treatment targets
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Targeting Maladaptive Emotional Memories to Treat Mental Health Disorders: Insights from Rodent Models
Maladaptive emotional memories contribute to the persistence of numerous mental health disorders, including post-traumatic stress disorder (PTSD), drug addiction and obsessive-compulsive disorder (OCD). Using rodent behavioural models of the psychological processes relevant to these disorders, it is possible to identify potential treatment targets for the development of new therapies, including those based upon disrupting the reconsolidation of maladaptive emotional memories. Using examples from rodent models relevant to multiple mental health disorders, this talk will consider some of the opportunities and challenges that this approach provides.
Hallucinating mice, dopamine and immunity; towards mechanistic treatment targets for psychosis
Hallucinations are a core symptom of psychotic disorders and have traditionally been difficult to study biologically. We developed a new behavioral computational approach to measure hallucinations-like perception in humans and mice alike. Using targeted neural circuit manipulations, we identified a causal role for striatal dopamine in mediating hallucination-like perception. Building on this, we currently investigate the neural and immunological upstream regulators of these dopaminergic circuits with the goal to identify new biological treatment targets for psychosis
Linking GWAS to pharmacological treatments for psychiatric disorders
Genome-wide association studies (GWAS) have identified multiple disease-associated genetic variations across different psychiatric disorders raising the question of how these genetic variants relate to the corresponding pharmacological treatments. In this talk, I will outline our work investigating whether functional information from a range of open bioinformatics datasets such as protein interaction network (PPI), brain eQTL, and gene expression pattern across the brain can uncover the relationship between GWAS-identified genetic variation and the genes targeted by current drugs for psychiatric disorders. Focusing on four psychiatric disorders---ADHD, bipolar disorder, schizophrenia, and major depressive disorder---we assess relationships between the gene targets of drug treatments and GWAS hits and show that while incorporating information derived from functional bioinformatics data, such as the PPI network and spatial gene expression, can reveal links for bipolar disorder, the overall correspondence between treatment targets and GWAS-implicated genes in psychiatric disorders rarely exceeds null expectations. This relatively low degree of correspondence across modalities suggests that the genetic mechanisms driving the risk for psychiatric disorders may be distinct from the pathophysiological mechanisms used for targeting symptom manifestations through pharmacological treatments and that novel approaches for understanding and treating psychiatric disorders may be required.
Clinical neuroscience and the heart-brain axis (BACN Mid-career Prize Lecture 2021)
Cognitive and emotional processes are shaped by the dynamic integration of brain and body. A major channel of interoceptive information comes from the heart, where phasic signals are conveyed to the brain to indicate how fast and strong the heart is beating. This talk will discuss how interoceptive processes operate across conscious and unconscious levels to influence emotion and memory. The interoceptive channel is disrupted in distinct ways in individuals with autism and anxiety. Selective interoceptive disturbance is related to symptomatology including dissociation and the transdiagnostic expression of anxiety. Interoceptive training can reduce anxiety, with enhanced interoceptive precision associated with greater insula connectivity following targeted interoceptive feedback. The discrete cardiac effects on emotion and cognition have broad relevance to clinical neuroscience, with implications for peripheral treatment targets and behavioural interventions.
Dissecting the neural circuits underlying prefrontal regulation of reward and threat responsivity in a primate
Gaining insight into the overlapping neural circuits that regulate positive and negative emotion is an important step towards understanding the heterogeneity in the aetiology of anxiety and depression and developing new treatment targets. Determining the core contributions of the functionally heterogenous prefrontal cortex to these circuits is especially illuminating given its marked dysregulation in affective disorders. This presentation will review a series of studies in a new world monkey, the common marmoset, employing pathway-specific chemogenetics, neuroimaging, neuropharmacology and behavioural and cardiovascular analysis to dissect out prefrontal involvement in the regulation of both positive and negative emotion. Highlights will include the profound shift of sensitivity away from reward and towards threat induced by localised activations within distinct regions of vmPFC, namely areas 25 and 14 as well as the opposing contributions of this region, compared to orbitofrontal and dorsolateral prefrontal cortex, in the overall responsivity to threat. Ongoing follow-up studies are identifying the distinct downstream pathways that mediate some of these effects as well as their differential sensitivity to rapidly acting anti-depressants.
Hallucinating mice and dopamine – towards mechanistic treatment targets for psychosis
Psychotic disorders are devastating conditions without any mechanistic treatment available. One major hurdle in the biological study of psychosis is the challenge of rigorously probing this condition in pre-clinical animal models. The goal of our research is to develop and exploit innovative frameworks for the study of psychosis in mice. In our present work, where we developed a cross-species computational psychiatry approach to probe hallucination-like perception. This enabled us to directly relate human and mouse behavior, and to demonstrate and dissect the causal role of striatal dopamine in hallucination-like perception. Our results suggest a neural circuit mechanism for the long-standing dopamine hypothesis of psychosis, and provide a new translational framework for the biological study of psychosis. This opens up exciting possibilities for advancing the biological understanding of psychosis and to identify mechanistic treatment targets.
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