Thesis advisor: John P. Christianson / In 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.

Thesis advisor: John P. Christianson / Accurate discrimination between safety and danger is necessary for survival, but is aberrant in individuals with post-traumatic stress disorder (PTSD). Despite its clinical relevance, very little is known about the cognitive and neural processes that underlie safety learning. Understanding how cues become safety signals is critical to understanding the impairments in fear modulation observed in individuals with PTSD. PTSD is more prevalent in women than men, and while research on sex differences in safety learning is limited, there is substantial evidence that males and females acquire and utilize safety signals differently. The aim of this dissertation is to describe behavioral sex differences in learning and recall of fear discrimination and explore the neural circuitry that allows this discrimination to occur. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

The prefrontal cortex (PFC) is considered a critical node in the neural circuitry underlying drug-seeking behaviors. However, the mechanisms by which this region influences drug seeking and whether or not the lateral PFC mediates cocaine or heroin seeking are questions that have yet to be answered. To expand on the role of the PFC in drug seeking, rats were trained on either heroin or cocaine self-administration for a minimum of 12 days before undergoing extinction training and subsequent reinstatement tests (cued and drug-prime). All pharmacological manipulations were delivered immediately prior to reinstatement testing and were targeted at either the ventral region of the medial PFC, the infralimbic cortex (IL), the anterior portion of the medial PFC, the medial orbitofrontal cortex (mOFC), the anterior region of the insular cortex, the dorsal agranular insular cortex (AId), or the posterior region of the insular cortex, the posterior insular cortex (PIc). In chapter 1, D1 and D2 antagonists were administered into the IL and mOFC prior to cued and cocaine-prime reinstatement. Although previous studies found that the IL inhibits cocaine seeking, blocking D1 receptor activity in this region reduced cued reinstatement and had no effect on cocaine-prime reinstatement, indicating that the IL can promote cocaine seeking under certain circumstances. In contrast, blocking D1 receptors in the mOFC reduced all forms of reinstatement that were examined. Blocking D2 receptors in either region had no effect on cocaine seeking. Our data are the first to demonstrate a role for the mOFC in cocaine seeking and suggest that although the IL and mOFC lie immediately adjacent to one another, they play distinct roles in mediating cocaine seeking. In chapter 2, we pharmacologically inactivated the AId and PIc via a GABA agonist administered immediately prior to both cocaine and food seeking. Reversible inactivation of the AId reduced cued reinstatement but had no effect on cocaine-prime reinstatement. In contrast, inactivating the PIc had no effect on any form of cocaine seeking. Additionally, blocking the AId during cued and food-prime reinstatement had no effect on food seeking, indicating the role of the AId in reinstatement is specific to cocaine seeking and not general motivated behavior. Additionally, blocking CRF1 receptors in the AId blocked cued reinstatement, suggesting a possible mechanism whereby the AId is influencing cocaine seeking. These data are the first to establish a role for the AId in cocaine seeking and demonstrate that although the PIc influences alcohol and nicotine seeking, it does not mediate cocaine seeking. Chapter 3 further examined the role of the AId in cocaine seeking and expanded the influence of the insular cortex in drug seeking to heroin. AId D1 receptor blockade reduced both cued and cocaine-prime reinstatement following extinction training, whereas D2 receptor blockade had no effect on cocaine seeking. These results establish a role for the AId in cocaine-prime reinstatement, as pharmacological inactivation showed no role for the AId in cocaine-induced drug seeking. Additionally, blocking the AId during heroin seeking potentiated cued reinstatement whereas blocking the PIc during heroin seeking reduced cued reinstatement. These results demonstrate a role for the insular cortex in heroin seeking that has never been shown before and further explain how the AId may be influencing cocaine seeking.

