This Merit proposal is part of a BLR&D Collaborative Merit Award for TBI (CTBI) proposal (RFP #BX-19-006) involving three separate but integrated proposals that together investigate the mechanisms by which TBI enhances impulsivity and suicidal behavior in Veterans. The rationale for the collaborative project is to combine neurobiological mechanistic studies in animals with human imaging and biomarker analysis to understand the manner in which TBI influences impulsivity and suicidal behavior. The overarching hypothesis is that TBI enhances impulsivity, a risk factor for suicide particularly in response to stress, through inflammation and dysfunction of the serotonin system and frontal lobe circuitry. The number of new traumatic brain injury (TBI) cases for U.S. Military forces has more than doubled in the last five years and will continue to grow. TBI is a risk factor for suicidality. Moreover, increased impulsivity is one of the most prevalent symptoms following TBI, and is itself a risk factor for suicide, depression and drug abuse. Thus, understanding the underlying mechanisms responsible for high impulsivity following TBI is key to understanding the link between TBI and suicide. Serotonin is important for rational decision-making and loss of serotonin neurons leads to increased impulsivity. Previously, we demonstrated that mild TBI (mTBI) in an animal model caused long-lasting suppression of the acoustic startle response (ASR), pathological inflammation and degeneration of neurons in the nucleus reticularis pontis caudalis (PnC), a brain region essential for ASR. Anatomically, serotonergic neurons in the pontine raphe nucleus are located in the immediate vicinity of the PnC, and it is not unreasonable to expect inflammation and neurodegeneration in the raphe nucleus following mTBI, as in the PnC. Our preliminary data support this idea. We also present preliminary results that mTBI increases motor and cognitive impulsivity following lateral fluid percussion injury in rats. The proposed studies will build on these preliminary results and investigate the hypothesis that inflammation and degeneration of the serotonergic raphe nuclei lead to increased impulsivity after TBI. This hypothesis will be tested in three aims.
Aim 1 will determine whether mild TBI (mTBI) alone and in combination with social isolation stress enhances impulsivity. The lateral fluid percussion injury model will be used to generate mTBI in rats. Two aspects of impulsivity will be assessed: motor impulsivity and cognitive impulsivity using a Go/No-Go and a delay discounting procedure, respectively. It is predicted that impulsivity will be increased at 1 month and continue to worsen at 3 months after TBI.
Aim 2 will determine whether mTBI causes inflammation and degeneration of serotonergic raphe neurons. The prediction is that mTBI will cause an early inflammatory response in the raphe nuclei, followed by loss of serotonergic neurons starting at 1 month after mTBI with greater degeneration at 3 months.
Aim 3 will determine if blocking inflammation immediately or 1 week after mTBI or enhancing serotonin levels at the time of behavioral testing will prevent/reverse the TBI-induced impulsivity. It is predicted that blocking inflammation with an inhibitor of NF?B will prevent inflammation from occurring after mTBI and thereby prevent degeneration of serotonergic neurons, and impulsivity. Additionally, selective serotonin reuptake inhibitors are expected to enhance synaptic serotonin and thereby reverse the enhanced impulsivity due to TBI. The proposed studies will test the novel hypothesis that loss of brainstem serotonin neurons is a key mechanism by which mTBI increases impulsiveness, a risk factor for suicide. While animal models are not able to directly assess suicide risk, this specific proposal will provide a mechanistic explanation of TBI-induced impulsivity, while human studies in this Collaborative Merit application will provide the final link between impulsivity and suicidality.
The number of new traumatic brain injury (TBI) cases for U.S. Military forces has more than doubled in the last five years and will continue to grow. TBI increases impulsivity and the risk for suicidality. Moreover, impulsivity is a risk factor for suicide. This proposal is part of a Collaborative Merit Award for TBI application that will investigate the mechanisms by which TBI enhances suicidality in Veterans. This specific application will test the hypothesis that neuroinflammation and degeneration of serotonergic neurons in the raphe nucleus leads to increased impulsivity in an animal model of TBI. This work extends previous results showing that serotonin is important for decision-making and pontine neurons in proximity to serotonergic neurons degenerate after TBI. The predicted results will identify a key mechanism by which TBI enhances impulsivity and suicide risk, allowing for therapeutic targeting to ultimately benefit Veterans quality of life.