Hippocampal neuroinflammation induced by lipopolysaccharide causes sex-specific disruptions in action selection, food approach memories, and neuronal activation.

Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt this behaviour is unknown. We investigated this question here using mice. First, the application of an endotoxin to primary cultures containing only hippocampal neurons did not affect their activation.

Striatal Acetylcholine and Dopamine Interactions Produce Situationappropriate Action Selection.

Individuals often learn how to perform new actions for particular outcomes against a complex background of existing action-outcome associations. As such, this new knowledge can interfere or even compete with existing knowledge, such that individuals must use internal and external cues to determine which action is appropriate to the current situation. The question thus remains as to how this problem is solved at a neural level.

Diet and obesity effects on cue-driven food-seeking: insights from studies of Pavlovian-instrumental transfer in rodents and humans.

Our modern environment is said to be obesogenic, promoting the consumption of calorically dense foods and reducing energy expenditure. One factor thought to drive excess energy intake is the abundance of cues signaling the availability of highly palatable foods. Indeed, these cues exert powerful influences over food-related decision-making.

L-Proline Prevents Endoplasmic Reticulum Stress in Microglial Cells Exposed to L-azetidine-2-carboxylic Acid.

L-Azetidine-2-carboxylic acid (AZE) is a non-protein amino acid that shares structural similarities with its proteogenic L-proline amino acid counterpart. For this reason, AZE can be misincorporated in place of L-proline, contributing to AZE toxicity. In previous work, we have shown that AZE induces both polarization and apoptosis in BV2 microglial cells.

Cognitive effects of thalamostriatal degeneration are ameliorated by normalizing striatal cholinergic activity.

The loss of neurons in parafascicular thalamus (Pf) and their inputs to dorsomedial striatum (DMS) in Lewy body disease (LBD) and Parkinson's disease dementia (PDD) have been linked to the effects of neuroinflammation. We found that, in rats, these inputs were necessary for both the function of striatal cholinergic interneurons (CINs) and the flexible encoding of the action-outcome (AO) associations necessary for goal-directed action, producing a burst-pause pattern of CIN firing but only during the remapping elicited by a shift in AO contingency. Neuroinflammation in the Pf abolished these changes in CIN activity and goal-directed control after the shift in contingency.

Goal-Directed Action Is Initially Impaired in a hAPP-J20 Mouse Model of Alzheimer's Disease.

Cognitive-behavioral testing in preclinical models of Alzheimer's disease has failed to capture deficits in goal-directed action control. Here, we provide the first comprehensive investigation of goal-directed action in a transgenic mouse model of Alzheimer's disease. Specifically, we tested outcome devaluation performance in male and female human amyloid precursor protein (hAPP)-J20 mice.

Association learning: Dopamine and the formation of backward associations.

The activity of dopamine neurons is critical for the ability to learn and update cue-reward associations. New work in rats shows that dopamine transients are also critical for the formation of backward associations in which the reward precedes the neutral stimulus.

Outcome-selective reinstatement is predominantly context-independent, and associated with c-Fos activation in the posterior dorsomedial striatum.

Research from human and animal studies has found that after responding has been successfully reduced following treatment it can return upon exposure to certain contexts. An individual in recovery from alcohol use disorder, for example, might relapse to drinking upon visiting their favourite bar. However, most of these data have been derived from experiments involving a single (active) response, and the context-dependence of returned responding in situations involving choice between multiple actions and outcomes is less well-understood.

Medial Orbitofrontal Cortex Regulates Instrumental Conditioned Punishment, but not Pavlovian Conditioned Fear.

Bidirectionally aberrant medial orbitofrontal cortical (mOFC) activity has been consistently linked with compulsive disorders and related behaviors. Although rodent studies have established a causal link between mOFC excitation and compulsive-like actions, no such link has been made with mOFC inhibition. Here, we use excitotoxic lesions of mOFC to investigate its role in sensitivity to punishment; a core characteristic of many compulsive disorders.

