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Brain tumour patients diagnosed with grade IV glioblastoma often show dismal prognosis despite the standard of care chemo- and radiation therapies. The Cancer Genome Atlas effort demonstrated that transcriptomic profiles distinguish three glioma-intrinsic subtypes, each with unique genetic aberrations and prognosis. While significant effort has been made to characterize glioblastomas based on their molecular content, functional or biological validation remains lacking. STAT3 activation represents the final molecular switch that precedes transition into the highly aggressive, recurrent mesenchymal subtype. Furthermore, there are several STAT3 small molecule inhibitors in clinical trials for solid malignancies. Our work provides an insight into STAT3 stratification in GBM using our unique STAT3 functionally-tuned gene signature. We show that this gene signature stratifies GBM patients, and is not confounded by current clinical and molecular classification. To provide preclinical evidence that stratification leads to more effective STAT3-targeted treatment outcomes, we applied this signature to our collection of tumour cells with matched primary and xenograft tumour molecular information. We identified STAT3-sensitive and -resistant tumours, and validated STAT3 dependence in vitro using pharmacologically-treated and genetically manipulated, matched GBM cells. We validated responsiveness to STAT3 inhibition through in vitro and animal experimentation. Importantly, by analysing up-regulated genes in the STAT3-resistant profile, corroborated by our kinome screen data, dual inhibition of IGF-1R and STAT3 presents a viable strategy to sensitize this cohort. Our study highlights the importance of patient stratification for the utility of STAT3 inhibitors in GBM. This represents a new paradigm challenging the current use of morphological methods such as histology to diagnose and subsequently treat patients. Doctor of Philosophy

Significance Impulsivity is a tendency to act with little or no forethought or consideration of the consequences and is a major component of various psychiatric disorders. However, little is known about the brain circuits that regulate reward-related impulsivity. Our genetic manipulations reveal that dopamine D2 receptors in the central nucleus of the amygdala have a crucial role in reward-related impulsive behavior. By using optogenetics to control the neurons that possess these receptors, we have identified elements of a neural circuit that contributes to regulating impulsivity. This information should enable approaches to managing impulsivity associated with neuropsychiatric disorders such as attention-deficit/hyperactivity disorder, bipolar disorder, and addiction-related disorders., Impulsivity is closely associated with addictive disorders, and changes in the brain dopamine system have been proposed to affect impulse control in reward-related behaviors. However, the central neural pathways through which the dopamine system controls impulsive behavior are still unclear. We found that the absence of the D2 dopamine receptor (D2R) increased impulsive behavior in mice, whereas restoration of D2R expression specifically in the central amygdala (CeA) of D2R knockout mice (Drd2−/−) normalized their enhanced impulsivity. Inhibitory synaptic output from D2R-expressing neurons in the CeA underlies modulation of impulsive behavior because optogenetic activation of D2R-positive inhibitory neurons that project from the CeA to the bed nucleus of the stria terminalis (BNST) attenuate such behavior. Our identification of the key contribution of D2R-expressing neurons in the CeA → BNST circuit to the control of impulsive behavior reveals a pathway that could serve as a target for approaches to the management of neuropsychiatric disorders associated with impulsivity.

Parkinson disease (PD) is a common neurodegenerative disorder which manifests as bradykinesia, movement rigidity and tremors in affected individuals. Our understanding of the genetic basis of PD has been steadily increasing since the initial report of a-synuclein mutations two decades ago. Mutations implicated in familial PD fully account for monogenic inheritance and point to potential functional mechanisms underlying PD. However, most sporadic PD cannot be accounted for by known familial PD genes, with the late-onset nature of PD making further linkage studies challenging. Genome-wide association and whole exome sequencing studies have implicated a growing list of mutations and genes in PD, which are expected to provide new insights into potential pathways involved in PD pathogenicity. NRF (Natl Research Foundation, S’pore) NMRC (Natl Medical Research Council, S’pore) Accepted version