Project Summary The objective of this proposal is to make the chronic injured brain receptive to cognitive rehabilitation. After traumatic brain injury (TBI), there is synaptic deafferentation followed by responsive neuroplastic change in surviving synaptic terminals. Without intervention after TBI, the natural disease course involves uncoordinated regenerative responses and maladaptive circuit formation. The degenerative and regenerative cellular processes alter circuit structure and manifest in neurological dysfunction, including cognitive deficits. Veterans with a history of TBI report memory and cognition challenges that impair their activities of daily living. Laboratory evidence from the research team shows persistent short-term, long-term, and sequential memory impairments for months after experimental TBI. Further, when a novel spatial navigation rehabilitation strategy – Peg Forest rehabilitation – is provided at one week post-injury, cognitive impairments are not detectable in brain-injured rats. Therapeutic efficacy is evident in brain-injured male and female rats only when a novel spatial arrangement of pegs is provided each day, rather than repeated presentation of the same arrangement. However, Peg Forest rehabilitation is no longer effective when initiated at one month post-injury, once cognitive impairments have manifested and injury-related neuroplasticity has waned. A new approach is required to make the chronic injured brain receptive to rehabilitation. Until recently, relatively few (if any) compounds were known to possess neuroplastic-promoting properties. A group of compounds known as psychoplastogens have recently gained widespread attention for their ability to ameliorate depression, anxiety, PTSD and other congenital and chronic mental health disorders for months up to a year with a single administration. The underlying benefits are attributed to increased dendritic arborization and spine density in cortical regions and hippocampus, which can promote new neural pathways. New preliminary data replicate the inefficacy of Peg Forest rehabilitation alone in the chronic period of TBI and the significant improvement in sequential memory with a single dose of ketamine (20 mg/kg, i.p.) preceding Peg Forest rehabilitation (15 min/day; 5 days/week for 2 weeks). The aims of this proposal are built on the premise that the reintroduction of a neuroplastic state by the psychoplastogens ketamine and psilocybin preceding Peg Forest cognitive rehabilitation can rescue cognitive function. In the context of TBI associated cognitive impairments, we hypothesize that psychoplastogen administration preceding dynamic spatial navigation cognitive rehabilitation in the Peg Forest can rescue cognitive function in the chronic TBI period, as a neuroplastic state has been induced. Diffuse TBI by midline fluid percussion results in novel object cognitive impairments in male and female rats. In Aim 1, the lowest doses are determined for each sex for ...