2021 Pilot Projects

Description

Recovery from Traumatic Brain Injuries (TBIs) can be slow and difficult to predict, and the neural processes underlying such recovery are not well understood. In this proposal, we will use noninvasive neuroimaging techniques to precisely track changes in brain structure and function that happen during recovery from TBI. This tracking will be done separately within individual acute TBI patients, which will help us understand how individuals’ recoveries may vary from each other. Tracking will continue for up to six months in order to characterize the entire recovery timeframe. The knowledge gained from this work will help us understand how and why TBI symptoms resolve when they do, and why recovery can vary so much across individuals. It may thus allow more accurate prognoses of TBI recovery. It will also be critical for developing future personalized, neurologically-based treatments that target dysfunctional brain structures within individual patients.

Updated February 2024

Description

Photoreceptors translate light into neural signals that form the basis of vision. A diverse group of inherited retinal degenerations (IRDs) causes photoreceptor loss and visual impairment, including blindness, in approximately 1:2000 people. The genetic heterogeneity of IRDs makes the development of mutation-specific therapies, with few exceptions, impractical. Here, we will perform a genome-wide search for mutation-agnostic neuroprotective strategies that could benefit many IRD patients. To speed up the translation from animal models to humans, we developed a sequential search strategy combining in vivo experiments in mice and large-scale candidate testing in human retinas.

Updated March 2024

Description

In addition to cancer cells, brain tumors form in an environment with non-cancerous cells (immune and nerve cells) that are critical for tumor formation. Brain injury may create changes in the brain microenvironment similar to those found in brain tumors, raising the intriguing possibility that brain injury creates a supportive environment for brain tumor formation. Using a mouse model of the Neurofibromatosis type 1 (NF1) brain cancer predisposition syndrome, we propose to determine whether injury can facilitate tumorigenesis. Insights from these studies may provide potential therapeutic opportunities to block tumor growth in children and adults with NF1 unrelated to brain injury, as well as in other tumor predisposition syndromes.

Publications

Chatterjee, J., Koleske, J.P., Chao, A., Sauerbeck, A.D., Chen, J.-K., Qi, X., Ouyang, M., Boggs, L.G., Idate, R., Marco Y Marquez, L.I., Kummer, T.T., Gutmann, D.H. Brain injury drives optic glioma formation through neuron-glia signaling. (2024) Acta Neuropathologica Communications, 12 (1), .

Updated March 2024

Description

Anhedonia—defined as diminished pleasure from, or interest in, previously rewarding activities—is a widely reported symptom of many psychiatric and neurological illnesses. A promising and novel treatment for anhedonia is represented by ketamine. Indeed, recent clinical evidence has shown that a single injection of ketamine ameliorates anhedonic symptoms within a matter of hours. However, understanding of the neurobiological mechanisms underpinning ketamine’s anti-anhedonic effects is lacking. Accordingly, the goal of this proposal is to develop a circuit and synaptic framework for ketamine’s mechanism of action in alleviating anhedonia. Specifically, using chronic stressed mice as a model system, we are planning to identify specific cellular and synaptic elements recruited by in vivo K administration and responsible for its anti-anhedonic effects within the Nucleus Accumbens, a brain region critical for mood and hedonic drive. No therapeutics are currently approved for the treatment of anhedonia despite its prevalence across multiple psychiatric and neurological disorders, therefore identifying mechanisms mediating ketamine’s ability to ameliorate hedonic deficits may provide cardinal stepping stones toward treatment improvements for this tractable endophenotype.

Grants and Awards

A synaptic substrate for ketamine-mediated amelioration of stress-induced anhedonia
NIH/NIMH – 5R01MH130610-02 (PI, Pignatelli)
Public Health Relevance Statement: PROJECT NARRATIVE There is a major unmet need for the treatment of depression because current pharmacotherapies for depression require prolonged administration for clinical improvement and they are often associated with high non-response rate. Recent clinical evidence has shown that a single sub-anesthetic dose of ketamine, a glutamate-NMDA receptor antagonist, induces a robust antidepressant effect within hours of treatment in 70% of treatment- resistant patients, however a circuit and synaptic-level dissection of ketamine’s mechanisms of action is lacking. Accordingly, the goal of this proposal is to identify circuits, cellular and molecular determinants responsible for the rapid antidepressant action of ketamine.

Publications

Lucantonio F, Li S, Lu J, Roeglin J, Bontempi L, Shields BC, Zarate CA, Tadross MR, Pignatelli M. Ketamine rescues anhedonia by cell-type and input specific adaptations in the Nucleus Accumbens. bioRxiv [Preprint]. 2023 Jun 9:2023.06.08.544088. doi: 10.1101/2023.06.08.544088. PMID: 37333325; PMCID: PMC10274891.

Updated February 2024

Description

Injuries to the Peripheral Nervous System are burdensome on individuals and society as a whole. Despite advances in neuroscience and reconstructive nerve surgery, recovery after peripheral nerve injuries often remains incomplete. Functional outcome worsens with increased time for nerves to reconnect with muscles. Compared to nerves, less investigative focus has centered on the muscle and the neuromuscular junction (NMJ), which is the interface between nerve signals and muscle movements. Terminal Schwann cells (tSCs) help with NMJ function, and following nerve injury, these tSCs guide nerve fibers back to the NMJs. We have identified Vascular Endothelial-derived Growth Factor A (VEGFA) as a key growth factor required for NMJ recovery after nerve injury with immediate nerve repair. Specifically, we have found that blocking VEGFA signaling results in a reduction of tSCs guidance of nerve fibers to the NMJs and overall fewer nerve fibers reaching NMJs. Additionally, we showed an increase in VEGFA receptors on tSCs after injury. Clearly, VEGF signaling loss after early nerve repair results in worse muscle function. What happens to VEGFA and the NMJ after delayed repair is not known, nor is the possible benefit of VEGFA enhancement to muscle after nerve injury in either the acute or chronic settings. This project investigates whether exogenous VegfA delivery to the end target muscle following nerve injury and immediate or delayed repair can enhance functional recovery. If successful, additional studies will be planned to translate this finding clinically for localized delivery at the affected muscle. With this knowledge, treatment of the high number of nerve injuries can be improved.

Updated March 2024