Adaptive Responding to Stimulus-Outcome Associations Requires Noradrenergic Transmission in the Medial Prefrontal Cortex.

A dynamic environment, such as the one we inhabit, requires organisms to continuously update their knowledge of the setting. While the prefrontal cortex is recognized for its pivotal role in regulating such adaptive behavior, the specific contribution of each prefrontal area remains elusive. In the current work, we investigated the direct involvement of two major prefrontal subregions, the medial prefrontal cortex (mPFC, A32D + A32V) and the orbitofrontal cortex (OFC, VO + LO), in updating pavlovian stimulus-outcome (S-O) associations following contingency degradation in male rats. Specifically, animals had to learn that a particular cue, previously fully predicting the delivery of a specific reward, was no longer a reliable predictor. First, we found that chemogenetic inhibition of mPFC, but not of OFC, neurons altered the rats' ability to adaptively respond to degraded and non-degraded cues. Next, given the growing evidence pointing at noradrenaline (NA) as a main neuromodulator of adaptive behavior, we decided to investigate the possible involvement of NA projections to the two subregions in this higher-order cognitive process. Employing a pair of novel retrograde vectors, we traced NA projections from the locus ceruleus (LC) to both structures and observed an equivalent yet relatively segregated amount of inputs. Then, we showed that chemogenetic inhibition of NA projections to the mPFC, but not to the OFC, also impaired the rats' ability to adaptively respond to the degradation procedure. Altogether, our findings provide important evidence of functional parcellation within the prefrontal cortex and point at mPFC NA as key for updating pavlovian S-O associations.

The CRF1 receptor mediates social behavior deficits induced by opiate withdrawal.

Poor sociability and aggressive behavior are key clinical features of opioid use disorders. The corticotropin-releasing factor (CRF) system may mediate behavioral effects of substances of abuse but its implication in substance-induced social behavior deficits and outward-directed hostility remains largely unknown. CRF signaling is mediated by two receptor types, termed CRF1 and CRF2 . The present study aimed at understanding the role for the CRF1 receptor in social and aggressive behavior induced by withdrawal from repeated opiate administration. Thus, wild-type (CRF1 +/+), CRF1 receptor heterozygous (CRF1 +/-), and null mutant (CRF1 -/-) female and male mice were treated with saline or escalating doses of morphine (20-100 mg/kg, i.p.) during six consecutive days and tested in the three-chamber task for sociability (i.e., preference for an unfamiliar same-sex conspecific vs. an object) 7 days after the last administration. Moreover, aggressive biting behavior toward the unfamiliar conspecific was assessed during the three-chamber test. Opiate withdrawal disrupted sociability in CRF1 +/+ and CRF1 +/-, but not in CRF1 -/-, female mice, without affecting aggressive biting behavior in any genotype. In contrast, opiate withdrawal did not affect sociability but increased aggressive biting behavior in male mice, independently of CRF1 receptor-deficiency. Nevertheless, in opiate-withdrawn CRF1 +/+, but not CRF1 +/- and CRF1 -/-, male mice, sociability directly correlated with aggressive biting behavior, suggesting a role for the CRF1 receptor in hostility-linked social approach. These findings demonstrate the implication of the CRF1 receptor in social behavior deficits associated with repeated opiate administration and withdrawal, revealing a new potential target for the treatment of opioid use disorders.

Involvement of Autophagy in Levodopa-Induced Dyskinesia.

BACKGROUND: Autophagy is intensively studied in cancer, metabolic and neurodegenerative diseases, but little is known about its role in pathological conditions linked to altered neurotransmission. We examined the involvement of autophagy in levodopa (l-dopa)-induced dyskinesia, a frequent motor complication developed in response to standard dopamine replacement therapy in parkinsonian patients. METHODS: We used mouse and non-human primate models of Parkinson's disease to examine changes in autophagy associated with chronic l-dopa administration and to establish a causative link between impaired autophagy and dyskinesia. RESULTS: We found that l-dopa-induced dyskinesia is associated with accumulation of the autophagy-specific substrate p62, a marker of autophagy deficiency. Increased p62 was observed in a subset of projection neurons located in the striatum and depended on l-dopa-mediated activation of dopamine D1 receptors, and mammalian target of rapamycin. Inhibition of mammalian target of rapamycin complex 1 with rapamycin counteracted the impairment of autophagy produced by l-dopa, and reduced dyskinesia. The anti-dyskinetic effect of rapamycin was lost when autophagy was constitutively suppressed in D1 receptor-expressing striatal neurons, through inactivation of the autophagy-related gene protein 7. CONCLUSIONS: These findings indicate that augmented responsiveness at D1 receptors leads to dysregulated autophagy, and results in the emergence of l-dopa-induced dyskinesia. They further suggest the enhancement of autophagy as a therapeutic strategy against dyskinesia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Sex-linked roles of the CRF1 and the CRF2 receptor in social behavior.

