Oxytocin Facilitates Social Learning by Promoting Conformity to Trusted Individuals

There is considerable interest in the role of the neuropeptide oxytocin in promoting social cohesion both in terms of promoting specific social bonds and also more generally for increasing our willingness to trust others and/or to conform to their opinions. These latter findings may also be important in the context of a modulatory role for oxytocin in improving the efficacy of behavioral therapy in psychiatric disorders. However, the original landmark studies claiming an important role for oxytocin in enhancing trust in others, primarily using economic game strategies, have been questioned by subsequent meta-analytic approaches or failure to reproduce findings in different contexts. On the other hand, a growing number of studies have consistently reported that oxytocin promotes conformity to the views of groups of in-group individuals. Most recently we have found that oxytocin can increase acceptance of social advice given by individual experts without influencing their perceived trustworthiness per se, but that increased conformity in this context is associated with how much an expert is initially trusted and liked. Oxytocin can also enhance the impact of information given by experts by facilitating expectancy and placebo effects. Here we therefore propose that a key role for oxytocin is not in facilitating social trust per se but in conforming to, and learning from, trusted individuals who are either in-group members and/or perceived experts. The implications of this for social learning and use of oxytocin as an adjunct to behavioral therapy in psychiatric disorders are discussed

Role of the Oxytocin System in Alcohol Consumption and Stress-Induced Alcohol Relapse-like Behavior

Alcoholism is a widespread public health concern with limited therapeutic interventions available to help individuals battle relapse, moderate their use, and sustain abstinence. While many variables contribute to relapse vulnerability, stress is considered to play a prominent role in triggering relapse. The neuropeptide oxytocin (OXT) has recently been implicated in a number of neuropsychiatric disorders, including drug and alcohol use disorders. Given that OXT is known to interact with brain reward systems and exert anxiolytic and anti-stress effects in humans and rodents, the main overall hypothesis of this dissertation is that OXT (and OXT receptor signaling) will be effective in reducing alcohol consumption and stress-induced alcohol relapse-like behavior. We demonstrate that systemic administration of OXT reduced binge-like alcohol drinking, operant oral self-administration of alcohol, and stress-induced relapse-like behavior in a dose-related manner in male and female mice. Targeted chemogenetic activation of OXT neurons in the paraventricular nucleus of the hypothalamus (PVN) reduced binge-like alcohol drinking and operant oral self-administration in a similar manner as systemic administration of the neuropeptide and this effect was reversed by pretreatment with the centrally-active OXTR antagonist in males. Finally, administration of an OXTR antagonist systemically and directly into the central amygdala blocked the effects of OXT on stress-induced alcohol relapse-like behavior in male, but not female mice. These data highlight potential sex differences in oxytocin receptor signaling and support the therapeutic potential for OXT in treating alcohol use disorder

Psychological and Neural Dynamics of Trust

Trust is a key feature of social interactions and central to interpersonal cooperation. Acts of trust are not only pivotal aspects of interpersonal cooperation and group cohesion, they also have important consequences for individual health and life expectancy. However, which social qualities of others foster trust, how individuals learn whom to trust, and how the brain integrates this information for optimal behavioral updating is yet unexplored. Here, I will outline two lines of research. On one hand, I will show the psychological and neural predictors of trust in different social contexts. On the other, pharmacological modulations of the neural brain structures involved in trust will be presented. In the first two behavioral experiments, I show that honesty functions as an antecedent of trustworthiness impressions and that an honest reputation is associated with higher trust during a future social interaction. Next, I delineate the neural signatures of these honesty-based trustworthiness impressions. Notably, similar to the behavioral effects of honesty on future trust decisions, I found that honesty-encoding brain regions predicted those future trust decisions, providing evidence of honesty-related brain regions that entail neural signal predictive of trusting behavior. Furthermore, an honest reputation also modulated neural responses to feedback information. Such neural modulation likely biases information integration during social learning. Consequently, I show in a further behavioral study that an honest reputation seems to indeed impair learning due to an honesty-dependent asymmetry in information weighting. Finally, I demonstrate how the pharmacological modulation of brain dynamics impacts trusting behaviors leaving trustworthiness impressions unchanged. On the one hand, these findings shed light on how honesty not only increases trust in others but also hampers learning processes for optimal behavioral adaptation. On the other, they provide the first pharmacological evidence of how impression-based trust can be changed without impacting those very first trustworthiness impressions. I finally propose accounts that might explain the observed behavioral and neural patterns and outline potential directions for new studies

