Outcomes of a ketogenic dietary intervention on the gut microbiome-microglial brain axis and schizophrenia-like behaviour in mice exposed to a double-hit immune challenge

Alterations in microorganisms present in the gut are associated with various mental health disorders. It is possible that this is due to changes in microglia, the immune cells that fight infections in the brain. Microglia can consume neurons, which are the cells that talk to one another in the brain. It is possible that changes in gut microorganisms make these immune cells to eat up brain cells excessively and uncontrollably, which causes mental illness. To understand this, we will infect laboratory mice with infectious agents during pregnancy and expose them to stress during adolescence. After testing the mice for behavioral alterations, we will use imaging techniques to assess how gut microorganisms can influence microglia. We will then determine if ketogenic treatments with a clinically approved high fat and low carbohydrate diet, showing benefits on the gut and brain, can reverse harmful effects on these immune cells in the brain. Together these investigations will provide novel insights into how the gut microorganisms can affect the brain immune cells and alter behavior, resulting in mental illnesses. This research may provide new targets for the therapeutic management of mental health conditions that include schizophrenia.

The impact of the COVID-19 pandemic on access to adequate care for serious mental disorders in British Columbia

The Covid-19 pandemic has created new challenges for the treatment of serious mental disorders such as schizophrenia and bipolar disorder. Patient avoidance of health services and the rapid switch from in-person to virtual delivery of services may have created barriers to accessing specialist services. The aim of the current study is to evaluate whether access to adequate psychiatric care for serious mental disorders changed between 2015 and 2022, and particularly after the onset of the pandemic. In addition, we will examine whether any disparities in access by demographic (age, sex, neighbourhood income quintile, geographic location) clinical (diagnosis and presence of substance use disorder) and health system factors have increased or decreased over this time period. Findings from this study will have important implications for the provision of mental health services for serious mental disorders in British Columbia.

Neuropsychological functioning in treatment resistant schizophrenia

Schizophrenia is a severe and disabling psychiatric illness involving primary symptoms of psychosis (hallucinations, delusions, disordered thinking and behavior). Unfortunately, as many as 30% of patients respond poorly to standard antipsychotic medications and are considered to have treatment resistant schizophrenia (TRS). Neuropsychological impairment is an important clinical feature of schizophrenia, as cognitive deficits predict poor treatment response, daily functioning, and disability. However, very little is known about cognitive functioning in the clinically complex subset of patients with TRS. The aims of this project are therefore to investigate the severity, pattern, and variation in cognitive functioning among individuals with TRS, and to determine whether cognitive difficulties predict treatment response and functioning. This will be achieved by analyzing clinical and neuropsychological data that has been collected on TRS patients who have been treated within the BC Psychosis Program since 2012. Findings using this unique dataset will have a direct impact on shaping assessment and treatment strategies, improving prognosis and ability to predict functioning, and improving clinical decision-making and planning.

Counteracting the “Jumping to Conclusion” bias in schizophrenia with a combination of neuromodulation and metacognitive training

In Canada around 1% of the population is diagnosed with schizophrenia, roughly corresponding to 40 000 people in British Columbia. One typical feature of Schizophrenia is making hasty decisions without weighing evidence; this is known as the “Jumping to Conclusion” (JTC) bias. The bias can be understood as a tendency of quickly committing a final decision based only on the first available evidence. One of the most successful forms of treating the bias in schizophrenia is Metacognitive Training. During this therapy, patients try to question the logic of their own decisions. The goal of this project is to enhance the beneficial effect of this treatment and establish methods for objective monitoring of successful therapy. The previous research of Prof. Woodward lab showed that is possible to track neural connections of brain regions involved in the JTC bias. Here, we plan to identify these networks in each of our patients. Next, using a new technology for safe electric modulation of neural connectivity, we will strengthen connections in the network. Through multiple testing sessions we will monitor changes in the brains of patients and thus the progress of therapy. This project can help us improve the treatment of schizophrenia.

