directly implicates this circuit in the acquisition of goal-directed actions. Finally we review evidence suggesting the PF, although not critical for the acquisition or performance of instrumental actions, plays a specific role in regulating action flexibility.

Interaction of Insular Cortex and Ventral Striatum Mediates the Effect of Incentive Memory on Choice Between Goal-Directed Actions

The anterior insular cortex (IC) and the nucleus accumbens (NAc) core have been separately implicated in the selection and performance of actions based on the incentive value of the instrumental outcome. Here, we examined the role of connections between the IC and the NAc core in the performance of goal-directed actions. Rats were trained on two actions for distinct outcomes, after which one of the two outcomes was devalued by specific satiety immediately before a choice extinction test. We first confirmed the projection from the IC to the NAc core and then disconnected these structures via asymmetrical excitotoxic lesions before training. Contralateral, but not ipsilateral, disconnection of the IC and NAc core disrupted outcome devaluation. We hypothesized that communication between the IC and NAc core is necessary for the retrieval of incentive value at test. To test this, we infused the GABAA agonist muscimol into the IC and the μ-opioid receptor antagonist CTAP into the contralateral NAc before the choice extinction test. As expected, inactivation of the IC in one hemisphere and blocking μ-opioid receptors in the contralateral NAc core abolished outcome-selective devaluation. These results suggest that the IC and NAc core form part of a circuit mediating the retrieval of outcome values and the subsequent choice between goal-directed actions based on those values.

Hierarchical and binary associations compete for behavioral control during instrumental biconditional discrimination.

In two experiments we investigated the role of hierarchical S-(R-O) associations, as opposed to associative alternatives, in solving biconditional discrimination problems in rats. Using lesions of posterior dorsomedial striatum known to attenuate R-O associative learning, and lesions of the dorsolateral striatum that attenuate S-R learning, we found that whereas the lesions affecting R-O learning abolished biconditional discrimination, lesions of dorsolateral striatum did not (Experiment 1). Furthermore, in Experiment 2, we found, using a more challenging discrimination protocol, that dorsolateral striatal lesions actually enhanced biconditional discrimination learning. These results provide evidence that hierarchical S-(R-O) associations influence instrumental discrimination learning and compete with S-R associations for control of performance.

The Role of Nucleus Accumbens Shell in Learning about Neutral versus Excitatory Stimuli during Pavlovian Fear Conditioning.

We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.

Unblocking in Pavlovian fear conditioning.

Six experiments used rats to study blocking and unblocking of fear learning. An excitatory stimulus (A) blocked fear learning to a neutral stimulus (B). Unblocking of B occurred if the AB compound signaled an increase in unconditioned stimulus (US) intensity or number. Assessments of associative change during blocking showed that more was learned about B than A. Such assessments during unblocking revealed that more was learned about B than A following an increase in US intensity but not US number. These US manipulations had no differential effects on single-cue learning. The results show that variations in US intensity or number produce unblocking of fear learning, but for each there is a different profile of associative change and a potentially different mechanism.

Thalamic Control of Dorsomedial Striatum Regulates Internal State to Guide Goal-Directed Action Selection

We (Bradfield et al., 2013) have demonstrated previously that parafascicular thalamic nucleus (PF)-controlled neurons in the posterior dorsomedial striatum (pDMS) are critical for interlacing new and existing action–outcome contingencies to control goal-directed action. Based on these findings, it was suggested that animals with a dysfunctional PF–pDMS pathway might suffer a deficit in creating or retrieving internal contexts or “states” on which such information could become conditional. To assess this hypothesis more directly, rats were given a disconnection treatment using contralateral cytotoxic lesions of the PF and pDMS (Group CONTRA) or ipsilateral control lesions (Group IPSI) and trained to press a right and left lever for sucrose and pellet outcomes, after which these contingencies were reversed. The rats were then given an outcome devaluation test (all experiments) and a test of outcome-specific reinstatement (Experiments 1 and 3). We found that devaluation performance was intact for both groups after training of initial contingencies, but impaired for Group CONTRA after reversal. However, performance was restored by additional reversal training. Furthermore, when tested a second time after reversal training, rats in both groups demonstrated responding in accordance with the original contingencies, providing direct evidence of modulation of action selection by state. Finally, we found that external context could substitute for internal state and so could rescue responding in Group CONTRA, but only in the reinstatement test. Together, these findings suggest that animals use internal state information to guide action selection and that this information is modulated by the PF–pDMS pathway. SIGNIFICANCE STATEMENT Individuals with Parkinsons disease dementia often suffer a characteristic deficit in “cognitive flexibility.” It has been suggested that neurodegeneration in the pathway between the centromedian/parafascicular thalalmic nucleus (PF) and striatum might underlie such deficits (Smith et al., 2014). In rats, we have similarly observed that a functional disconnection of the PF–posterior dorsomedial striatal pathway produces a specific impairment in the ability to alter goal-directed actions (Bradfield et al., 2013). It was suggested that this impairment could be a result of a deficit in state modulation. Here, we present four experiments that provide evidence for this hypothesis and suggest several ways (e.g., extended practice, providing external cues) in which this state modulation can be rescued.