A estimulação elétrica cerebral é uma alternativa terapêutica para pacientes com dor neuropática refratária à terapia convencional sendo o córtex insular (CI) um alvo promissor para seu tratamento. Este trabalho investigou o efeito da estimulação elétrica do córtex insular (EECI) sobre a sensibilidade dolorosa de ratos submetidos à constrição crônica do nervo isquiático. Ratos foram avaliados nos testes de pressão da pata e por filamentos de von Frey após 15 min de EECI (60 Hz, µs, 1 V). A EECI induziu antinocicepção na pata contralateral ao hemisfério estimulado, sem alterar a resposta da pata ipsilateral. Naloxona e rimonabanto reverteram a antinocicepção induzida pela EECI. Ioimbina e metisergida não interferiram neste efeito, demonstrando participação dos sistemas opióide e canabinóide, mas não adrenérgico e serotonérgico. Este estudo propõe um novo modelo experimental de estimulação cerebral profunda para o tratamento de dor neuropática e caracteriza o CI como um alvo promissor no estudo de novas terapêuticas para controlar dor crônica refratária. / Electrical brain stimulation is a therapeutic alternative for neuropathic pain patients, refractory to conventional treatments and the insular cortex (IC) is a promising target for their treatment. Herein the effects of electrical stimulation of the insular cortex (ICS) on pain sensitivity of rats with chronic constriction injury (CCI) of the sciatic nerve were investigated. Paw pressure test and von Frey filaments evaluated mechanical pain sensitivity at the end of a 15 min session of ICS (60 Hz, 210 µs, 1 V). ICS induced antinociception at the paw contralateral to the stimulated hemisphere, without changing ipsilateral paw threshold. Both naloxone and rimonabanto, but not yohimbine and methysergide reversed ICS-induced antinociception, demonstrating the involvement of opioid and cannabinoid systems, but not adrenergic and serotonergic. This study proposes a new experimental model of deep brain stimulation for the treatment of neuropathic pain and characterizes IC as a promising target to the study of new therapies to control refractory chronic pain.

Long-term memories turn labile with reactivation and undergo a re-stabilization process, termed reconsolidation, involving molecular changes that allow updating of an existing memory trace. Such molecular changes may involve the activation of kinases and expression of proteins related to the increase of synaptic plasticity and memory formation. A kinase reported to have a role in a variety of memory tasks is the extracellular signal-regulated kinase 1/2 (ERK1/2). The downstream activation of ERK targets other regulatory enzymes, transcription factors and cytoskeletal proteins, which allow structural changes in the neuron due to protein synthesis up-regulation. Among the proteins up-regulated by ERK activity is the activity-regulated cytoskeleton-associated protein (ARC), an immediate early gene related to synaptic plasticity. The phase-dependent roles of ERK and ARC have not been examined as part of the molecular mechanisms triggered after a learning experience. In this study I used conditioned taste aversion (CTA) as the learning paradigm and investigated the expression of pERK and ARC in brain regions critical for taste information processing such as the insular cortex and the amygdala. A differential pattern of protein expression was observed in the insular cortex (IC) two hours after taste memory acquisition: pERK activity increased in the aversively conditioned group while ARC increased in the group that received only the novel taste. The central amygdala (CeA) showed a significant increase in pERK, but not ARC activity after CTA training. Immunoblotting experiments performed after memory retrieval in the appetitive group show that pERK continues to signal aversive taste to the IC with ARC exhibiting heightened expression an hour later. An increase in ARC expression 30 minutes after reactivation of the aversive taste was seen in the basolateral amygdala and the CeA exhibited a similar increase at 60 and 90 minutes. Local infusion of ARC antisense oligonucleotides within the IC interfered with the consolidation of safe taste memories, but not with their acquisition. Trace update experiments showed that ARC influences the memory switch from aversive to safe, but not the reverse. Our results indicate that ARC plays a critical role in consolidation and updating of safe taste memories, and the ARC signaling could possibly elicit ERK activation.