Re-establishing cognitive function in models of mental illness by boosting neural activity in the prefrontal cortex

The frontal cortex (FC) of the brain plays a critical role in higher cognitive functions including attention, working memory, and planning future goal-directed actions. Cognitive deficits arising from deceased neural activity within the FC (hypofrontality) are features of many forms of mental illness, including schizophrenia, attention-deficit hyperactivity disorder, dementia and addiction. Neurochemical, physiological and pharmacological research implicates reductions in the function of key neurotransmitter systems: catecholamines, glutamate and GABA.

Dr. Axierio-Cilies and team have developed a novel compound that alters key subtypes of glutamate receptors. Using optogenetic (light) stimulation of dopaminergic and glutamatergic pathways, this research will assess the usefulness of this novel compound for the treatment of clinical conditions that are attributed to a reduction of neurotransmitter function within the FC as part of a multifaceted drug development program.

Flicking the switch: cross-species translation of rapid context-based switching between tasks

Successful interaction with a constantly changing world requires behavioral adaptation. Unraveling the mechanisms underlying flexible control is essential to stimulate advances in the treatments of disorders where deficits in these functions are a core symptom, such as schizophrenia and Parkinson’s disease. For humans, this type of behavior is commonly assessed using the task-switching paradigm, which uses cues to instruct on a trial-by-trial basis which of two tasks to perform. Comparing behavior when the task is repeated to when it is switched allows measuring rapid behavioral adaptations. Existing tests of behavioral flexibility in rodents (e.g. set shifting tests) often assess the ability to learn that a rule changed, yet real-life situations often entail contextual cues explicitly indicating that changes in behavior are required. In addition, current shifting paradigms do not allow assessment of trial-by-trial switching between tasks, as human assays do. An important step in preclinical animal research is to develop tests of behavioral flexibility that directly translate between species.

Previous research I have conducted used a combination of brain imaging, stimulation, and pharmacology to assess the neural basis of adaptive flexible behavior in humans. My work revealed important roles for the striatum, prefrontal cortex, and the neurotransmitter dopamine in task switching. However, these approaches lack the spatial and pharmacological specificity required to answer questions about the causal and specific role of these regions and transmitter systems. Thus, to complement my work with human subjects, I used a novel translational version of a human task-switching paradigm that is suitable for testing in rodents.

In my post-doctoral work, I aim to fully explore the contribution of specific brain circuits to these processes (focusing on the striatum and prefrontal cortex). I will also investigate how the transmission of the neurotransmitters dopamine and gamma-Aminobutyric acid (GABA) mediate successful task-switching. This is important because dysfunction in these transmitter systems underlie numerous psychiatric disorders associated with impairments in these functions, such as schizophrenia and Parkinson’s disease. These studies will be complemented by those using temporally-discrete optogenetic silencing. This will allow the trial-by-trial manipulation of brain circuits and clarify the precise moments when activity in these circuits are necessary for facilitating flexible behavior.

Ion channels: Molecular determinants of health and disease in the head and heart

Though vastly different, both the brain and the heart rely on large complicated proteins called ion channels in order to function properly. These proteins facilitate the controlled flow of ions in and out of cells by forming pores that stud cellular membranes. Specialized brain cells called neurons utilize ion channels and the electrical signals they generate to communicate with one another. A repertoire of different ion channels also shapes the birth, growth and development of neurons. During brain injury, ion channel activity can render populations of neurons vulnerable to damage. However, following injury, ion channels can also sensitize surviving neurons and modify their structure and function in ways that allow them to respond, adapt and promote repair. Similarly, the electrical activity underlying the coordinated beating of heart muscle cells is generated by the concerted actions of a cohort of ion channels. It follows that mutations in the proteins that form ion channels can manifest in a spectrum of clinical neurological and heart conditions.

