Biology subjects

Piccin, A.

Publications and source records attributed to Piccin, A..

3 recordsLinked to original sources

bioRxiv2024

Disruption of the CRF1 receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice

Substance-induced social behavior deficits dramatically worsen the clinical outcome of substance use disorders; yet, the underlying mechanisms remain poorly understood. Herein, we investigated the role for the corticotropin-releasing factor receptor 1 (CRF1) in the acute sociability deficits induced by morphine and the related activity of oxytocin (OXY)-and arginine-vasopressin (AVP)-expressing neurons of the paraventricular nucleus of the hypothalamus (PVN). For this purpose, we used both the CRF1 receptor-preferring antagonist compound antalarmin and the genetic mouse model of CRF1 receptor-deficiency. Antalarmin completely abolished sociability deficits induced by morphine in male, but not in female, C57BL/6J mice. Accordingly, genetic CRF1 receptor-deficiency eliminated morphine-induced sociability deficits in male mice. Ex vivo electrophysiology studies showed that antalarmin also eliminated morphine-induced firing of PVN neurons in male, but not in female, C57BL/6J mice. Likewise, genetic CRF1 receptor-deficiency reduced morphine-induced firing of PVN neurons in a CRF1 gene expression-dependent manner. The electrophysiology results consistently mirrored the behavioral results, indicating a link between morphine-induced PVN activity and sociability deficits. Interestingly, in male mice antalarmin abolished morphine-induced firing in neurons co-expressing OXY and AVP, but not in neurons expressing only AVP. In contrast, in female mice antalarmin did not affect morphine-induced firing of neurons co-expressing OXY and AVP or only OXY, indicating a selective sex-specific role for the CRF1 receptor in opiate-induced PVN OXY activity. The present findings demonstrate a major, sex-linked, role for the CRF1 receptor in sociability deficits and related brain alterations induced by morphine, suggesting new therapeutic strategy for opiate use disorders.

neuroscience↗

bioRxiv2023

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 contributions of each prefrontal area remain elusive. In the current work, we investigated the direct involvement of two major prefrontal subregions, the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (vlOFC), in updating Pavlovian stimulus-outcome (S-O) associations following contingency degradation. Specifically, animals had to learn that a specific 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 vlOFC, 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 coeruleus (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 vlOFC, 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. Significant statementThe ability to update stimulus-outcome (S-O) associations is a key adaptive behavior, essential for surviving in an ever-changing environment. The prefrontal cortex is well-known for playing a key role in this process. The discrete contribution of each prefrontal subregion and of different neurotransmitters, however, remains unclear. In the current study, we show that inhibiting medial prefrontal (mPFC), but not ventrolateral orbitofrontal cortex (vlOFC), neurons impairs the rats ability to update S-O associations following contingency degradation. Moreover, we demonstrate that discrete noradrenergic projections to the two subregions exist and that inhibiting the ones projecting to the mPFC, but not to the vlOFC, once again impairs the rats behavior, thereby implying a substantial contribution of noradrenaline in orchestrating this higher-order cognitive process.

neuroscience↗

bioRxiv2022

Noradrenergic signaling in the rodent orbitofrontal cortex is required to update 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 behavior 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 behavior 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 behavioral flexibility might depend upon the noradrenergic modulation of prefrontal cortex. Therefore, we assessed whether noradrenergic innervation of the OFC plays a role in updating action-outcome relationships. 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 medial prefrontal cortex or depletion of dopaminergic inputs in the OFC did not reproduce this deficit. Together, our results indicate that noradrenergic projections to the OFC are required to update goal-directed actions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/498245v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@afc586org.highwire.dtl.DTLVardef@1d10ff4org.highwire.dtl.DTLVardef@6e6863org.highwire.dtl.DTLVardef@874b30_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIRats learn initial action-outcome associations in an instrumental task C_LIO_LINoradrenergic depletion in the OFC prevents the encoding and expression of these associations following reversal learning C_LIO_LIDopaminergic depletion in the OFC does not result in behavioral deficits C_LIO_LILC:OFC noradrenergic projections are required to update action-outcome associations C_LI IN BRIEFCerpa et al. investigate whether noradrenergic projections from the locus coeruleus (LC) to the orbitofrontal cortex are involved in updating previously established goal-directed actions following environmental change. They find that these LC projections are required to both encode and express reversed action-outcome associations in rats.

neuroscience↗