Leili Mortazavi

All Publications

• Insight into differing decision-making strategies that underlie cognitively effort-based decision making using computational modeling in rats. Psychopharmacology Hales, C. A., Silveira, M. M., Calderhead, L., Mortazavi, L., Hathaway, B. A., Winstanley, C. A. 2024

  Abstract

  The rat cognitive effort task (rCET), a rodent model of cognitive rather than physical effort, requires animals to choose between an easy or hard visuospatial discrimination, with a correct hard choice more highly rewarded. Like in humans, there is stable individual variation in choice behavior. In previous reports, animals were divided into two groups-workers and slackers-based on their mean preference for the harder option. Although these groups differed in their response to pharmacological challenges, the rationale for using this criterion for grouping was not robust.We collated experimental data from multiple cohorts of male and female rats performing the rCET and used a model-based framework combining drift diffusion modeling with cluster analysis to identify the decision-making processes underlying variation in choice behavior.We verified that workers and slackers are statistically different groups but also found distinct intra-group profiles. These subgroups exhibited dissociable performance during the attentional phase, linked to distinct decision-making profiles during choice. Reanalysis of previous pharmacology data using this model-based framework showed that serotonergic drug effects were explained by changes in decision boundaries and non-decision times, while scopolamine's effects were driven by changes in decision starting points and rates of evidence accumulation.Modeling revealed the decision-making processes that are associated with cognitive effort costs, and how these differ across individuals. Reanalysis of drug data provided insight into the mechanisms through which different neurotransmitter systems impact cognitively effortful attention and decision-making processes, with relevance to multiple psychiatric disorders.

  View details for DOI 10.1007/s00213-023-06521-5

  View details for PubMedID 38172238

  View details for PubMedCentralID 5325181

• Noradrenergic regulation of cue-guided decision making and impulsivity is doubly dissociable across frontal brain regions. Psychopharmacology Chernoff, C. S., Hynes, T. J., Schumacher, J. D., Ramaiah, S., Avramidis, D. K., Mortazavi, L., Floresco, S. B., Winstanley, C. A. 2023

  Abstract

  Win-paired stimuli can promote risk taking in experimental gambling paradigms in both rats and humans. We previously demonstrated that atomoxetine, a noradrenaline reuptake inhibitor, and guanfacine, a selective α2A adrenergic receptor agonist, reduced risk taking on the cued rat gambling task (crGT), a rodent assay of risky choice in which wins are accompanied by salient cues. Both compounds also decreased impulsive premature responding.The key neural loci mediating these effects were unknown. The lateral orbitofrontal cortex (lOFC) and the medial prefrontal cortex (mPFC), which are highly implicated in risk assessment, action selection, and impulse control, receive dense noradrenergic innervation. We therefore infused atomoxetine and guanfacine directly into either the lOFC or prelimbic (PrL) mPFC prior to task performance.When infused into the lOFC, atomoxetine improved decision making score and adaptive lose-shift behaviour in males, but not in females, without altering motor impulsivity. Conversely, intra-PrL atomoxetine improved impulse control in risk preferring animals of both sexes, but did not alter decision making. Guanfacine administered into the PrL, but not lOFC, also altered motor impulsivity in all subjects, though in the opposite direction to atomoxetine.These data highlight a double dissociation between the behavioural effects of noradrenergic signaling across frontal regions with respect to risky choice and impulsive action. Given that the influence of noradrenergic manipulations on motor impulsivity could depend on baseline risk preference, these data also suggest that the noradrenaline system may function differently in subjects that are susceptible to the risk-promoting lure of win-associated cues.

  View details for DOI 10.1007/s00213-023-06508-2

  View details for PubMedID 38001266

  View details for PubMedCentralID 4529674

• Blunted Neurobehavioral Loss Anticipation Predicts Relapse to Stimulant Drug Use Biological Psychiatry Mortazavi*, L., MacNiven*, K. H., Knutson, B. 2023

  Abstract

  Stimulant Use Disorder (SUD) patients suffer from high rates of relapse. While neurobehavioral mechanisms involved in initiating drug use have been extensively studied, less research has focused on relapse.To assess motivational processes involved in relapse and diagnosis, we acquired Functional Magnetic Resonance Imaging (FMRI) responses to nondrug (monetary) gains and losses in detoxified SUD patients (n=68) and community controls (n=42). In a prospective multi-modal design, we combined imaging of brain function, brain structure, and behavior to longitudinally track subsequent risk for relapse. At the six-month follow-up assessment, 27 patients remained abstinent, but 33 had relapsed.Patients with blunted Anterior Insula (AIns) activity during loss anticipation were more likely to relapse, an association which remained robust after controlling for potential confounds (i.e., craving, negative mood, years of use, age, and gender). Lower AIns activity during loss anticipation was associated with lower self-reported negative arousal to loss cues and slower behavioral responses to avoid losses, which independently also predicted relapses. AIns activity during loss anticipation was further associated with structural coherence of a tract connecting the AIns and Nucleus Accumbens (NAcc), as was functional connectivity between the AIns and NAcc during loss processing. These neurobehavioral responses did not, however, differ between patients and controls.Together, neurobehavioral markers predicted relapse above and beyond conventional self-report measures with a cross-validated accuracy of 72.7%. These findings offer convergent multi-modal evidence implicating blunted avoidance motivation in relapse to stimulant use, and so may guide interventions targeting those most vulnerable to relapse.