In a series of coordinated projects, Dr. Swayne is working to shed light on how ion channels impact on brain and heart health. Dr. Swayne has been examining the cell biology of pannexin ion channels and their role in neuronal development and injury-triggered plasticity. In collaboration with a group at the University of Ottawa, Dr. Swayne’s team is also studying how probenecid, a drug that stops the function of pannexins, impacts stroke recovery. In parallel, to identify novel ion channel regulators of developmental and injury-triggered neuronal plasticity, her lab is combining basic biochemistry with cutting edge expertise at the UVIC Genome BC Proteomics Centre. Finally, in partnership with the UBC Community Genetics Research Program, Dr. Swayne is also investigating the cell biological underpinnings of clinically relevant cardiac ion channel mutations affecting certain BC First Nations communities.

Overall, Dr. Swayne’s research will bridge critical knowledge gaps in the understanding of ion channel function and dysfunction in the brain and heart.

Screening and development of molecules targeting presynaptic SNARE protein-protein interactions as novel pharmacological strategy in schizophrenia and other mental illnesses

Screening and development of molecules targeting presynaptic SNARE protein-protein interactions as novel pharmacological strategy in schizophrenia and other mental illnesses Schizophrenia is one of the major disabling mental disorders with a worldwide prevalence of about one percent. Although the cause  of schizophrenia remains unclear, converging data indicate that dysfunctions altering neurotransmitter levels in the synaptic cleft, the tiny space between nerve cells in which nerve impulses are conducted, might be at the core of this disorder. In presynaptic cells, neurotransmitter release is governed by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor).  Findings in the schizophrenic postmortem brain have revealed increased SNARE protein-protein interactions, which may explain the unbalanced neurotransmitter levels in schizophrenia, and reduced SNARE complexes in antipsychotic-treated patients. In accordance, genetic differences in SNARE-coding genes have been associated with schizophrenia.

Despite the growing evidence involving presynaptic dysfunction in mental illnesses, no attempts have been made to develop a pharmacological approach targeting the SNARE complex. Furthermore, the sole active agent against SNARE proteins, Botox cannot be used due to its irreversible, and lethal effects, presenting a challenge to finding SNARE-interfering compounds and pharmaceutically treating schizophrenia.

Against this background, the objective of Dr. Ramos-Miguel’s clinical research project is to find SNARE-interfering compounds, and further address their potential benefits in the pharmacological management of schizophrenia.

To meet this goal, an  agreement involving UBC, the Centre for Drug Research and Development (CDRD), and Roche-Canada, will allow Dr. Ramos-Miguel’s team to  screen the company’s largest library, containing more than one million compounds. Additionally, an immunoassay-derived method has been automated for high throughput screening of compounds modifying SNARE interactions. This assay successfully screened the CDRD 26,000-compound library, and identified at least two SNARE “inhibitors”. Further hits from the screening project will be subjected to a number of preclinical tests, including immunological, electrophysiological, toxicological and behavioral assays.

Identification of SNARE-interfering substances may have potential to improve pharmacological treatment of schizophrenia through a completely novel strategy.

Mechanisms of cardiovascular disease in children with mental health conditions

Prescriptions of second-generation antipsychotic  (SGA) medication for children in British Columbia increased 22-fold from 1996 to 2010. These medications treat the underlying mental health issues (e.g. psychosis, depression, attention deficit/hyperactivity disorder) but often come with side-effects, including metabolic syndrome.

Metabolic syndrome is a cluster of clinical features that includes excess weight around the middle, high blood pressure, and high blood sugar or triglyceride concentrations. Given that metabolic syndrome is a risk factor for cardiovascular disease, there are serious implications for the long-term health of these children. Development of a secondary chronic disease such as CVD, on top of an existing mental health condition, further marginalizes the life-long health of these children.

Accordingly, there is a need to develop a means by which to distinguish children at risk for developing metabolic syndrome from those who are not. The goal of this research is to identify genetic markers that will indicate which children will develop risk factors for heart disease and stroke when treated with SGAs so that appropriate prevention strategies may be implemented in these children.