Cortical Functional Hyperconnectivity in a Mouse Model of Depression and Selective Network Effects of Ketamine
This week we profile a recent publication in Brain from Dr. Timothy Murphy (left) and
Dr. Alexander McGirr (right) at the University of British Columbia.
Can you provide a brief overview of your lab’s current research focus?
The Murphy laboratory uses mice to study disorders of brain connectivity. Recently, scientists have conceptualized disorders of brain function as being disturbances in functional connectivity. Functional connectivity describes how different brain areas work together. The laboratory pioneers the development of technologies to visualize changes in mouse brain functional connectivity. We study the mouse since this allows us to model aspects of human disorders and pilot new therapies.
The lab studies models of both depression and stroke in mice. These two disorders couldn’t be more different in terms of their effects on brain connections. Stroke, results from local tissue damage (lesions) due to a lack of blood flow, while the root causes of depression are much more difficult to pin down.
Using the mouse as a model, my lab led by Psychiatry resident and PhD student Alex McGirr mapped how depression alters the function of mouse cortex. McGirr literally came upstairs from the clinic to do his PhD and in the process led the lab to novel research. Surprisingly, the lab’s results indicated there is not a single focus of altered cortical activity during depression. Depression led to widespread patterns of cortical hyperactivity resembling aspects of network changes observed in human patients. Furthermore, the lab helped to establish the mechanism by which a leading prototype anti-depressant ketamine works through normalizing these wide-scale networks.
What is the significance of the findings in this publication?
The work is significant for three main reasons. First, we show that models of depression in mouse produce brain function changes resembling those observed in humans who are depressed. This, of course, opens up the possibility of testing questions that are prohibitive in humans. As such, we used a next generation fluorescent sensor that allowed us to look at a specific neurotransmitter system (glutamate) in a specific population of cells in the cortex, allowing us to narrow down on an important piece of the puzzle. Finally, a major challenge in studying depression and its treatment is the substantial lag to treatment response, making it difficult to pin down exactly what is changing and when, and more importantly, how it is related successful treatment or side effects. To circumvent this, we decided to focus on ketamine, which is not only an emerging rapid acting antidepressant that results in benefit within hours, but also implicated in glutamatergic signaling, in order to capture the early changes that result in improvement in depressive symptoms.
We provide strong data showing the mechanism by which ketamine acts is by normalizing regional brain communication. Our work suggests that mouse models can be used to accurately pilot aspects of anti-depressant development with specific focus on normalizing patterns of aberrant activity flow.
What are the next steps for this research?
The next steps in this research are to devise systems where mice can be assessed continually to longitudinally pilot and assess anti-depressant treatments. The current theme in the lab is automating imaging procedures, so that multiple parallel experiments can be undertaken to devise treatments that can help to normalize depression symptoms. The lab is developing platforms to simultaneously evaluate brain networks, depression symptoms, and explore therapeutic treatments while mice are within their own cages. Other frontiers include modifiers of depression, such as social interactions between mice. We know in humans that family or other social networks can serve as powerful modifiers of depressive symptoms. We are currently evaluating how animal social interactions might be important for influencing outcomes.
This research was funded by:
We are grateful for support from the Canadian Institutes of Health Research for funding the laboratory through the Foundation Grant program and funding the PhD training of Alex McGirr through the Vanier Canada Graduate Scholarship.