# Psychoplastogens to make the injured brain receptive to cognitive rehabilitation during the chronic period ofTBI

> **NIH VA I01** · PHOENIX VA HEALTH CARE SYSTEM · 2024 · —

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10750308
- **Project number:** 1I01RX004536-01A1
- **Recipient organization:** PHOENIX VA HEALTH CARE SYSTEM
- **Principal Investigator:** Jonathan Lifshitz
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10750308

## Citation

> US National Institutes of Health, RePORTER application 10750308, Psychoplastogens to make the injured brain receptive to cognitive rehabilitation during the chronic period ofTBI (1I01RX004536-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10750308. Licensed CC0.

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