Protecting Neural Circuitry Underlying Memory-Dependent Learned Behavior
Abstract
The Focus Area addressed by our proposal is foundational research to improve understanding of the mechanisms, etiology, comorbidities, and therapeutics/treatments for Alzheimer s Disease (AD) and related dementias (ADRD) after traumatic brain injury (TBI). TBI triggers AD/ADRD through promotion of chronic brain inflammation. There are currently no preventative or curative treatments for this type of neuroinflammation and the few drugs that address symptoms can produce significant side effects, particularly when used long term. This makes identification and development of safer and more effective anti-inflammatory treatments a high priority, and this is the objective of our proposed research. Using a unique songbird animal model that learns a form of vocal communication during a sensitive period of development, we have found that pharmaceutical grade cannabidiol (CBD) protects song quality and speeds recovery following damage to vocal motor cortex. Our rationale for using songbirds is that song is a motor skill learned during development in a way not exhibited by more common rodent models. Also, vocal learning depends upon maturation of a network of interconnected brain regions similar to those underlying human speech. There are very few animals that, like humans, learn a sensorimotor skill during development and are also suited to laboratory study. Thus, our approach is particularly and uniquely translational. CBD was recently U.S. Food and Drug Administration (FDA)-approved to treat childhood seizure disorders (marketed as Epidiolex). Ability of CBD to reduce seizures involves anti-inflammatory properties. Our preliminary results indicate it improves vocal recovery at least in part through this mechanism. We now propose to test ability of CBD to activate anti-inflammatory microglia and promote homeostatic processes of autophagy and synaptic scaling that can protect circuits established during sensorimotor learning. If CBD has these effects, clinical evaluation in TBI will be warranted, particularly as it is already FDA-approved. By reducing or preventing TBI-related neuroinflammation, our research promises to decrease the incidence and severity of dementias that are more likely to develop in these patients. Neuroinflammation-related dementias often lead to mood disorders (e.g., depression, anxiety) and cognitive deficits that impact learning and memory. By reducing incidence of these problems our research will improve quality of life of patients and caregivers. Late dementia often involves motor control problems and disruption of learned motor skills that can profoundly impact ability of TBI survivors to live independently. Preservation of motor skills is critical because they are only obtained through significant practice. Some are learned well only during development and are difficult and/or impossible to reacquire when learning begins after childhood. Because of this, adult loss of skills can lead to irreplaceable loss of a lifetime of effort. If our hypotheses are correct and CBD promotes protection of neural circuits underlying learned behavior, a strong case can be made to initiate clinical investigation. Note that our research will also address the timing of CBD administration that is relevant to clinical application. Preliminary work to date has employed pre-injury treatments. Part of our proposed work will be to determine if post-injury treatments are effective. CBD will be most useful in mitigating TBI-related neuroinflammation in injured military personnel if it is still effective after injuries occur. If pre-injury CBD treatments are required CBD may still have prophylactic application, that, given a favorable side-effect profile, may be worth associated risks. Problems reported for Epidiolex include diarrhea (caused by the oil vehicle), increased liver function enzymes (without clear liver toxicity), fatigue, vomiting and somnolence (that may be particularly undesirable in militar
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310927
Entities
People
- Kenneth Soderstrom
Organizations
- East Carolina University
- United States Army