abstract: Opioid use rates and related deaths continue to be a public health crisis; while there are many contributing factors to opioid use disorders, criteria for diagnosis include problems related to social functioning. Previous research indicates that laboratory rats, which are frequently used as animal models of addiction-related behaviors, are capable of prosocial behavior. The following collection of studies were performed to determine the effects of heroin on prosocial behavior in rats, as well as the role of the insula in both self-administration of heroin and prosocial behaviors. All of the experiments were conducted utilizing an established model of prosocial behavior in rats in which a performing rat releases a cagemate from a restrainer. The occurrence of and latency to free the confined rat was recorded. After baseline rescuing behavior was established, rats were allowed to self-administer heroin (0.06 mg/kg/infusion i.v.), and subsequent experimental conditions were imposed. Experimental conditions, in a series of different studies, included comparing heroin reinforcers with sucrose, chemogenetically modulating the insular cortex (both stimulatory and inhibitory processes) and administering excitotoxic lesions in the insula. There were significant differences in saving behaviors between heroin and sucrose groups demonstrating an opioid induced loss of prosocial behavior. Modulating the insula chemogenetically resulted in some restoration of these opioid related deficits, and insular lesions did not significantly impact prosocial behaviors, however, there were significant differences between rates of heroin intake in lesioned animals versus non-lesioned controls. Taken together, these results demonstrate the deleterious effects of heroin on prosocial behaviors and offer further support for the role of the insula in both addiction and social constructs. / Dissertation/Thesis / Doctoral Dissertation Psychology 2020

Numerous social and educational psychologists propose that intrinsic motivation generated by personal interests and spontaneous satisfactions is qualitatively different from extrinsic types of motivation generated by external compensations and also that intrinsic motivation is more beneficial to learning than extrinsic types of motivation. However, in the field of neuroscience, intrinsic motivation has been little studied while extrinsic types of motivation (e.g., incentive motivation) have been thoroughly studied. The purpose of the present studies was to expand the neural understanding of motivation to include intrinsic motivational processes. To do so, a series of three event-related functional magnetic resonance imaging (fMRI) studies were conducted. Study 1 and Study 2 compared the neural activities when participants decided to act for intrinsic reasons (i.e., self-determined volitional and agentic behavior) versus when they decided to act for extrinsic reasons (i.e., non-self-determined volitional and agentic behavior). Both studies showed that the anterior insular cortex, known to be related to a sense of agency, was more activated during self-determined behavior associated with intrinsic reasons for acting while the posterior parietal regions (e.g., posterior cingulate cortex, angular gyrus), known to be related to a sense of a loss of agency, were more activated during non-self-determined behavior associated with extrinsic reasons for acting. These findings confirm the existence of neural-based intrinsic motivational processes, differentiate intrinsic motivation from incentive motivation, and document the important neural activities which function for generating self-determined agentic action. Study 3 examined these same neural activities as participants engaged in interesting and uninteresting versions of two experimental tasks. Results confirmed the results of the earlier two studies, as the anterior insular cortex was more recruited when participants performed the interesting, but not the uninteresting, version of the tasks. Results also extended the findings from Studies 1 and 2 in an important way in that the ventral striatum, a well-known brain region for reward processing, was more activated when participants performed the interesting, but not the uninteresting, version of the experimental tasks. These findings suggest that intrinsic motivation is generated based on the feeling of intrinsic need satisfaction (from anterior insular cortex activations) and the feeling of reward (from ventral striatum activations). Overall, the present research established three new findings: (1) the neural bases of intrinsic motivation lies largely in increased anterior insular cortical activities; (2) when people made decisions about self-determined intrinsically-motivated behavior, they show enhanced insular cortical activities and suppressed posterior parietal cortical activities; and (3) when people engaged in actual self-determined intrinsically-motivated behavior, they show enhanced insular cortical and ventral striatal activities. In establishing these new findings, the paper introduces a new area of study for motivational neuroscience--namely, intrinsic motivation.

