Altered dopaminergic function after repetitive closed head injury in adolescent mice

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Mild traumatic brain injury (mTBI) or concussion in adolescents is a major public health concern. Major symptoms resulting from mTBI include cognitive decline and, for some patients, acquired attention deficit hyperactivity disorder (ADHD)-like symptoms. These deficits often are not present at the time of head injury, but rather are diagnosed with a delayed onset, suggesting of progressive functional deterioration initiated by head trauma. Standard diagnostic techniques such as MRI and CT typically do not reveal abnormality in mTBI brains, leaving a pressing need to identify key neuronal factors associated with deficits induced by mTBI. As many cognitive/attention deficits are known to link to abnormal dopamine (DA) transmission in the brain, it has been suggested that altered DA function may play an important role in certain mTBI-induced abnormalities. The TBI- DA link is supported by the evidence that Ritalin (methylphenidate) or Adderall (d-amphetamine), two classes of dopamine transporter blockers, have been reported to temporarily alleviate mTBI-related cognitive impairment and ADHD-like symptoms. Although the emerging DA hypothesis is starting to gain attention in TBI research, there are still very few evidences to support the direct link of brain injury and DA function, especially with the ability of following DA-functionality in vivo longitudinally. In this proposal, we will investigate the hypothesis: mTBI-related deficits are linked to a progressive deterioration of dopaminergic function in the brain, providing a biomarker that can be used to track degree of brain injury and recovery after concussion in vivo and longitudinally. We propose to test this hypothesis using a clinically relevant rodent model of adolescent repetitive closed head injury (rCHI). We will use functional magnetic resonance imaging (fMRI) with d-amphetamine challenge to probe changes in dopamine innervation and in its downstream circuitries affected by mTBI. We will then use fMRI with DA receptor agonists to assess specific changes in dopaminergic (D1-like and D2-like) receptor function after rCHI. The fMRI results induced by D1-like/D2-like agonists will be compared to DAR protein density in key DA brain areas (western blot). In addition to pharmacological fMRI, we will use resting state fMRI to probe changes in neuronal connectivity throughout the whole brain, with specific emphasis on the dopaminergic circuitry. The non-invasive measurement of fMRI will allow us to assess changes in the DA- relevant functionality in the same animals longitudinally. Imaging results will be cross-checked with cognitive and behavioral tests relevant to dopamine deficits of mTBI mice. Overall, success in identifying dopaminergic function as a biomarker for mTBI that can track deteriorating effects of concussion will help to provide objective criteria for studying brain injury resolution and will offer an opportunity for clinical translation.