Biology subjects

D'Hooge, R.

Publications and source records attributed to D'Hooge, R..

7 recordsLinked to original sources

bioRxiv2025

Interdependency between oxytocin and dopamine in trust-based learning in mice

Oxytocin (OT) is a neuropeptide implicated in complex social behaviors including trust and attachment, yet the neural mechanisms underlying its effects remain unclear. OT is thought to modulate behavior by enhancing the salience of social cues and attenuating prediction error (PE) processing, the discrepancy between expected and actual outcomes that drives learning. Since both salience coding and PE processing involve dopamine (DA) neurons as well, the current study investigated the putative interdependence between OT and DA in social safety learning using the social transmission of food preference (STFP) paradigm. STFP is based on the observation that mice (observers) display neophobia toward novel food, but develop a preference for it after a conspecific demonstrator signals its safety. We interpreted STFP acquisition as a functional parallel to human trust-based learning and found that OT enhanced learning in a trust acquisition condition, but only when DA signaling was intact. In a trust violation condition, where demonstrated food was later paired with lithium chloride (LiCl)-induced food aversion, both OT and DA depletion blocked learning, resulting in retained preference for demonstrated food, but not when OT was administered under DA depletion. These findings reveal a functional interaction between the OT and DA systems to modulate social safety learning, which may have important implications for OTs potential in treating disorders involving DA dysfunction.

neuroscience↗

bioRxiv2024

Oxytocin enhances acquisition in a social trust task in mice, whereas both oxytocin and its antagonist block trust violation learning

The complex effects of the neurohormone oxytocin (OT) on socio-cognitive phenomena have recently been proposed to be complementary with safety learning, where a stimulus acquires safety-predicting properties when it predicts non-occurrence of an aversive event. OT may enhance saliency of safety stimuli and promote positive social behavior, such as trust, by reducing anxiety and stress. Complementary, OT may reduce the ability to modulate previously learned behaviors based on new, contradicting information. This occurs through its attenuation of prediction error (PE)--the discrepancy between expectations and actual outcomes. In the current study, we stimulated or inhibited (with antagonist cligosiban, CL) the OT system and subjected male and female mice to our social transmission of food preference (STFP) protocol to assess social safety learning. STFP is based on the observation that food neophobia of rodents is attenuated when a conspecific signals the safety of the food. We used safe food preference as putative murine homologue of human trust acquisition, and modeled trust violation (PE) using lithium chloride (LiCl)-induced food aversion after social interaction. In males, results revealed that OT enhanced trust acquisition, whereas both OT and its antagonist CL similarly blocked trust violation learning. None of the manipulations affected female behavior. Our findings highlight the complexities of OTs role in social behavior, emphasizing caution in therapeutic manipulations of this system.

neuroscience↗

bioRxiv2022

Lack of the glycine alpha 2 receptor impairs reward-motivated behavior and striatal signal integration.

Distinct developmental pathologies, including autism spectrum disorder and schizophrenia, exhibit impaired reward-motivated behavior. Key to proper reward-motivated behavior is dopamine-mediated modulation of striatal activity. The glycine alpha 2 receptor (GlyR2) is the single functionally expressed glycine receptor in adult striatum, and is therefore ideally positioned to modulate striatal behavior and cellular activity. Here, we report excessive appetitive conditioning in male GlyR2 knockout mice. We next show that depletion of GlyR2 enhances dopamine-induced increases in the activity of putative dopamine D1-expressing striatal projection neurons, while not affecting dopamine neuron activity. Moreover, we found that excessive locomotor responses to amphetamine in GlyR2 KO mice correlate with immediate early gene c-fos expression in the dorsal striatum. 3-D modeling revealed an increase in the number of activated cell ensembles in the striatum in response to D-amphetamine in GlyR2 KO mice. Taken together, we show that depletion of GlyR2 impairs reward-motivated behavior and altered striatal signal integration. This sheds important light onto the cellular mechanisms that underlie reward function, and pave the way towards novel therapeutics for the treatment of e.g. schizophrenia and addiction. Significance statementThe glycine receptor alpha 2 has long been studied for its role in development, with expression assumed to decline throughout adulthood in favor of the glycine receptor alpha 1 and 3. Yet, we showed that in the dorsal striatum, the glycine alpha 2 receptor is the only functionally expressed glycine receptor at adult age (Molchanova et al., 2017). In the present work, we show for the first time that the glycine alpha 2 receptor crucially affects striatal cell activity, which lies at the basis of reward-motivated behaviors, and which is impaired in many psychiatric pathologies. Indeed, a link between the mutations in the glycine alpha 2 receptor and autism as well as schizophrenia has been described, but a functional role for the glycine alpha 2 receptor in adult brain structures that are involved in psychiatric pathologies, was never shown before.

