Traumatic brain injury (TBI) is a leading cause of neurologic disability and the most common associated cogni- tive deficits affec prefrontal cortex (PFC)-dependent functions such as: attention, working memory, social be- havior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology of frontal corti- cal microcircuits associated with these cognitive deficits. Our lab developed a mouse model of frontal lobe con- tusion that recapitulates higher order cognitive dysfunction observed in humans after trauma. Mice exhibit aberrant sociability and mental flexibility measured in a rule reversal behavior, implying damage to the or- bitofrontal cortex (OFC) despite a lack of overt tissue loss. My preliminary data indicate selective vulnerability of somatostatin-positive (SOM+) inhibitory neurons within the OFC. These neurons exhibit widening of the ac- tion potential, an increase in adaptation rate and a decrease in excitability, while intrinsic firing deficits are not identified in other neuronal types after TBI. With this proposal, I will investigate how these deficits in intrinsic firing propagate through the OFC network to affect synaptic, microcircuit and behavioral function.
In aim 1, I will use optogenetic techniques to analyze how SOM+-mediated inhibition in pyramidal neurons is affected by TBI in vitro.
In aim 2, I will evaluate the impact of TBI on feedforward and feedback inhibition, including the fre- quency-dependent disynaptic inhibition between pyramidal neurons that is mediated by SOM+ inhibitory neu- rons.
In aim 3, I will explore how optogenetic inhibition or stimulation of SOM+ neurons in vivo can impair or restore mental flexibility during rule reversal learning after TBI, respectively. These studies will significantly ad- vance our mechanistic understanding of the maladaptive circuit reorganization that occurs after TBI and will give insight into therapeutic targets for cognitive deficits. This mentored award will provide the training needed for an independent career as an academic physician sci- entist. I will develop technical expertise with training in animal models of TBI, inhibitory neuron physiology, op- togenetics, and cognitive testing under the mutual direction of Drs. Susanna Rosi and Vikaas Sohal, leading experts in their fields, and with feedback from my multidisciplinary scientific and career advisory committee. I will supplement this training with coursework in neural circuits, optogenetics, statistics and grant writing, along with attendance at local seminars and national meetings to foster collaborations. These activities will develop me into a respected member of the research community with expertise in systems neuroscience and neu- ropathology.
Traumatic brain injury is a frequent cause of disability in this country, with up to up to 90% of patients experi- encing chronic neurologic deficits including aberrant changes in social behavior, anxiety, attention, memory, task switching and mental flexibility- behaviors associated with neuronal circuits in the prefrontal cortex. Yet little is known about the maladaptive circuit reorganization that occurs after trauma in these cortical networks, limiting ability to develop appropriate therapeutics for these patients. This proposal will establish how intrinsic deficits in neuronal networks may contribute to cognitive dysfunction after trauma and provide vital information that could influence clinically relevant treatment strategies.