  View details for DOI 10.1016/j.biopsych.2023.07.020

• Cardiogenic control of affective behavioural state. Nature Hsueh, B., Chen, R., Jo, Y., Tang, D., Raffiee, M., Kim, Y. S., Inoue, M., Randles, S., Ramakrishnan, C., Patel, S., Kim, D. K., Liu, T. X., Kim, S. H., Tan, L., Mortazavi, L., Cordero, A., Shi, J., Zhao, M., Ho, T. T., Crow, A., Yoo, A. W., Raja, C., Evans, K., Bernstein, D., Zeineh, M., Goubran, M., Deisseroth, K. 2023

  Abstract

  Emotional states influence bodily physiology, as exemplified in the top-down process by which anxiety causes faster beating of the heart1-3. However, whether an increased heart rate might itself induce anxiety or fear responses is unclear3-8. Physiological theories of emotion, proposed over a century ago, have considered that in general, there could be an important and even dominant flow of information from the body to the brain9. Here, to formally test this idea, we developed a noninvasive optogenetic pacemaker for precise, cell-type-specific control of cardiac rhythms of up to 900beats per minute in freely moving mice, enabled by a wearable micro-LED harness and the systemic viral delivery of a potent pump-like channelrhodopsin. We found that optically evoked tachycardia potently enhanced anxiety-like behaviour, but crucially only in risky contexts, indicating that both central (brain) and peripheral (body) processes may be involved in the development of emotional states. To identify potential mechanisms, we used whole-brain activity screening and electrophysiology to find brain regions that wereactivated by imposed cardiac rhythms. We identified the posterior insular cortex as a potential mediator of bottom-up cardiac interoceptive processing, and found that optogenetic inhibition of this brain region attenuated the anxiety-like behaviour that was induced by optical cardiac pacing. Together, these findings reveal that cells of both the body and the brain must be considered together to understand the origins of emotional or affective states. More broadly, our results define a generalizable approach for noninvasive, temporally precise functional investigations of joint organism-wide interactions among targeted cells during behaviour.

  View details for DOI 10.1038/s41586-023-05748-8

  View details for PubMedID 36859543

• D2/3 Agonist during Learning Potentiates Cued Risky Choice. The Journal of neuroscience : the official journal of the Society for Neuroscience Mortazavi, L., Hynes, T. J., Chernoff, C. S., Ramaiah, S., Brodie, H. G., Russell, B., Hathaway, B. A., Kaur, S., Winstanley, C. A. 2023; 43 (6): 979-992

  Abstract

  Impulse control and/or gambling disorders can be triggered by dopamine agonist therapies used to treat Parkinson's disease, but the cognitive and neurobiological mechanisms underlying these adverse effects are unknown. Recent data show that adding win-paired sound and light cues to the rat gambling task (rGT) potentiates risky decision-making and impulsivity via the dopamine system, and that changing dopaminergic tone has a greater influence on behavior while subjects are learning task contingencies. Dopamine agonist therapy may therefore be potentiating risk-taking by amplifying the behavioral impact of gambling-related cues on novel behavior. Here, we show that ropinirole treatment in male rats transiently increased motor impulsivity but robustly and progressively increased choice of the high-risk/high-reward options when administered during acquisition of the cued but not uncued rGT. Early in training, ropinirole increased win-stay behavior after large unlikely wins on the cued rGT, indicative of enhanced model-free learning, which mediated the drug's effect on later risk preference. Ex vivo cFos imaging showed that both chronic ropinirole and the addition of win-paired cues suppressed the activity of dopaminergic midbrain neurons. The ratio of midbrain:prefrontal cFos+ neurons was lower in animals with suboptimal choice patterns and tended to predict risk preference across all rats. Network analyses further suggested that ropinirole induced decoupling of the dopaminergic cells of the VTA and nucleus accumbens but only when win-paired cues were present. Frontostriatal activity uninformed by the endogenous dopaminergic teaching signal therefore appeared to perpetuate risky choice, and ropinirole exaggerated this disconnect in synergy with reward-paired cues.SIGNIFICANCE STATEMENT D2/3 receptor agonists, used to treat Parkinson's disease, can cause gambling disorder through an unknown mechanism. Ropinirole increased risky decision-making in rats, but only when wins were paired with casino-inspired sounds and lights. This was mediated by increased win-stay behavior after large unlikely wins early in learning, indicating enhanced model-free learning. cFos imaging showed that ropinirole suppressed activity of midbrain dopamine neurons, an effect that was mimicked by the addition of win-paired cues. The degree of risky choice rats exhibited was uniquely predicted by the ratio of midbrain dopamine:PFC activity. Depriving the PFC of the endogenous dopaminergic teaching signal may therefore drive risky decision-making on-task, and ropinirole acts synergistically with win-paired cues to amplify this.