Prefrontal Corticostriatal Disconnection Blocks the Acquisition of Goal-Directed Action

The acquisition of goal-directed action requires encoding of the association between an action and its specific consequences or outcome. At a neural level, this encoding has been hypothesized to involve a prefrontal corticostriatal circuit involving the projection from the prelimbic cortex (PL) to the posterior dorsomedial striatum (pDMS); however, no direct evidence for this claim has been reported. In a series of experiments, we performed functional disconnection of this pathway using targeted lesions of the anterior corpus callosum to disrupt contralateral corticostriatal projections with asymmetrical lesions of the PL and/or pDMS to block plasticity in this circuit in rats. We first demonstrated that unilaterally blocking the PL input to the pDMS prevented the phosphorylation of extracellular signal-related kinase/mitogen activated protein kinase (pERK/pMAPK) induced by instrumental training. Next, we used a full bilateral disconnection of the PL from the pDMS and assessed goal-directed action using an outcome-devaluation test. Importantly, we found evidence that rats maintaining an ipsilateral and/or contralateral connection between the PL and the pDMS were able to acquire goal-directed actions. In contrast, bilateral PL–pDMS disconnection abolished the acquisition of goal-directed actions. Finally, we used a temporary pharmacological disconnection to disrupt PL inputs to the pDMS by infusing the NMDA antagonist dl-2-amino-5-phosphonopentanoic acid into the pDMS during instrumental training and found that this manipulation also disrupted goal-directed learning. These results establish that, in rats, the acquisition of new goal-directed actions depends on a prefrontal–corticostriatal circuit involving a connection between the PL and the pDMS. SIGNIFICANCE STATEMENT It has been hypothesized that the prelimbic cortex (PL) and posterior dorsomedial striatum (pDMS) in rodents interact in a corticostriatal circuit to mediate goal-directed learning. However, no direct evidence supporting this claim has been reported. Using targeted lesions, we performed functional disconnection of the PL–pDMS pathway to assess its role in goal-directed learning. In the first experiment, we demonstrated that PL input to the pDMS is necessary for instrumental training-induced neuronal activity. Next, we disrupted ipsilateral, contralateral, or bilateral PL–pDMS connections and found that only bilateral PL–pDMS disconnection disrupted the acquisition of goal-directed actions, a finding we replicated in our final study using a pharmacological disconnection procedure.

Inferring action-dependent outcome representations depends on anterior but not posterior medial orbitofrontal cortex

&NA; Although studies examining orbitofrontal cortex (OFC) often treat it as though it were functionally homogeneous, recent evidence has questioned this assumption. Not only are the various subregions of OFC (lateral, ventral, and medial) hetereogeneous, but there is further evidence of heterogeneity within those subregions. For example, several studies in both humans and monkeys have revealed a functional subdivision along the anterior‐posterior gradient of the medial OFC (mOFC). Given our previous findings suggesting that, in rats, the mOFC is responsible for inferring the likelihood of unobservable action outcomes (Bradfield, Dezfouli, van Holstein, Chieng, & Balleine, 2015), and given the anterior nature of the placements of our prior manipulations, we decided to assess whether the rat mOFC also differs in connection and function along its anteroposterior axis. We first used retrograde tracing to compare the density of efferents from mOFC to several structures known to contribute to goal‐directed action: the mediodorsal thalamus, basolateral amygdala, posterior dorsomedial striatum, nucleus accumbens core and ventral tegmental area. We then compared the functional effects of anterior versus posterior mOFC excitotoxic lesions on tests of Pavlovian‐instrumental transfer, instrumental outcome devaluation and outcome‐specific reinstatement. We found evidence that the anterior mOFC had greater connectivity with the accumbens core and greater functional involvement in goal‐directed action than the posterior mOFC. Consistent with previous findings across species, therefore, these results suggest that the anterior and posterior mOFC of the rat are indeed functionally distinct, and that it is the anterior mOFC that is particularly critical for inferring unobservable action outcomes.