One-year study of spatial memory performance, brain morphology, and cholinergic markers after moderate controlled cortical impact in rats

Persistent cognitive deficits are one of the most important sequelae of hea d injury in humans. In an effort to model some of the structural and neurop harmacological changes that occur in chronic postinjury brains, we examined the longitudinal effects of moderate vertical controlled cortical impact ( CCI) on place learning and memory using the Morris water maze (MWM) test, m orphology, and vesicular acetylcholine (ACh) transporter (VAChT) and muscar inic receptor subtype 2 (M-2) immunohistochemistry. Vertical CCI (left pari etal cortex, 4 m/sec, 2.5 mm; n = 10) or craniotomy (sham) was produced in male Sprague-Dawley rats (n = 10). Place learning was tested at 2 weeks, 4 weeks, 3 months, 6 months, and 12 months postinjury with the escape platfor m in a different maze quadrant for each time point. At each interval, rats received 5 days of water maze acquisition (latency to find hidden platform) , a probe trial to measure place memory, and 2 days of visible platform tri als to control for nonspecific deficits. At 3 weeks, half the animals were sacrificed for histology. At these injury parameters, CCI produced no signi ficant differences in place learning between injured and sham rats at 2 wee ks, 4 weeks, or 6 months after injury. However, at 3 and 12 months, the inj ured rats took significantly longer to find the hidden platform than the sh am rats. Probe trial performance differed only at 12 months postinjury betw een injured (25.73 +/- 2.1%, standard error of the mean) and sham rats (44. 09 +/- 7.0%, p < 0.05). The maze deficits at 1 year were not due to a worse ning of performance, but may have resulted from a reduced ability of injure d rats to benefit from previous water maze experience. Hemispheric loss of 30.4 +/- 5.5 mm(3) was seen at 3 weeks after injury (versus respective sham ). However, hemispheric loss almost doubled by 1 year after injury (51.5 +/ - 8.5 mm(3), p < 0.05 versus all other groups). Progressive tissue loss was also reflected by a three- to fourfold increase in ipsilateral ventricular volume between 3 weeks and 1 year after injury. At 1 year after injury, im munostaining for VAChT was dramatically increased in all sectors of the hip pocampus and cortex after injury. Muscarinic receptor subtype 2 (M-2) immun oreactivity was dramatically decreased in the ipsilateral hippocampus. This suggests ai compensatory response of cholinergic neurons to increase the e fficiency of ACh neurotransmission. Moderate CCI in rats produces subtle MW M performance deficits accompanied by persistent alteration in M-2 and VACh T immunohistochemistry and progressive tissue atrophy. The inability of inj ured rats to benefit from repeated exposures to the MWM may represent a def icit in procedural memory that is independent of changes in hippocampal cho linergic systems.