One-Year Study of Spatial Memory Performance, Brain Morphology, and Cholinergic Markers After Moderate Controlled Cortical Impact in Rats

Abstract

Persistent cognitive deficits are one of the most important sequelae of head injury in humans. In an effort to model some of the structural and neuropharmacological 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, morphology, and vesicular acetylcholine (ACh) transporter (VAChT) and muscarinic receptor subtype 2 (M2) immunohistochemistry. Vertical CCI (left parietal 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 platform 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 trials to control for nonspecific deficits. At 3 weeks, half the animals were sacrificed for histology. At these injury parameters, CCI produced no significant differences in place learning between injured and sham rats at 2 weeks, 4 weeks, or 6 months after injury. However, at 3 and 12 months, the injured rats took significantly longer to find the hidden platform than the sham rats. Probe trial performance differed only at 12 months postinjury between 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 worsening of performance, but may have resulted from a reduced ability of injured rats to benefit from previous water maze experience. Hemispheric loss of 30.4+/-5.5 mm3 was seen at 3 weeks after injury (versus respective sham). However, hemispheric loss almost doubled by 1 year after injury (51.5+/-8.5 mm3, 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, immunostaining for VAChT was dramatically increased in all sectors of the hippocampus and cortex after injury. Muscarinic receptor subtype 2 (M2) immunoreactivity was dramatically decreased in the ipsilateral hippocampus. This suggests a compensatory response of cholinergic neurons to increase the efficiency of ACh neurotransmission. Moderate CCI in rats produces subtle MWM performance deficits accompanied by persistent alteration in M2 and VAChT immunohistochemistry and progressive tissue atrophy. The inability of injured rats to benefit from repeated exposures to the MWM may represent a deficit in procedural memory that is independent of changes in hippocampal cholinergic systems.

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

“…Clinically, progression of damage has been observed in stroke and TBI patients using MRI (Anderson and Bigler, 1995;Baird et al, 1997). Experimentally, progressive atrophy of gray and white matter structures has been reported in models of TBI (Bramlett et al, 1997a;Bramlett and Dietrich 2002;Dixon et al, 1999;Smith et al, 1997). In one study, severe atrophy of multiple white matter tracts was described 1 year after TBI (Bramlett and Dietrich, 2002).…”

Voluntary exercise or amphetamine treatment, but not the combination, increases hippocampal brain-derived neurotrophic factor and synapsin I following cortical contusion injury in rats

“…Because oxidative stress plays an important role in neuronal injury after TBI (Shohami et al, 1997;Sullivan et al, 1998;Hall et al, 2004), we also determined if these treatments would alter oxidative stress after TBI. We employed the controlled cortical impact (CCI) model of TBI for this study, as this injury model is known to produce molecular changes and cellular damage in the hippocampus (Dash et al, 1995;Colicos et al, 1996;Oyesiku et al, 1999;McCullers et al, 2002;Saatman et al, 2006), induce hippocampal-dependent learning deficits (Hamm et al, 1992;Lindner et al, 1998;Dixon et al, 1999), and to reduce brain NE levels and turnover (Dunn-Meynell et al, 1994;Levin et al, 1995). While increased expression or production of hippocampal BDNF and synapsin I has been reported to occur after exercise in both intact rats and in rats with FPI (Timmusk et al, 1993;Neeper et al, 1996;Molteni et al, 2002;Griesbach et al, 2004bGriesbach et al, , 2007, exercise-induced effects of these markers of plasticity have not yet been evaluated in the CCI model.…”

Mechanisms and Treatment of Progressive Damage After Traumatic Brain Injury

“…Both studies [5,47] reported expansion of the lateral ventricle, a phenomenon which is also observed in TBI patients [3]. Additionally, Dixon et al [20] recently reported similar findings in a model of controlled cortical impact trauma (CCI). Comparison of tissue obtained at 3 weeks and 1 year post-injury demonstrated a significant hemispheric volume loss, and again expansion of the ipsilateral lateral ventricle.…”

“…To provide adequate treatment strategies for these behavioral abnormalities, an understanding of acute as well as progressive neuropathological changes after traumatic brain injury (TBI) must be clarified. Whether progressive damage is due to long-lasting consequences of the primary insult (i.e., Wallerian degeneration) [1, 24,43,49], or results from progressive secondary injury mechanisms remains to be determined [6,10,11,20,42], Several clinical [3,4,12,22,49,56] and experimental [5,20,47,51] studies have reported evidence for progressive atrophic changes after TBI. After human TBI, Anderson and Bigler [3] reported widespread atrophy of both white and gray matter structures.…”