Insights into how new cells function in injured brains
Dec. 1, 2015November's featured paper is "Functional Integration of Adult-Born Hippocampal Neurons after Traumatic Brain Injury," published in eNeuro. The paper is published by Drs. Laura Villasana, Kristine Kim, Gary Westbrook and Eric Schnell in the OHSU School of Medicine.
We've all heard the dogma that the brain does not make new neurons in adults. While this is mostly true, there are new neurons being made in the hippocampus, even in fully grown adults.
"We now know that the mammalian brain increases the generation of new neurons in a few select brain regions, including the hippocampus," said Laura Villasana, Ph.D., assistant professor of anesthesiology/perioperative medicine in the OHSU School of Medicine.
"Although these new neurons may be few in number, they have a surprisingly large role in learning and memory," said Mary Heinricher, Ph.D., associate dean for basic research in the OHSU School of Medicine.
The production of new neurons, also known as neurogenesis, increases dramatically after a variety of neuronal insults, including stokes, seizures, and traumatic brain injuries (TBI). Many studies of TBI have focused on trying to enhance neurogenesis after injury, although it was not even known whether or not these cells had wired properly into circuits.
"After some types of injuries, new neurons may wire into circuits abnormally and contribute to brain dysfunction" said Eric Schnell, M.D., Ph.D., staff clinician/scientist at the VA Portland Health Care System and assistant professor of anesthesiology/perioperative medicine in the OHSU School of Medicine. "We didn't know whether neurogenesis following injury produced synaptically integrated cells, and if so, whether this was compatible with a beneficial role in recovery, as has been postulated," added Dr. Schnell. "Since non-functional or dysfunctional neurons could cause more problems than they solved, we wanted to understand whether these new neurons were properly wired into circuits," said Dr. Villasana.
Drs. Villasana and Schnell, along with Kristine Kim and Gary Westbrook, recently published their results in this month's highlighted paper, "Functional Integration of Adult-Born Hippocampal Neurons after Traumatic Brain Injury."
"Drs. Villasana, Schnell and colleagues looked at the effects of a controlled brain injury on the development of 'adult-born' neurons in mice and found that they are surprisingly normal at the cellular level, but have an unusual anatomy, possibly hinting at higher-order network alterations," said Dr. Heinricher.
"Using a combination of confocal imaging, single cell electrophysiology and transgenic mice, we found that although there was a substantial increase in the generation of new neurons after TBI, these cells migrated into aberrant locations in the hippocampus and had unusual morphology of their dendritic processes," said Dr. Villasana.
"However, despite their grossly abnormal location and morphology, these new cells were not only functionally integrated into the brain, they had maintained an overall balance of both intrinsic and extrinsic excitability," added Dr. Schnell.
Their research found that new neurons generated after TBI received inputs from the cortex and the appropriate amount of synaptic inhibition, suggesting that they would likely be able to contribute to information processing. However, the unusual dendritic morphology and location of these cells suggests that they might still have functional differences from cells born in healthy brains.
"The possibility that the brain has some regenerative capacity after injury has profound implications, and an understanding of how this capacity might contribute to functional recovery, or ongoing pathology, will be critical to efforts to improve patient outcomes after injury," said Dr. Villasana. "By understanding how new cells function in injured brains, we can pursue strategies to promote the beneficial aspects of plasticity after injury and attempt to prevent those that might cause harm."
"Now that we know that these new cells receive functional inputs from the cortex, we will focus on understanding the higher order functional capacities of these cells, and how the outputs from these cells influence circuit function," said Dr. Schnell. "We are also planning to look at how these cells contribute to behavioral recovery, using genetic tools to reversibly and irreversibly inhibit these cells."
The Schnell laboratory is also developing molecular tools to modify the maturation and synaptic integration of new cells at the single cell level. "We hope to eventually combine these approaches to develop strategies to maximize functional recovery after injury," said Dr. Schnell.
Functional Integration of Adult-Born Hippocampal Neurons after Traumatic Brain Injury eNeuro. 2015 Sep 28;2(5). pii: ENEURO.0056-15.2015. doi: 10.1523/ENEURO.0056-15.2015 Laura Villasana, Kristine Kim, Gary Westbrook, Eric Schnell
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About the OHSU School of Medicine Paper of the Month
The OHSU School of Medicine spotlights a recently published faculty research paper each month. The goals are to describe to the public the exceptional research happening at OHSU as well as inform our faculty of the innovative work underway across the school’s departments, institutes and disciplines. The monthly paper is selected by Associate Dean for Basic Research Mary Heinricher, Ph.D.