Dysfunctional social behavior is a major clinical feature of mood, anxiety, autism spectrum, and substance-related disorders, and may dramatically contribute to the poor outcome of these diseases. Nevertheless, the mechanisms underlying social behavior deficits are still largely unknown. The corticotropin-releasing factor (CRF) system, a major coordinator of the stress response, has been hypothesized to modulate social behavior. CRF signaling is mediated by two receptor types, termed CRF1 and CRF2 . Using the three-chamber task for sociability (i.e., preference for an unfamiliar conspecific vs. an object), this study demonstrates that CRF2 receptor null mutation (CRF2 -/-) reduces sociability in female mice but increases it in male mice. Both female and male CRF2 -/- mice display a preference for social odor cues over neutral cues, indicating that sex- and CRF2 receptor-dependent sociability is not due to altered olfaction or impaired social cues discrimination. Moreover, treatment with the CRF1 receptor-preferring antagonist, antalarmin, consistently induces sociability in non-social mice but disrupts it in social mice, independently of CRF2 receptor deficiency. Sex, CRF2 receptor deficiency, or antalarmin affect locomotor activity during the three-chamber test. However, throughout the study CRF1 and CRF2 receptor-linked sociability is independent of locomotor activity. The present findings highlight major functions for the CRF system in the regulation of social behavior. Moreover, they provide initial evidence of sex-linked roles for the CRF1 and the CRF2 receptor, emphasizing the importance of sex as a major biological variable to be taken into consideration in preclinical and clinical studies.

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.

Morphine reduces the interest for natural rewards.

RATIONALE: Alongside a pathological, excessive, motivation for substances of abuse, substance use disorder (SUD) patients often show a dramatic loss of interest for naturally rewarding activities, such as positive peer social interaction and food intake. Yet, pre-clinical evidence of the latter SUD features remains scarce and inconsistent. OBJECTIVES: In the current study, we investigated the effect of non-rewarding and rewarding doses of morphine upon social behaviour, motivation for and intake of palatable food, in male and female C57BL/6J mice. METHODS: First, the rewarding effects of two relatively low morphine doses (1.25 and 2.5 mg/kg) were assessed using a newly established single substance administration/conditioning trial conditioned place preference (CPP) paradigm. Then, morphine (1.25 and 2.5 mg/kg) effects upon social behaviour, motivation for and intake of palatable food were examined by the three-chamber (3-CH), an operant behaviour and a palatable food preference test, respectively. RESULTS: Morphine (2.5 mg/kg) induced CPP in both male and female mice, whereas morphine (1.25 mg/kg) induced CPP only in female mice. Both morphine doses (1.25 and 2.5 mg/kg) reduced sociability, motivation for and intake of palatable food in male and female mice, independently of cognitive function or locomotor activity. CONCLUSIONS: Female mice were more sensitive than male mice to the rewarding effects of morphine. Moreover, both a non-rewarding and a rewarding dose of morphine impaired the interest for naturally rewarding activities, indicating that brain reward systems might be more sensitive to the deleterious than to the rewarding effects of substances of abuse.

Long-lasting pseudo-social aggressive behavior in opiate-withdrawn mice.

Poor sociability and aggressive behavior are major clinical features of opiate use disorders that may contribute to the establishment and maintenance of these harmful diseases. The present study investigated the long-term effects of chronic morphine administration and withdrawal upon social and aggressive behavior as well as the interrelationship between these two behaviors. Thus, social behavior was measured in C57BL/6J male mice 7, 21, 35 and 49 days after cessation of escalating morphine doses (20-100 mg/kg, i.p.) administered during 6 consecutive days, using the three-chamber task for sociability (i.e., preference for an unfamiliar conspecific vs. an object) and social novelty preference (i.e., preference for a novel vs. a familiar conspecific). Moreover, aggressive biting behavior towards an unfamiliar conspecific was assessed throughout the three-chamber tests. Opiate withdrawal increased both social approach and aggressive biting behavior. Moreover, in morphine-withdrawn, but not in control, mice social approach and aggressive behavior followed a similar time-course and positively correlated one with each other, suggesting that social interest was mainly driven by aggressiveness. Aggressive biting behavior was still elevated 49 days after the last morphine administration, revealing that opiate withdrawal is followed by long-lasting aggressiveness. Throughout, opiate withdrawal did not affect social novelty preference, ruling out a role for olfactory or social discrimination dysfunction in the elevated social approach and aggressive behavior. The present findings of very long-lasting aggressive behavior and aggression-driven social approach in opiate-withdrawn mice might help understanding the behavioral and brain underpinnings of poor sociability and aggressiveness commonly observed in opiate use disorders patients.