Seminars

Although stress can be considered as an ongoing process that helps an organism to cope with present and future challenges, when it is too intense or uncontrollable, it can lead to adverse consequences for physical and mental health. Social stress specifically, is a highly prevalent traumatic experience, present in multiple contexts, such as war, bullying and interpersonal violence, and it has been linked with increased risk for major depression and anxiety disorders. Nevertheless, not all individuals exposed to strong stressful events develop psychopathology, with the mechanisms of resilience and vulnerability being still under investigation. During this talk, I will identify key gaps in our knowledge about stress vulnerability and I will present our recent data from our contextual fear learning protocol based on social defeat stress in mice.

In this talk I will present our recent behavioural and neuroscience research on how the brain motivates itself to form particular beliefs and why it does so. I will propose that the utility of a belief is derived from the potential outcomes associated with holding it. Outcomes can be internal (e.g., positive/negative feelings) or external (e.g., material gain/loss), and only some are dependent on belief accuracy. We show that belief change occurs when the potential outcomes of holding it alters, for example when moving from a safe environment to a threatening environment. Our findings yield predictions about how belief formation alters as a function of mental health. We test these predictions using a linguistic analysis of participants’ web searches ‘in the wild’ to quantify the affective properties of information they consume and relate those to reported psychiatric symptoms. Finally, I will present a study in which we used our framework to alter the incentive structure of social media platforms to reduce the spread of misinformation and improve belief accuracy.

Nearly every aspect of life involves decisions between options that differ in both their expected rewards and the potential costs (such as delay to reward delivery or risk of harm) that accompany those rewards. The ability to choose adaptively when faced with such decisions is critical for well-being and overall quality of life. In neuropsychiatric conditions such as substance use disorders, however, decision making is often compromised, which can prolong and exacerbate their severity and co-morbidities. In this seminar, Dr. Setlow will discuss research in rodent models investigating behavioral and biological mechanisms of cost-benefit decision making. In particular, he will focus on factors (including sex) that contribute to differences in cost-benefit decision making across the population, how variability in decision making is related to substance use, and how substance use can produce long-lasting changes in decision preference.

Dysregulation of emotional processing and its integration with cognitive functions are central features of many mental/emotional disorders associated both with externalizing problems (aggressive, antisocial behaviors) and internalizing problems (anxiety, depression). As Dr. Joseph LeDoux, our invited speaker of this program, wrote in his famous book “Synaptic self: How Our Brains Become Who We Are”—the brain’s synapses—are the channels through which we think, act, imagine, feel, and remember. Synapses encode the essence of personality, enabling each of us to function as a distinctive, integrated individual from moment to moment. Thus, exploring the functioning of synapses leads to the understanding of the mechanism of (patho)physiological function of our brain. In this context, we have investigated the pathophysiology of psychiatric disorders, with particular emphasis on the synaptic function of model mice of various psychiatric disorders such as schizophrenia, autism, depression, and PTSD. Our current interest is how synaptic inputs are integrated to generate the action potential. Because the spatiotemporal organization of neuronal firing is crucial for information processing, but how thousands of inputs to the dendritic spines drive the firing remains a central question in neuroscience. We identified a distinct pattern of synaptic integration in the disease-related models, in which extra-large (XL) spines generate NMDA spikes within these spines, which was sufficient to drive neuronal firing. We experimentally and theoretically observed that XL spines negatively correlated with working memory. Our work offers a whole new concept for dendritic computation and network dynamics, and the understanding of psychiatric research will be greatly reconsidered. The second half of my talk is the development of a novel synaptic tool. Because, no matter how beautifully we can illuminate the spine morphology and how accurately we can quantify the synaptic integration, the links between synapse and brain function remain correlational. In order to challenge the causal relationship between synapse and brain function, we established AS-PaRac1, which is unique not only because it can specifically label and manipulate the recently potentiated dendritic spine (Hayashi-Takagi et al, 2015, Nature). With use of AS-PaRac1, we developed an activity-dependent simultaneous labeling of the presynaptic bouton and the potentiated spines to establish “functional connectomics” in a synaptic resolution. When we apply this new imaging method for PTSD model mice, we identified a completely new functional neural circuit of brain region A→B→C with a very strong S/N in the PTSD model mice. This novel tool of “functional connectomics” and its photo-manipulation could open up new areas of emotional/psychiatric research, and by extension, shed light on the neural networks that determine who we are.

Monetary incentive delay task (MID) is a well-validated human functional MRI task widely used in probing affective-motivational processes in psychiatric disorders. We are developing a mouse version of the MID task in order to facilitate translations of findings from the wealth of human imaging studies. This talk presents our task design and behavioural data from the ongoing work.

Uncertainty regarding which psychological mechanisms are fundamental in mediating SSRI treatment outcomes and wide-ranging variability in their efficacy has raised more questions than it has solved. Since subjective mood states are an abstract scientific construct, only available through self-report in humans, and likely involving input from multiple top-down and bottom-up signals, it has been difficult to model at what level SSRIs interact with this process. Converging translational evidence indicates a role for serotonin in modulating context-dependent parameters of action selection, affect, and social cognition; and concurrently supporting learning mechanisms, which promote adaptability and behavioural flexibility. We examine the theoretical basis, ecological validity, and interaction of these constructs and how they may or may not exert a clinical benefit. Specifically, we bridge crucial gaps between disparate lines of research, particularly findings from animal models and human clinical trials, which often seem to present irreconcilable differences. In determining how SSRIs exert their effects, our approach examines the endogenous functions of 5-HT neurons, how 5-HT manipulations affect behaviour in different contexts, and how their therapeutic effects may be exerted in humans – which may illuminate issues of translational models, hierarchical mechanisms, idiographic variables, and social cognition.

My research focuses, broadly speaking, on how emotions impact decision making. Specifically, I am interested in affective biases, a phenomenon known to be important in depression. Using a rodent decision-making task, combined with computational modelling I have investigated how different antidepressant and pro-depressant manipulations that are known to alter mood in humans alter judgement bias, and provided insight into the decision processes that underlie these behaviours. I will also highlight how the combination of behaviour and modelling can provide a truly translation approach, enabling comparison and interpretation of the same cognitive processes between animal and human research.

A long-term treatment with antidepressants reduces the risk to develop AD and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently studied for their neuroprotective properties in AD. An impairment of neurotrophic factors signaling seems to be a common pathophysiological event in depression and AD. In particular a deficit of transforming growth factor-β1 (TGF-β1) and increased oxidative stress have been found both in depression and AD. In the present work the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype in a non-transgenic mouse model of AD (i.c.v. Aβ1-42 injection) by rescue of TGF-β1 signaling. The same drugs were also tested for their ability to modulate the expression of pro-oxidant genes as well as of genes related to the antioxidant machinery.