Inhibition of noradrenergic signalling in rodent orbitofrontal cortex impairs the updating of goal-directed actions.

In a constantly changing environment, organisms must track the current relationship between actions and their specific consequences and use this information to guide decision-making. Such goal-directed behaviour relies on circuits involving cortical and subcortical structures. Notably, a functional heterogeneity exists within the medial prefrontal, insular, and orbitofrontal cortices (OFC) in rodents. The role of the latter in goal-directed behaviour has been debated, but recent data indicate that the ventral and lateral subregions of the OFC are needed to integrate changes in the relationships between actions and their outcomes. Neuromodulatory agents are also crucial components of prefrontal functions and behavioural flexibility might depend upon the noradrenergic modulation of the prefrontal cortex. Therefore, we assessed whether noradrenergic innervation of the OFC plays a role in updating action-outcome relationships in male rats. We used an identity-based reversal task and found that depletion or chemogenetic silencing of noradrenergic inputs within the OFC rendered rats unable to associate new outcomes with previously acquired actions. Silencing of noradrenergic inputs in the prelimbic cortex or depletion of dopaminergic inputs in the OFC did not reproduce this deficit. Together, our results suggest that noradrenergic projections to the OFC are required to update goal-directed actions.

Dopamine and noradrenaline modulation of goal-directed behavior in orbital and medial prefrontal cortex: Toward a division of labor?

The prefrontal cortex is considered to be at the core of goal-directed behaviors. Notably, the medial prefrontal cortex (mPFC) is known to play an important role in learning action-outcome (A-O) associations, as well as in detecting changes in this contingency. Previous studies have also highlighted a specific engagement of the dopaminergic pathway innervating the mPFC in adapting to changes in action causality. While previous research on goal-directed actions has primarily focused on the mPFC region, recent findings have revealed a distinct and specific role of the ventral and lateral orbitofrontal cortex (vlOFC). Indeed, vlOFC is not necessary to learn about A-O associations but appears specifically involved when outcome identity is unexpectedly changed. Unlike the mPFC, the vlOFC does not receive a strong dopaminergic innervation. However, it receives a dense noradrenergic innervation which might indicate a crucial role for this neuromodulator. In addition, several lines of evidence highlight a role for noradrenaline in adapting to changes in the environment. We, therefore, propose that the vlOFC's function in action control might be under the strong influence of the noradrenergic system. In the present article, we review anatomical and functional evidence consistent with this proposal and suggest a direction for future studies that aim to shed light on the orbitofrontal mechanisms for flexible action control. Specifically, we suggest that dopaminergic modulation in the mPFC and noradrenergic modulation in the vlOFC may underlie distinct processes related to updating one's actions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Targeting Catecholaminergic Systems in Transgenic Rats With a CAV-2 Vector Harboring a Cre-Dependent DREADD Cassette.

Techniques that allow the manipulation of specific neural circuits have greatly increased in the past few years. DREADDs (Designer receptors exclusively activated by designer drugs) provide an elegant way to manipulate individual brain structures and/or neural circuits, including neuromodulatory pathways. Considerable efforts have been made to increase cell-type specificity of DREADD expression while decreasing possible limitations due to multiple viral vectors injections. In line with this, a retrograde canine adenovirus type 2 (CAV-2) vector carrying a Cre-dependent DREADD cassette has been recently developed. In combination with Cre-driver transgenic animals, the vector allows one to target neuromodulatory pathways with cell-type specificity. In the present study, we specifically targeted catecholaminergic pathways by injecting the vector in knock-in rat line containing Cre recombinase cassette under the control of the tyrosine hydroxylase promoter. We assessed the efficacy of infection of the nigrostriatal pathway and the catecholaminergic pathways ascending to the orbitofrontal cortex (OFC) and found cell-type-specific DREADD expression.

Corticosteroid-Binding Globulin Deficiency Specifically Impairs Contextual and Recognition Memory Consolidation in Male Mice.

