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We use a wide array of pre-clinical translational assays to measure various endophenotypes associated with a variety of neuropsychiatric disorders. We use localized intra-cerebral microinfusion procedures to precisely map out brain circuits associated with opiate and nicotine addiction and the effects of specific cannabinoids on emotional processing and memory formation.
Our behavioural assays can model both affective and cognitive symptoms associated with numerous mental health conditions, including schizophrenia, PTSD, anxiety, depression and addiction. Our neural regions of interest include the Prefrontal Cortex, Ventral Tegmental Area, Amygdala, Nucleus Accumbens (pictured below) hippocampus, dorsal raphe and pedunculopontine tegmental nucleus.
Conditioned Place Preference
In Vivo Neuronal Electrophysiology
Behavioural tools provide a wealth of information at the systems and translational levels of analysis. However, to really understand how drugs modulate the brain, its necessary to perform recordings of neurons, either individually or at the population level, in our brain circuits of interest. To do this, we use a variety of in vivo neuronal electrophysiological recording tools to measure a variety of features of the activity states of neurons. We measure specific firing patterns and rates of individual neurons, such as pyramidal neurons in the prefrontal cortex, medium spiny neurons in the ventral striatum and dopamine neurons in the ventral tegmental area.
In addition, we perform recordings of population neuronal activity states which allows us to analyse phenomena like long-term potentiation, a measure of memory-related synaptic plasticity. In addition, we can analyse specific oscillation patterns of neurons, which provide insights into how defined brain regions communicate with each other within and across brain circuits. These tools allow us to draw direct, functional comparisons between how behavioural pharmacological effects are related to specific alterations in neuronal activity patterns and how they may underlie neuropsychiatric phenotypes.
Molecular Signaling Analyses
To really understand the underlying mechanisms of complex neuropsychiatric disorders like opiate and nicotine addiction, schizophrenia and mood disorders, its necessary to go beyond the level of behavioural and electrophysiological analyses. This requires a careful investigation and characterization of the specific molecular signaling pathways that are associated with the effects of drugs on the brain. To accomplish this, we use several techniques to examine how acute or neurodevelopmental exposure to specific drugs of abuse might alter select molecular signaling events within our brain circuits of interest.
For example, by taking samples of tissue from brain regions like the prefrontal cortex, hippocampus or amygdala, we can examine the precise molecular signaling events that underlie the addictive effects of opioids or nicotine. We can examine how exposure to certain drugs like cannabinoids, might influence molecular signaling pathways that are involved in normal brain development. Using cell culture methods such as HEK cell lines transfected with specific receptor substrates allows us to isolate specific membrane receptor signaling effects and further clarify downstream signaling pathways associated with the effects of specific drug exposures. More importantly, once we identify these molecular pathways, we directly test their functional relevance by determining how manipulations of these signaling pathways may prevent or even reverse the effects of addiction within these brain circuits. These studies are performed in collaboration with the laboratory of Dr. Walter Rushlow, at the University of Western Ontario.
MALDI imaging (matrix-assisted laser desorption ionization imaging) is a cutting edge new brain imaging tool that allows us to directly image molecules of interest within specific brain regions. With the use of Mass Spectrometry, MALDI allow us to visualize specific neurotransmitters within select brain regions to determine how acute or neurodevelopmental exposure to specific drugs might functionally modulate levels of these transmitters. For example, we are currently using MALDI to directly image dopamine, glutamate, GABA, serotonin and fatty acids within specific neural regions of interest like the prefrontal cortex, nucleus accumbens and hippocampus. In addition to giving us a quantifiable readout of these neurochemical levels, we are applying MALDI imaging to neural bioavailability assays, in order to determine how novel drugs and formulations may interact with specific neural circuits related to neuropsychiatric disorders. Thus, by identifying specific molecular signatures and metabolites of specific cannabinoid compounds and formulations, we can successfully trace their disposition within our brain circuits of interest. These studies are being performed in collaboration with Dr. Shawn Whitehead and Dr. Ken Yeung, both at the University of Western Ontario.
Adolescent and Pre-Natal Neurodevelopmental Modeling
The brain is particularly vulnerable to drug exposure during critical periods of development. Exposure to certain drugs or chemicals during these windows of development can have long-lasting and permanent effects on brain function later in life. Thus, a major direction for our lab is the exploration of how exposure to drugs during specific windows of brain development may lead to long-term alterations in brain pathways and function associated with neuropsychiatric conditions. We focus specifically on the periods of pre-natal and adolescent brain development since it is well established that toxic exposures during these vulnerable windows can pre-dispose the individual to a variety of serious mental health problems in later life, including, schizophrenia, addiction, depression and anxiety. Currently we are exploring how exposure to specific phytochemicals found in marijuana, such as THC may impact vulnerability to certain disorders in later adulthood. In addition, we are examining how exposure to nicotine can lead to long-term vulnerability to mood disorders. In these studies, we use an integrative research approach including translational modelling of neuropsychiatric symptoms as well as electrophysiology, molecular signaling analyses and MALDI imaging techniques.
Cerebral Organoids to Model Early Brain Development
Beyond the effects of drug exposure during developmental windows of vulnerability, imagine being able to model the earliest phases of human brain development by re-programming cells in the body into stem cells, and allowing those cells to form miniature brains (cerebral organoids) in vitro! This is the amazing potential found in Cerebral Organoid technology and our laboratory is currently modelling early brain development using stem cell samples from patient populations in order to determine how exposure to certain drugs during early brain development might alter cellular architecture, neuronal activity states and molecular signaling pathways linked to a variety of neuropsychiatric conditions. These tools will give us remarkable new insights into how specific drugs and chemicals may fundamentally alter both normal brain development as well as how these early developmental events may be particularly sensitive in individuals pre-disposed to specific neuropsychiatric conditions like schizophrenia, addiction and mood disorders.
Our lab uses the ProOx 110 Oxygen Controller and C-Chamber Incubator Subchamber from BioSpherix Ltd to control either hypoxic or physioxic O2 levels during in vitro neuroscience experiments. More information can be found at: https://biospherix.com/neuroscience/
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