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

TheRole of the Insular Cortex in Rodent Social Affective Behavior:

Thesis advisor: John P. ChristiansonIn social species, animals must detect, evaluate and respond to the states of other individuals in their group. A constellation of gestures, vocalizations, and chemosignals enable animals to convey affect and arousal to others in nuanced, multisensory ways. Observers integrate such social information with environmental cues and internal physiology to general social behavioral responses via a process called social decision-making. The mechanisms and anatomical correlates of social decision-making, particularly those that allow behavioral responses to others’ emotional states, are not fully known. Therefore, the objective of this dissertation is to broaden the anatomical understanding of social decision-making by investigating the role of the insular cortex in social behaviors that depend upon others’ emotional state. Using a novel behavioral paradigm, I present causal evidence that implicates the insular cortex and its projections to the nucleus accumbens in social affective behavior. These findings are consistent with evidence from the literature that suggests insular cortex is positioned to convey sensory cues to social brain structures to produce flexible and appropriate behavioral responses to social affective cues.Thesis (PhD) — Boston College, 2019.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Psychology

Acetaldehyde as a drug of abuse: Involvement of endocannabinoid- and dopamine neurotransmission

Acetaldehyde (ACD), the first metabolite of ethanol, directly enhances dopamine neurotransmission (1) and has rewarding and motivational properties in paradigms tailored for studying addictive-like behaviours (2, 3). The endocannabinoid system affects distinct drug-related behaviours, since it may in turn fine-tune dopamine cell activity (4, 5). In light of this, the present study aimed at investigating the effects of a direct manipulation of the DAergic synapse, and the contribution of the endocannabinoid system on oral ACD self-administration in rats. ACD drinking-behaviour was evaluated in an operant paradigm consisting of acquisition and maintenance; extinction; deprivation and relapse; conflict. D2-receptor agonists, quinpirole (0.03 mg/Kg, i.p.) and ropinirole (0.03 mg/Kg, i.p.), and CB1-receptor antagonist, AM281 (1 mg/Kg, i.p.), were administered during different phases of the experiment. Our results show that oral ACD readily induced the acquisition and maintenance of an operant drinking-behaviour, even during reinstatement and conflict. Quinpirole decreased lever presses for ACD during extinction (p<0.05) and relapse (p<0.01; p<0.001) Ropinirole, administered during abstinence, reduced ACD intake during reinstatement (p<0.001). AM281 significantly decreased lever presses for ACD during extinction (p<0.001), relapse (p<0.001) and conflict (p<0.001). These data suggest that whereas the direct modulation of the dopaminergic synapse influences drug-seeking and relapse behaviour, the endocannabinoid system may also play a role in shock-paired compulsive ACD intake. These findings highlight the mandatory need for further investigation on the therapeutical potential played by the endocannabinoid system taking into account its crucial role in alcohol, and ACD neuropharmacology

Inhibition of prandial and waterspray-induced rat grooming by 8-OH-DPAT

The effects of 8-OH-DPAT treatment on rat grooming behaviour, elicited either prandially or in response to spraying with water were investigated. Dose (≤0.1 mg/kg s.c.) response studies employed momentary time sampling over 30 or 60 min with behaviour being scored in one of 6 or 7 (depending on food availability) mutually exclusive categories (feeding, active, scratching, face-grooming, body grooming, genital-grooming and resting) at 15 s intervals. In non-deprived rats, tested with wet mash available, feeding and activity frequencies were increased, but resting and total grooming were inhibited by 8-OH-DPAT. Face-, body- and genital-grooming occurred at higher levels than scratching, but all categories were reduced with reductions in scratching occurring at a lower dose (0.01 mg/kg). Misting rats with a fine water spray selectively increased body grooming and decreased activity without altering feeding, while 8-OH-DPAT increased feeding and reduced face-, body- and genital-grooming, without affecting already low levels of scratching. In misted rats, tested without food, 8-OH-DPAT reduced face-, body- and genital-grooming and increased resting. These results confirm i) that the water spray technique is a useful method for increasing grooming and ii) that 8-OH-DPAT has a suppressant effect on grooming independent of response competition from enhanced feeding

