Depression and suicide are of increasing incidence, especially in early adulthood. We are studying how various forms of negative stimuli trigger common mechanisms within brain reward/aversion circuitry. We find that many types of negative stimuli including chronic unpredicted stress, chronic exposure to cocaine and drugs of abuse, obesity and prediabetes, bowel inflammation, chemotherapy, and pain induce changes in neurotransmission that limit aversion/reward circuitry excitability. We are conducting large multiomic analysis to identify the mechanisms driving this maladaptive condition. We have discovered two therapeutic approaches so far that reverse this condition. We seek to gain more mechanistic information, model these problematic mental health states, and develop treatments for depression and suicide risk, addiction, eating disorders, and other problematic or fatal behaviors associated with these negative states.

Cancer survivors, such as those who have been treated for breast cancer, often experience a fog in cognitive and mental performance that can be long-lasting. This condition, known as “chemobrain”, is a major disorder and comorbidity which is poorly understood. We have been studying this disorder and have derived a large amount of exciting new data showing what may cause it and how it might be treated both prophylactically and to reverse the symptoms. This is a very well-developed project with a large amount of unpublished data.

We are working to understand the intersystemic biology by which stress, diet, and metabolic state impact brain function. We have found that a high fructose corn-syrup, fat, and salt diet induces anxiodepressive-like behavior. We believe this is mediated through changes in the gut microbiome, immune function, and blood metabolites. We have found that we can reverse some of these effects by targeting specific bacteria in the gut as well as signaling mechanisms in the brain. This is an exciting novel project on which we hope to bring to bear innovative techniques.

We serendipitously discovered that mechanisms of neuronal injury can also cause neuroendocrine cancer. Since our first publication of a cover article in Cancer Cell in 2013 we have had a robust and exciting neuroendocrine cancer research program. We are among the current leaders in this field, and we have more exciting projects and translational approaches waiting to be pursued. We have generated first time models for several of these cancers, brought forth new treatments, new diagnostic biomarkers, and new target mechanisms. We have several new models to make, mechanistic targets that have promise of major new discoveries, and we plan to find new drugs that can be brought to the clinic. While neuroendocrine cancers are relatively rare, there are very few effective treatments other than surgery and they are responsible for a significant portion of cancer-related deaths. Moreover, the mechanisms and drivers we are studying appear to apply to other more widespread cancers, such as colorectal cancer, melanoma, and hepatocellular cancer.

Neuronal injury including that resulting from ischemic stroke, traumatic brain injury, neurotoxicity, or neurodegenerative diseases involves neuronal cell death. We aim to understand the deleterious mechanisms that cause neuronal injury and identify ways to protect neurons and mediate recovery. We have shown we can keep tissue alive for an hour or more in the absence of oxygen and glucose by selectively targeting critical neuronal injury pathways. We have shown mice lacking these pathways are profoundly neuroprotected from stroke and various forms of traumatic head injury. We have developed novel models of head injury and have a new drug candidate that completely protects from the cognitive effects of radial force-induced diffuse axonal injury. We are extending this work to understand the causes and develop new treatments for head trauma and stroke.

The beginning of our studies of the integration of slow and fast neurotransmission was marked by a paper published in Nature by Dr. Bibb and colleagues during his postdoctoral training that was cited in the Nobel Prize in Physiology or Medicine awarded to Paul Greengard in 2000. It showed Cdk5 regulates dopamine neurotransmission. Later, in a Nature Neuroscience paper in 2007 and a Neuron paper in 2014, the Bibb lab showed that Cdk5 regulates synaptic plasticity through control of NMDA receptor function. Those studies demonstrated that cognition enhancement could be achieved by selective disruption of Cdk5-NR2B mechanisms. Now, with new brain permeable Cdk5 inhibitors and new cell type specific proteomics techniques, an opportunity exists to return to these observations to better understand the mechanisms that characterize the metaplastic state when memories are coded and target these mechanisms to overcome cognitive disorders.

Our work on CNS diseases, intersystemic comorbidities, and common mechanisms of neuronal injury and cancer point to the need to translate our findings into therapeutic approaches and the discovery of drugs that can be applied in the clinic. For 20 years, we have been discovering and testing anti-Cdk5 therapies, most of which have lacked specificity and exhibited toxicity at doses relatively close to those required for efficacy. We are now creating new biosensors and assays to target Cdk5 and its activating cofactors from multiple perspectives, including inhibiting its catalytic function, protein-protein disruption, and targeted protein degradation. Our work on therapeutic development is exciting and represents opportunities for students to conduct biotechnology/pharmaceutical industry relevant research.