Effects of a Serotonin Receptor Peptide on Behavioral Pattern Separation in Sham- vs. Mild Traumatic Brain Injured Rats.

Abstract

Aims: Behavioral pattern separation is a hippocampal-dependent component of episodic memory and a sensitive marker of early cognitive decline. Here we tested whether mild traumatic injury causes loss of pattern separation in the rat and for its prevention by a novel neuroprotective peptide fragment of the human serotonin 2A receptor (SN..8).

Methods: Lateral fluid percussion was used to induce mild traumatic brain injury in male Sprague- Dawley rats. Rats were trained to distinguish between a stable vs unstable swim platform separated by increasing distances (4.5 vs 3.0 vs 1.5 feet) in a modification to the classic Morris water maze. Peptide SN..8 vs scrambled version of same amino acids (2 mg/kg) was administered via intraperitoneal route (1-, 3- and 5-days) after lateral fluid percussion or sham injury. Rats received three weeks of training and two weeks of testing before injury and were tested again at 2 and 5-weeks after injury.

Results: There was a gradient of decreasing incorrect responses to the choice between (stable vs unstable platform) as the platform separation distance was increased from 1.5 to 3.0 to 4.5 feet consistent with behavioral pattern separation. Systemic administration of SN..8 peptide (vs scrambled) peptide was associated with statistically significant lower rate of incorrect responses (at both 4.5 feet and 3.0 feet platform separation) in traumatic brain-injured rats (but not in sham-injured rats) tested at 2-weeks post-injury. Five weeks after injury, the rats had largely recovered and exhibited a much lower overall rate of incorrect responses across both drug and injury subgroups.

Conclusions: Introduction of an unstable platform (choice phase of the Morris water maze) at varying distances from the stable platform resulted in behavior having the hallmark of pattern separation. Our data are the first to suggest that systemic administration of (2 mg/kg) SN..8 peptide immediately after mild traumatic brain injury (lateral fluid percussion) appeared to protect against loss of behavioral pattern separation in the rat.