Biology subjects

Laurent, V.

Publications and source records attributed to Laurent, V..

8 recordsLinked to original sources

bioRxiv2026

Distinct amygdala-striatal and amygdala-cortical circuits encode and retrieve predictive learning to guide choice and decision-making

It has long been known that Pavlovian cues can influence choice between instrumental actions, although how this is achieved at a neural level is not fully understood. Here we examined the neural processes engaged during the encoding and retrieval of the Pavlovian stimulus-outcome (S-O) associations prior to and during their influence on choice. Using a Pavlovian-instrumental transfer paradigm (PIT), we found, as previously reported, that a circuit connecting the basolateral amygdala (BLA) and nucleus accumbens shell (BLA[->]NAc-S) is necessary to encode specific S-O associations within the NAc-S. However, this circuit was not required for the retrieval of those associations: optogenetic inhibition of this circuit had no effect on the ability of specific S-O associations to influence choice between instrumental actions. The BLA also projects to the infralimbic cortex (IL) although, using circuit mapping, we found that this projection was largely independent of the projection to the NAc-S. Nevertheless, using a circuit-specific disconnection approach, we found that the BLA[->]IL circuit is necessary for both the encoding and retrieval of specific S-O associations to influence choice. Furthermore, expanding on this disconnection approach, optogenetic inhibition of the BLA[->]IL circuit in one hemisphere and the IL[->]NAc-S contralaterally provided evidence that the broader BLA[->]IL[->]NAc-S circuit is necessary to retrieve specific S-O associations to influence choice during PIT. These data reveal, therefore, evidence of an amygdala-cortico-striatal circuit necessary for the retrieval of predictive learning to influence choice that differs from the circuit involved in encoding those predictive associations.

animal behavior and cognition↗

bioRxiv2026

Silencing basal forebrain cholinergic input to the infralimbic cortex renders fear extinction resistant to renewal

The infralimbic cortex (IL) is critical for the extinction of conditioned fear and receives dense cholinergic innervation from the basal forebrain, particularly from the horizontal limb of the diagonal band of Broca (HDB). Acetylcholine release in the IL regulates fear-related processes, but the mechanisms involved remain poorly understood. We investigated whether cholinergic projections from the HDB to the IL regulate the formation, extinction, and renewal of fear memories. Using optogenetics in male and female transgenic rats, we silenced the HDB to IL cholinergic pathway during either fear conditioning or extinction. Silencing during fear conditioning had no effect, whereas silencing during extinction enhanced extinction retrieval and prevented fear renewal. These effects were anatomically specific, as silencing the neighboring HDB to prelimbic cortex pathway had no such consequence. In ex vivo IL slices, stimulation of HDB cholinergic terminals preferentially excited interneurons over pyramidal neurons, consistent with feedforward inhibition of IL output. Finally, blockade of IL nicotinic acetylcholine receptors during extinction fully reproduced the effects of silencing the pathway, whereas muscarinic blockade attenuated renewal without affecting extinction retrieval. These findings indicate that cholinergic input from the HDB to the IL controls the acquisition and contextual specificity of extinction and identify nicotinic signaling in the IL as a potential target for improving extinction-based therapies.

neuroscience↗

bioRxiv2026

Identification of non-covalent inhibitors for the atypical peroxiredoxin PRDX5 as a therapeutic strategy in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-linked cancer with limited therapeutic options and a dismal 5-year survival rate of [~]5%. While aberrant production of reactive oxygen and nitrogen species (ROS/RNS) is a hallmark of MPM, targeted approaches to exploit these redox vulnerabilities remain scarce. Here, using the MOSAIC multimodal cancer patient atlas, we identify Peroxiredoxin 5 (PRDX5) as being significantly upregulated in the epithelioid subtype of MPM. We show that MPM cells exhibit enhanced resistance to nitrosative and oxidative stress compared to healthy mesothelial cells, a phenotype correlated with basal PRDX5 expression. Next, utilising a machine learning guided discovery pipeline, we identified three putative allosteric pockets in PRDX5 and conducted a virtual screen of 3.6 million compounds. High-throughput biochemical validation of 452 candidates yielded 36 non-covalent hits, including sub-micromolar inhibitors. These findings establish PRDX5 as a novel, subtype specific therapeutic target in MPM and provide a chemical framework for the development of next-generation redox-modulating oncology treatments.

cancer biology↗

bioRxiv2025

Backward Conditioning Reveals Flexibility in Infralimbic Cortex Inhibitory Memories

While the infralimbic cortex (IL) is recognized as critical for behavioral inhibition, the content of the inhibitory memories stored in this region remains elusive. To probe this content, we examined some of the conditions that allow retrieval and facilitation of an inhibitory memory stored in the IL using optogenetic stimulation in female and male rats. We found that IL stimulation did not facilitate an initial fear extinction session. However, prior experience with fear extinction enabled IL stimulation to facilitate subsequent fear extinction. Importantly, the facilitative effects of IL stimulation were not limited to fear extinction experience, as prior exposure to backward fear conditioning also enabled IL stimulation to enhance later fear extinction. The effects were stimulus-specific and did not depend on the motivational context present during the prior experience, as backward appetitive conditioning allowed IL stimulation to facilitate later fear extinction. Additional experiments ruled out stimulus familiarity as an explanation for the facilitative effects of IL stimulation and demonstrated that IL-mediated facilitations occur in procedures other than fear extinction. Together, these findings demonstrate that the IL stores inhibitory memories that are extremely flexible since they can be retrieved and used across many inhibitory procedures and distinct motivational contexts. These features establish the IL as a critical hub for the flexible application of inhibitory knowledge that allows adaptive responses in dynamic environments.