BACKGROUND/AIMS: Glucocorticoids are essential in modulating memory processes of emotionally arousing experiences and we have shown that corticosteroid-binding globulin (CBG) influences glucocorticoid delivery to the brain. Here, we investigated the role of CBG in contextual and recognition long-term memory according to stress intensity. METHOD: We used adult male mice totally deficient in CBG (Cbg KO) or brain-specific Cbg KO (CbgCamk KO) to examine their performance in contextual fear conditioning (CFC) and au-ditory fear conditioning, both at short (1 h) and long-term (24 h). Long-term memory in Cbg KO was further analyzed in conditioned odor aversion and in novel object recognition task (NORT) with different paradigms, that is, with and without prior habituation to the context, with a mild or strong stressor applied during consolidation. In the NORT experiments, total and free glucocorticoid levels were measured during consolidation. RESULTS: Impaired memory was observed in the Cbg KO but not in the CbgCamk KO in the CFC and the NORT without habituation when tested 24 h later. However, Cbg KO displayed normal behavior in the NORT with previous habituation and in the NORT with a mild stressor. In condition of the NORT with a strong stressor, Cbg KO retained good 24 h memory performance while controls were impaired. Total and free glucocorticoids levels were always higher in controls than in Cbg KO except in NORT with mild stressor where free glucocorticoids were equivalent to controls. CONCLUSIONS: These data indicate that circulating but not brain CBG influences contextual and recognition long-term memory in relation with glucocorticoid levels.

Distinct regional patterns in noradrenergic innervation of the rat prefrontal cortex.

The anatomy and functions of the rodent prefrontal cortex (PFC) have been extensively studied. It is now clear that the PFC is at the core of various executive functions and that these functions depend on monoaminergic neuromodulation. The PFC receives extensive projections from monoaminergic nuclei and, in particular, from the locus cœruleus (LC) which is the major source of noradrenaline (NA) in the cortex. Projections of this nucleus have long been considered to act diffusely and uniformly throughout the entire brain. However, recent studies have revealed a separate innervation of prefrontal sub-regions by non-collateralizing LC neurons, suggesting a specific modulation of their functions. Following this idea, we aimed at describing more precisely the pattern of noradrenergic innervation into different orbital (OFC) and medial (mPFC) sub-regions of the PFC. We focused on the lateral (LO), ventral (VO) and medial (MO) portions of the OFC, and on areas 32d (A32d), 32v (A32v) and 25 (A25) in the mPFC. Using Dopamine-ß-Hydroxylase as a specific noradrenergic marker, we performed an automatic quantification of noradrenergic fibers and varicosities in each of these sub-regions. The results indicate that noradrenergic innervation is heterogeneous in some prefrontal sub-regions along the rostro-caudal axis. Functional dissociations have been recently reported in prefrontal sub-regions along the rostro-caudal direction. Our findings add neuroanatomical support to this emergent idea.

Insular and Ventrolateral Orbitofrontal Cortices Differentially Contribute to Goal-Directed Behavior in Rodents.

The medial prefrontal cortex (mPFC) has long been considered a critical site in action control. However, recent evidence indicates that the contribution of cortical areas to goal-directed behavior likely extends beyond mPFC. Here, we examine the function of both insular (IC) and ventrolateral orbitofrontal (vlOFC) cortices in action-dependent learning. We used chemogenetics to study the consequences of IC or vlOFC inhibition on acquisition and performance of instrumental actions using the outcome devaluation task. Rats first learned to associate actions with desirable outcomes. Then, one of these outcomes was devalued and we assessed the rats' choice between the 2 actions. Typically, rats will bias their selection towards the action that delivers the still valued outcome. We show that chemogenetic-induced inhibition of IC during choice abolishes goal-directed control whereas inhibition during instrumental acquisition is without effect. IC is therefore necessary for action selection based on current outcome value. By contrast, vlOFC inhibition during acquisition or the choice test impaired goal-directed behavior but only following a shift in the instrumental contingencies. Our results provide clear evidence that vlOFC plays a critical role in action-dependent learning, which challenges the popular idea that this region of OFC is exclusively involved in stimulus-dependent behaviors.