neuroscience↗

bioRxiv2022

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's Disease

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimers disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex, several years before amyloid deposition. We found the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astroglial calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral hyperactivity. In conclusion, we show for the first time that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

neuroscience↗

bioRxiv2021

Scopolamine blocks context-dependent reinstatement of fear responses in rats

Return of fear poses a problem for extinction-based therapies of clinical anxiety. Experimental research has discovered several pathways to return of fear, one of which is known as reinstatement. Here, we evaluated in rats the potential of scopolamine, a non-selective muscarinic receptor antagonist that is also safe for use in humans, to prevent the reinstatement of extinguished fear. We conducted three experiments with a total sample of 96 female rats. All rats went through a fear acquisition session (tone-shock pairings, CS-US), followed by two extinction sessions (CS only) and a post-extinction fear memory test. Twenty-four hours later, rats were placed in the same or a different context from extinction and received two unsignaled foot shock (US) presentations. On the following day, CS-evoked freezing returned when the reinstating USs had occurred in the same context compared to a different context (context-dependent reinstatement, Experiment 1). Systemic administration of scopolamine before or after the reinstating USs blocked the return of CS-evoked freezing on the following day (Experiments 2 and 3). Our findings suggest that administering scopolamine around the time of an aversive experience could prevent relapse of extinguished fears in humans.

neuroscience↗

bioRxiv2019

Social isolation impacts late-life socio-cognitive decline in APP/PS1 mice

In this study the effects of social isolation (SI) were investigated in APP/PS1 mice. It was found that SI during adolescence has an impact on anxiogenic behaviour, such that isolated animals tend to explore a threatening environment less than non-isolated animals as assessed with the EPM test, and that this holds for both AD and non-AD mice. While no evidence was found for any differences in short-term memory as assessed by the Y-maze, long-term memory seemed to be affected in a context-dependent manner. Object memory as assessed with the NOR test was affected in APP/PS1 mice compared to WT mice, but this deficit was not induced or influenced by SI. When it comes to social recognition memory however, we found that SI exacerbated the social memory deficit in AD mice, and even induced a deficit in WTs. Associative fear memory as assessed with the PA test suggested that WTs perform better when group housed, and APP/PS1 mice better when socially isolated. The link between isolation and AD, or cognition in general, may be more complex than initially thought. The effect of isolation may not be the same for AD versus non-AD subjects.

neuroscience↗

bioRxiv2019

Isolation housing exacerbates Alzheimer’s Disease phenotype in aged APP KI mice

In January 2018, Britain was the first in the world to adopt a Minister of Loneliness. This illustrates the changing view on loneliness: being lonely is not just a feeling of a lack of companionship, but also a serious health problem. For example, we know that loneliness is as bad as smoking 15 cigarettes a day. Moreover, research has shown that lonely people express higher levels of cortical amyloid. Amyloid burden is an important marker of Alzheimers Disease (AD), a chronic neurodegenerative disease and the main cause of dementia worldwide. Together with other findings a link between loneliness, (perceived) social isolation and AD is now undeniable, but it is hard to tell from human studies whether it is the cause or the effect of AD. We need standardized animal studies to answer this question.\n\nIn an effort to study how social isolation and AD interact, we used APP KI mice bearing human transgenes known to cause AD, and isolated part of the mice in order to mimic loneliness in late-life while part of them remained group-housed. We next looked at the effects of isolation on the behaviour and symptomatology typically present in AD patients to tap cognition.\n\nOur study reveals mixed results. Results indicate that at before isolation, at the age of 16 and 24 months, APPNL/NL and APPNL-G-F/NL-G-F mice do not differ to a significant extent on both the behavioural level. The APPNL-G-F/NL-G-F differentiated slightly worse between the conditioned context and a new context compared to the APPNL/NL mice. However, the difference appeared to be more pronounced after a period of social isolation. Social isolation had distinct effects on the AD-related anxiogenic and dementia-like phenotype. Spatial learning in the MWM task revealed distinct differences between our two models. After isolation APPNL-G-F/NL-G-F mice used less spatial search strategies, compared to control mice, thus reflecting perseveration and less behavioural flexibility due to the isolation period.

neuroscience↗