In Focus: The Denny Laboratory

Dr. Christine Ann Denny’s laboratory is interested in the molecular mechanisms underlying learning and memory. One important example of the work of the Denny Lab: the development of a novel technique to label the cells that encode individual memories in the brains of mice. Dr. Denny’s team genetically engineering a mouse line and have been able to indelibly tag neurons that correspond to an individual memory using fluorescent molecules. By then examining the brains of these mice, the researchers can identify how a number of conditions affect specific memory traces in the hippocampus. They have also been able to inhibit or excite these cells optogenetically (i.e., through the use of light) and show that they are critical for memory expression.

The Denny Laboratory is now using these mice to investigate what happens to individual memories in disease states such as in Alzheimer’s disease. By combining their unique genetic mouse line with disease mouse models, they hope to identify the altered memory circuits in these conditions and to figure out ways to manipulate them to improve memory. Dr. Denny’s team anticipates that these studies may halt, or even reverse, the process of Alzheimer's disease-related memory loss or cognitive ageing.

Denny’s group is also interested in understanding how rapid-acting antidepressants, such as ketamine, are able to prevent traumatic memories, improve mood, and decrease depressive-like behavior. Ketamine has been shown to be a rapid-acting antidepressant and have long-lasting effects in rodents and humans. The Denny Laboratory has identified a number of conditions in which ketamine improves behavior, and the researchers are interested in identifying the molecular mechanisms behind ketamine’s mood-enhancing effects. Current studies are aimed at utilizing ketamine or other novel prophylactic compounds in conjunction with the lab’s line of mice.

Dr. Denny and her group were prolific in 2018. Here we highlight some specific examples of her team’s recent major contributions to the research and the literature at the heart of cognitive and psychiatric memory disorders.

A paper published in Scientific Reports in July describes an exciting innovation developed in a collaboration between the Denny laboratory and the laboratory of Michal Lipson, Ph.D. (in Biomedical Engineering). They created a new platform for micro-fabricated lenses that can be used as minimally invasive endoscopic imaging instruments. This technology vastly improves the existing, larger instruments by creating probes that achieve high resolution despite their tiny size (probes with a diameter that is only tens of microns). The smaller size of this new lens keeps the cross section made by the probe extraordinarily small, which results in a less invasive procedure. The Denny and Lipson Labs received a Research Initiative for Scientific Enhancement (RISE) grant to fund this work.

The lab has also made significant contributions to the fascinating research investigating how memories are encoded and stored in the brain’s neural networks. Using the aforementioned line of mice specially designed for the indelible labeling of individual memory traces, the researchers, led by Ina Pavlova, PhD, compared the different leading methods for whole-brain clearing and immunolabeling. These processes are necessary for actually making memory traces visible in the brain. The team concluded that one protocol in particular (CUBIC with Reagent-1A*) appeared to be the ideal method for visualizing whole-brain memory traces in the brain tissue of the mice studied. In line with this work, the Denny laboratory also received the Kavli Award to study how multiple memories are encoded and stored throughout the brain. 

In 2018, the Denny Lab also advanced our understanding of the role that the ketamine could play in protecting against depression, and also in decreasing fear following stress. One such study, whose results were published in Biological Psychiatry, delved more deeply into the specific mechanisms underlying the anti-depressant effect of ketamine. In a collaboration with Alain Gardier’s laboratory and led by researcher Dr. Thu Ha Pham, the study found that ketamine and one of its metabolites had a common neurotransmission resulting in sustained antidepressant-like effects in mice.

Josephine McGowan, a graduate student in Neurobiology and Behavior and NSF Graduate Research Fellowship (GRFP) awardee, was lead author of another paper coming out of the Denny lab, published in Neuropsychopharmacology, that explored the metabolic changes that may underlie ketamine’s effectiveness for increasing stress resilience. Using a metabolomic platform, the team was able to identify metabolites in the brain and in the blood that may mediate ketamine’s long-lasting effects. Interestingly, the protective effects were seen only in mice subjected to stress, suggesting that the positive impact of ketamine injection interacted with the stress itself. In addition to highlighting the possible interaction between ketamine and stress, insights from this research provide new targets for future prophylactic development.

More ketamine-related research from the Denny Lab was published again in the journal Biological Psychiatry at the end of the year. The team had previously shown that an injection of ketamine prior to stress protects against depressive-like behavior and inhibits learned fear. In this new study they sought to pinpoint the possible mechanisms behind this phenomenon. The group, led by Alessia Mastrodonato, PhD, examined the brains of mice injected with either saline or ketamine to look for evidence of alteration in different parts of the brain. They were able to successfully identify the specific neural activity altered by the ketamine injection, providing more hope for future targeted intervention.