  View details for DOI 10.1523/JNEUROSCI.1459-22.2022

  View details for PubMedID 36623876

  View details for PubMedCentralID PMC9908318

• Multi‐band FMRI compromises detection of mesolimbic reward responses NeuroImage Srirangarajan*, T., Mortazavi*, L., Bortolini, T., Moll, J., Knutson, B. 2021; 244

  View details for DOI 10.1016/j.neuroimage.2021.118617

• Investigating serotonergic contributions to cognitive effort allocation, attention, and impulsive action in female rats JOURNAL OF PSYCHOPHARMACOLOGY Silveira, M. M., Wittekindt, S. N., Mortazavi, L., Hathaway, B. A., Winstanley, C. A. 2020; 34 (4): 452-466

  Abstract

  Individuals must frequently evaluate whether it is worth allocating cognitive effort for desired outcomes. Motivational deficits are a common feature of psychiatric illness such as major depression. Selective serotonin reuptake inhibitors are commonly used to treat this disorder, yet some data suggest these compounds are ineffective at treating amotivation, and may even exacerbate it.Here we used the rodent Cognitive Effort Task (rCET) to assess serotonergic (5-hydroxytryptamine, 5-HT) contributions to decision-making with cognitive effort costs.The rCET is a modified version of the 5-choice serial reaction time task, a well-validated test of visuospatial attention and impulse control. At the start of each rCET trial, rats chose one of two levers, which set the difficulty of an attentional challenge, namely the localization of a visual stimulus illuminated for 0.2 or 1 s on hard versus easy trials. Successful completion of hard trials was rewarded with double the sugar pellets. Twenty-four female Long-Evans rats were trained on the rCET and systemically administered the 5-HT1A agonist 8-OH-DPAT, the 5-HT2A antagonist M100907, the 5-HT2C agonist Ro-60-0175, as well as the 5-HT2C antagonist SB 242, 084.5-HT2A antagonism dose-dependently reduced premature responding, while 5-HT2C antagonism had the opposite effect. 8-OH-DPAT impaired accuracy of target detection at higher doses, while Ro-60-0175 dose-dependently improved accuracy on difficult trials. However, none of the drugs affected the rats' choice of the harder option.When considered with existing work evaluating decision-making with physical effort costs, it appears that serotonergic signalling plays a minor role in guiding effort allocation.

  View details for DOI 10.1177/0269881119896043

  View details for Web of Science ID 000506981100001

  View details for PubMedID 31913079

• Stigma, the Media, and Pre-exposure Prophylaxis for HIV Prevention: Observations for Enhancing Knowledge Translation and Resisting Stigma in the Canadian Context AIDS AND BEHAVIOR Card, K. G., Hawkins, B. W., Mortazavi, L., Gregory, A., Ng, K., Lachowsky, N. J. 2019; 23 (7): 1877-1887

  Abstract

  Pre-Exposure Prophylaxis (PrEP) is an effective, though sometimes stigmatized, strategy for HIV prevention. With the goal of examining how PrEP stigma can be addressed, this study examined the media's handling of stigma related to PrEP by searching the Canadian Newsstream and Daily Xtra news databases for key terms related to PrEP. Overall, 101 media articles were thematically coded in triplicate; 36.3% of which included mentions of PrEP stigma. LGBT media sources were more likely than mainstream sources to have included content coded as relating to PrEP stigma (p = 0.02). In these articles, uncertainty regarding PrEP, and neo-liberal attitudes towards sexual responsibility were major factors associated with media discussion of PrEP stigma. We discuss the role that heuristics play in shaping lay readers perceptions and interpretation of PrEP media coverage and discuss methods for overcoming stigma using evidence-based communication strategies.

  View details for DOI 10.1007/s10461-018-2332-x

  View details for Web of Science ID 000471709800020

  View details for PubMedID 30390190