Does disrupting the orbitofrontal cortex alter sensitivity to punishment? A potential mechanism of compulsivity.

Abnormal orbitofrontal cortex (OFC) activity is one of the most common findings from neuroimaging studies of individuals with compulsive disorders such as substance use disorder and obsessive-compulsive disorder. The nature of this abnormality is complex, however, with some studies reporting the OFC to be over-active in compulsive individuals relative to controls, whereas other studies report it being under-active, and a further set of studies reporting OFC abnormality in both directions within the same individuals. The OFC has been implicated in a broad range of cognitive processes such as decision-making and goal-directed action.

Threat perception: Fear and the retrorubal field.

A new study has found that neurons within a structure of the rat midbrain known as the retrorubral field show diverse responses to stimuli that signal different levels of threat, as well as a separate pattern of diverse responses to differentially predicted aversive outcomes.

Parafascicular Thalamic and Orbitofrontal Cortical Inputs to Striatum Represent States for Goal-Directed Action Selection.

Several lines of evidence accrued over the last 5-10 years have converged to suggest that the parafascicular nucleus of the thalamus and the lateral orbitofrontal cortex each represent or contribute to internal state/context representations that guide action selection in partially observable task situations. In rodents, inactivations of each structure have been found to selectively impair performance in paradigms testing goal-directed action selection, but only when that action selection relies on state representations. Electrophysiological evidence has suggested that each structure achieves this function inputs onto cholinergic interneurons (CINs) in the dorsomedial striatum.

Adaptive behaviour under conflict: Deconstructing extinction, reversal, and active avoidance learning.

In complex environments, organisms must respond adaptively to situations despite conflicting information. Under natural (i.e.

Goal-directed actions transiently depend on dorsal hippocampus.

The role of the hippocampus in goal-directed action is currently unclear; studies investigating this issue have produced contradictory results. Here we reconcile these contradictions by demonstrating that, in rats, goal-directed action relies on the dorsal hippocampus, but only transiently, immediately after initial acquisition. Furthermore, we found that goal-directed action also depends transiently on physical context, suggesting a psychological basis for the hippocampal regulation of goal-directed action control.

Punishment insensitivity emerges from impaired contingency detection, not aversion insensitivity or reward dominance.

Our behaviour is shaped by its consequences - we seek rewards and avoid harm. It has been reported that individuals vary markedly in their avoidance of detrimental consequences, that is in their sensitivity to punishment. The underpinnings of this variability are poorly understood; they may be driven by differences in aversion sensitivity, motivation for reward, and/or instrumental control.

Rodent medial and lateral orbitofrontal cortices represent unique components of cognitive maps of task space.

The orbitofrontal cortex (OFC) has been proposed to function as a cognitive map of task space: a mental model of the steps involved in a task. This idea has proven popular because it provides a cohesive explanation for a number of disparate findings regarding the OFC's role in a broad array of tasks. Concurrently, evidence has begun to reveal the functional heterogeneity of OFC subregions, particularly the medial and lateral OFC.

The Thalamostriatal Pathway and the Hierarchical Control of Action.

Sequential ordering of motor commands is required for the simplest of our daily activities. In this issue of Neuron, Díaz-Hernández et al. (2018) show that distinct thalamic inputs to different regions of the dorsal striatum critically modulate the initiation and execution of action sequences.

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

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).

The Bilateral Prefronto-striatal Pathway Is Necessary for Learning New Goal-Directed Actions.

The acquisition of new goal-directed actions requires the encoding of action-outcome associations. At a neural level, this encoding has been hypothesized to involve a prefronto-striatal circuit extending between the prelimbic cortex (PL) and the posterior dorsomedial striatum (pDMS); however, no research identifying this pathway with any precision has been reported. We started by mapping the prelimbic input to the dorsal and ventral striatum using a combination of retrograde and anterograde tracing with CLARITY and established that PL-pDMS projections share some overlap with projections to the nucleus accumbens core (NAc) in rats.

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.

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.

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.

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.

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.