neuroscience↗

bioRxiv2025

The influence of nucleus accumbens shell D1 and D2 neurons on outcome-specific Pavlovian instrumental transfer

The nucleus accumbens shell (NAc-S) and its projections to the ventral pallidum (VP) are thought to be critical for stimulus-based decisions. The NAc-S is predominantly composed of spiny projection neurons (SPNs) that express either the dopamine D1 (D1-SPNs) or the dopamine D2 receptor (D2-SPNs). Yet, the role of these two neuronal subpopulations and their inputs to the VP in stimulus-based decisions remains unknown. Here, we used optogenetics in female and male knock-in rats to selectively silence D1-or D2-SPNs and their projections to the VP at a time when the rats were required to use predictive stimuli to choose between two instrumental actions. Silencing either population of NAc-S SPNs disrupted choice. Silencing NAc-S D1-SPNs terminals in the VP also disrupted choice. However, choice was left intact by silencing NAc-S D2-SPNs terminals in the VP. Together, these findings provide novel insights into the cellular mechanisms and circuitry underlying stimulus-based decisions. We discuss how these insights are consistent with a recent model proposing that these decisions are controlled by an opioid-based memory system residing in the NAc-S.

neuroscience↗

bioRxiv2024

Integration of sensory and fear memories in the rat medial temporal lobe

Wong et al. (2019) used a sensory preconditioning protocol to examine how sensory and fear memories are integrated in the rat medial temporal lobe. In this protocol, rats integrate a sound-light (sensory) memory that forms in stage 1 with a light-shock (fear) memory that forms in stage 2 to generate fear responses (freezing) across test presentations of the sound in stage 3. Here, we advance this research by showing that: 1) how/when rats integrate the sound-light and light-shock memories (online in stage 2 or at test in stage 3) changes with the number of sound-light pairings in stage 1; and 2) regardless of how/when it occurs, the integration requires communication between two regions of the medial temporal lobe: the perirhinal cortex and basolateral amygdala complex. Thus, "event familiarity" determines how/when sensory and fear memories are integrated but not the circuitry by which the integration occurs: this remains the same.

neuroscience↗

bioRxiv2023

High fat diet allows food-predictive stimuli to energize action performance in the absence of hunger, without distorting insulin signaling on accumbal cholinergic interneurons.

Obesity can disrupt how food-predictive stimuli control action performance and selection. These two forms of control recruit cholinergic interneurons (CIN) located in the nucleus accumbens core (NAcC) and shell (NAcS), respectively. Given that obesity is associated with insulin resistance in this region, we examined whether interfering with CIN insulin signaling disrupts how food-predictive stimuli control actions. To interfere with insulin signaling we used a high-fat diet (HFD) or genetic excision of insulin receptor (InsR) from cholinergic cells. HFD left intact the capacity of food-predictive stimuli to energize performance of an action earning food when mice were tested hungry. However, it allowed this energizing effect to persist when the mice were tested sated. This persistence was linked to NAcC CIN activity but was not associated with distorted CIN insulin signaling. Accordingly, InsR excision had no effect on how food-predicting stimuli control action performance. Next, we found that neither HFD nor InsR excision altered the capacity of food-predictive stimuli to guide action selection. Yet, this capacity was associated with changes in NAcS CIN activity. These results indicate that insulin signaling on accumbal CIN does not modulate how food-predictive stimuli control action performance and selection. However, they show that HFD allows food-predictive stimuli to energize performance of an action earning food in the absence of hunger.

neuroscience↗

bioRxiv2019

Dopamine 2 receptor signaling controls the daily burst in phagocytic activity in the mouse retinal pigment epithelium

PurposeA burst in phagocytosis of spent photoreceptor outer fragments by retinal pigment epithelium (RPE) is a rhythmic process occurring 1-2 hours after the onset of light. This phenomenon is considered crucial for the health of the photoreceptors and RPE. We have recently reported that dopamine, via dopamine 2 receptor (D2R), shifts the circadian rhythm in the RPE.\n\nMethodsHere, we first investigated the impact of the removal of D2R on the daily peak of phagocytosis by RPE and then we analyzed the function and morphology of retina and RPE in the absence of D2R.\n\nResultsD2R KO mice do not show a daily burst of phagocytic activity after the onset of light. Also, in contrast to control, phosphorylation of FAK did not increase significantly in KO mice at ZT1. RNA sequencing revealed a total of 394 differentially expressed genes (DEGs) between ZT23 and ZT1 in the control mice, whereas in D2R KO mice, we detected 1054 DEGs. Pathway analysis of the gene expression data implicated integrin signaling to be one of the upregulated pathways in control but not in D2R KO mice. No difference in retinal thickness, visual function, or morphology of RPE cells was observed between WT and D2R KO mice at the age of 3 and 12 months.\n\nConclusionsOur data suggest that removal of D2R prevents the burst in phagocytosis and a related increase in the phosphorylation of FAK after light onset. The pathway analysis points towards a putative role of D2R in controlling integrin signaling, which is known to play an important role in the control of the daily burst of phagocytosis by the RPE. Our data also indicate that the absence in the burst of phagocytic activity in the early morning does not produce any apparent deleterious effect on the retina or RPE up to one year of age.

cell biology↗