Although the neural mechanisms regulating vomiting are well understood, the neurobiology of nausea is not. Unlike conditioned taste avoidance (CTA), conditioned disgust (indicated by orofacial gaping reactions) is a model of nausea-induced behaviour in rats because it is selectively produced by emetic drugs and anti-emetics attenuate it. Treatments that reduce serotonin (5-HT) availability selectively interfere with conditioned gaping (Limebeer and Parker, 2000; 2003) and forebrain serotonin is critical for the production of disgust reactions (Grill and Norgren, 1978b; Limebeer et al., 2004). The insular cortex (IC) is a site of taste-illness associations and is involved in the sensation of nausea and vomiting in humans (Penfield and Faulk, 1955; Fiol et al., 1988; Catenoix et al., 2008) and other animals (Kaada, 1951; Contreras et al., 2007). Therefore, we investigated the relationship between serotonin, conditioned gaping and CTA in the insular cortex. Systemic pretreatment with the classic anti-emetic ondansetron (OND) reduced both LiCl-induced unconditioned malaise (assessed by lying on belly) and conditioned gaping reactions, without modifying CTA. These experiments demonstrate that decreases in serotonin availability interfere with conditioned gaping and unconditioned malaise as well as provide further evidence of the validity of the conditioned gaping model. Rats with bilateral NMDA lesions of the agranular IC showed attenuated CTA learning but conditioned gaping reactions were unaffected. This finding suggests that the agranular IC, a site of gustatory input, may be required for CTA learning. Partial serotonergic depletion of the IC attenuated conditioned gaping reactions, suggesting that serotonin in the IC is required to establish conditioned gaping. A double dissociation in the regulation of disgust and taste avoidance, by selective 5-HT3 receptor antagonism/agonism in the visceral (granular) IC and the gustatory (agranular) IC was observed. Infusion of OND into the visceral IC attenuated conditioned gaping but spared CTA. Additionally, administration of the 5-HT3 receptor agonist m-chlorophenylbiguanide (mCPBG) enhanced LiCl-induced conditioned gaping reactions (which was prevented by intracranial administration of OND), but spared CTA. In contrast, intracranial OND pretreatment in the gustatory IC attenuated CTA and mCPBG infusions produced CTA, but neither affected the nausea-induced behaviour of conditioned gaping. Together, these studies shed light on the neurobiology of nausea. These results suggest that 5-HT activity (at the 5-HT3 receptor) in the visceral IC may selectively produce the nausea-induced reactions of conditioned disgust, while activity in the gustatory IC may be involved in the production of CTA learning. / This research was supported by a Natural Sciences and Engineering Research Council (NSERC) operating grant (92057) to L.A. Parker and a NSERC CGS-D scholarship to K.J. Tuerke. This work was also supported by an Ontario Graduate Scholarship to K.J. Tuerke.

Considerable evidence supports anandamide (AEA) as an important mediator in the regulation of nausea and vomiting. The present study investigates the effect of inhibiting a protein reported to mediate AEA transport, FLAT (FAAH-1-like AEA transporter), on nausea and vomiting and the neural correlates of AEA regulated nausea in the visceral insular cortex (VIC). The systemic administration of the AEA transport inhibitor ARN272 was evaluated in LiCl-induced conditioned gaping in rats, and vomiting in shrews. The effect of intra-cranial administration of ARN272 into the VIC was also investigated using LiCl-induced conditioned gaping in rats. Systemic administration of ARN272 dose-dependently suppressed LiCl-induced conditioned gaping in rats, and was reversed by CB1 receptor antagonism with SR141716. Systemic administration of ARN272 also attenuated vomiting in shrews. Delivery of ARN272 into the VIC produced no effect on LiCl-induced conditioned gaping in rats. These results suggest that preventing the cellular reuptake of AEA through transport inhibition tonically activates CB1 receptors to regulate toxin-induced nausea, but that this is not AEA regulated within the VIC. / This research was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC-92057) to LAP.

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