Immunohistochemical and electrophysiological investigation of E/I balance alterations in animal models of frontotemporal dementia

Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disease characterised by changes in behaviour. Apathy, behavioural disinhibition and stereotyped behaviours are the first symptoms to appear and all have a basis in reward and pleasure deficits. The ventral striatum and ventral regions of the globus pallidus are involved in reward and pleasure. It is therefore reasonable to suggest alterations in these regions may underpin bvFTD. One postulated contributory factor is alteration in E/I balance in striatal regions. GABAergic interneurons play a role in E/I balance, acting as local inhibitory brakes, they are therefore a rational target for research investigating early biological predictors of bvFTD. To investigate this, we will carry out immunohistochemical staining for GABAergic interneurons (parvalbumin and neuronal nitric oxide synthase) in striatal regions of brains taken from CHMP2B mice, a validated animal model of bvFTD. We hypothesise that there will be fewer GABAergic interneurons in the striatum which may lead to ‘reward-seeking’ behaviour in bvFTD. This will also enable us to investigate any preclinical alterations in interneuron expression within this region. Results will be analysed using a mixed ANOVA and if significant, post hoc t-tests will be used. The second part of our study will involve extracellular recordings from CHMP2B mouse brains using a multi-electrode array (MEA). This will enable us to determine if there are alterations in local field potentials (LFP) in preclinical and symptomatic animals. We will also be able to see if neuromodulators such as serotonin and dopamine effect LFPs after bath application. We will develop slice preparations to preserve pathways between the ventral tegmental area and the ventral pallidum, an output structure of the striatum, and the dorsal raphe nucleus and the VP. Using the MEA we will stimulate an endogenous release of dopamine and serotonin using the slice preparations as described above. This will enable us to see if there are any changes in LFPs after endogenous release of neuromodulators. We hypothesise there will be an increase in LFPs due to loss of GABAergic interneurons

Oxytocin as an appetite suppressant that reduces feeding reward

In the environment in which palatable and highly caloric foods are readily available, eating behavior is oftentimes not dictated by the necessity to replenish lacking energy, but rather by the pleasure of consumption. Centrally acting oxytocin (OT) is known to promote termination of feeding to protect internal milieu by preventing excessive stomach distension, hyperosmolality and ingestion of toxins. Initial evidence suggests that another possible role for OT in mechanisms governing food intake is to reduce consumption of select palatable tastants. This thesis explores the question whether OT is as an appetite suppressant that reduces feeding reward. The first set of experiments addresses whether OT affects intake of (a) all carbohydrates, (b) only sweet carbohydrates or (c) sweet non-carbohydrate saccharin in mice. In those studies, generalized injection of a blood brain barrier penetrant OT receptor antagonist, L-368,899, significantly increased the intake of sweet (sucrose, glucose, fructose, polycose) and non-sweet (cornstarch) carbohydrates and promoted a trend approaching significance in saccharin consumption. Consumption of carbohydrate-enriched foods led to an increase in OT mRNA levels in the hypothalamus. The second set of studies identifies the nucleus accumbens core (AcbC), a key component of the reward system, as a site that mediates anorexigenic effects of OT. Rats injected with OT directly in the AcbC showed a decreased intake of sucrose and saccharin solutions as well as of standard chow. This treatment did not cause taste aversion, hence the outcome was not due to sickness/malaise. The effects of AcbC OT on feeding could be observed only in animals offered a meal in a non-social environment. Once a social setting (devoid of direct antagonistic interactions between individuals) of a meal was introduced, AcbC OT failed to reduce feeding. AcbC levels of OT receptor transcript were affected by exposure to palatable food as well as by food deprivation. The third and final set of studies shows that aberrant integrity of neuronal circuitry within the neuroendocrine and reward systems due to genetic deletion of connexin 36 (Cx36) gap junctions leads to dysregulation of the OT system’s functioning in the Cx36 KO mouse. This dysregulation is associated with hypersensitivity to aversive properties of foods, reduced interest in feeding for reward (palatable carbohydrates and saccharin) and abnormal ingestion of energy. Overall, the findings suggest that OT diminishes feeding for reward, particularly the intake of palatable carbohydrates and saccharin, by acting – at least in part – via the reward system. OT appears to be part of central mechanisms that cross-link homeostasis-driven and palatability-related (i.e., flavor- and macronutrient-specific) termination of consumption