Models of focal cerebral ischemia in the rat have primarily focused on the consequences of MCA occlusion. However, the stereotaxic injection of the potent vasoconstrictor endothelin-1 in close proximity to the artery (Sharkey et al., 1993) provides a flexible method for inducing arterial occlusion. The procedure affords the opportunity to occlude any artery for which reliable stereotaxic co-ordinates can be determined. To exploit this versatility, a model of anterior cerebral artery occlusion has been developed, using stereotaxic injection of endothelin-1 to bilaterally occlude the ACA (Marston et al., 1995b), which results in an 80 % reduction of blood flow in the territory of the ACA (Sharkey et al., 1997). The development of ACA occlusion will permit the opportunity to verify the efficacy of various treatments in arterial territories other than the MCA.
Investigation of the behavioural consequences of middle cerebral arterial occlusion have provided a criterion in addition to quantitative histopathological assessment, by which to evaluate neuroprotective efficacy. Treatments such as neural transplants, enriched laboratory housing environments and growth factors have been demonstrated to facilitate behavioural recovery after the acute stage of ischemic cell death in the absence of a decrease in the extent of the infarct (Grabowski et al., 1995; Kawamata et al., 1996). Therefore, understanding of the behavioural consequences of MCA occlusion has an important role in establishing the characteristics of the model and response to a variety of treatment strategies. Similarly, in characterising the ACA occlusion model, an important objective is to establish the behavioural impairments following ACA occlusion.
The vascular territory of the ACA encompasses Zilles’s areas Cgl, Cg2, Cg3, IL, MO, VO, anteromedial Fr2 (Zilles, 1990) and extends subcortically to include septum, medial striatum and vertical diagonal band of Broca (Scremin, 1995). Occlusion of the ACA does not typically result in damage to primary motor (Frl and Fr3) or
lateral/posterior Fr2. The ischemic lesion following bilateral ACA occlusion involves medial prefrontal cortex in the rat, cortex which receives input from the mediodorsal thalamus (Groenewegen, 1988; Krettek & Price, 1977; Leonard, 1969), which has been used to define the rat homologue of primate prefrontal cortex (Kolb, 1990a; Van Eden et
Selective lesions of rat mediofrontal cortex have identified a range of deficits in spatial and delayed stimulns-response tasks (De Bruin et al., 1994; Granon & Poucet,
1995; Granon et al., 1994; Kolb, 1990a; Kolb et al., 1994; Kolb & Cioe, 1996; Mogensen & Holm, 1994) which are consistent with mediofrontal involvement in response
inhibition (Sokolowski & Salamone, 1994), selection (Granon et al., 1996; Barter et al., 1996) and response flexibility (Kolb et al., 1994). Selective excitotoxic lesions of anteromedial prefi-ontal cortex also result in response perseveration (Kolb et al., 1994;
1974; Muir et al., 1996b; Sanchez-Santed et al., 1997), while a more posterior prefrontal lesion has been reported to cause an increase in anticipatory responses, which is perhaps indicative of a failure to inhibit responses (Muir et al., 1996b). Response initiation (but not execution) also appears to be impaired in reaction time tasks, following prefrontal dopamine depletion (Hauber et al., 1994) and prefrontal excitotoxic lesions (Muir et al.,
1996b). These results in rodents are consistent with the observed consequences of prefrontal lesions in man, which include impulsive behaviour, slowed response initiation, increased distractibility and a tendency to perseverate (Alivisatos & Milner, 1989; Bogousslavsky, 1994; Degos et al., 1993; Rueckert & Grafinan, 1996; Viallet et al.,
1995). The behavioural consequences of ACA occlusion will thus, be investigated using simple and choice reaction tasks which assess a variety of functions including response selection, motivation, memory, learning and attention. The use of reaction time to measure performance provides a particularly sensitive measure of brain function (Godefroy et al., 1994) in addition to accuracy of performance measures.
The first experiment assesses the capacity to interpret motivationally salient cues, using a simple reaction time task (see Brown et al. 1996). The simple reaction time task used in the current experiment includes cues indicating proximity of reward. The task design maintains the same respoi^e requirements for every trial while varying the cues to indicate proximity of reward. Difficulty in initiating or executing movement can be distinguished from a deficit specific to the disruption of response vigour (Brown & Bowman, 1995) influenced by the visual cues. The test will permit an investigation of the involvement of mediofrontal cortex (which includes anterior cingulate) in motivational processes. Devinsky et al. (1995) in a recent review of the functions of primate anterior cingulate concludes “Overall, anterior cingulate appears to play a crucial role in
participate in a limbic-motor circuit underlying motivation to action. Following
postoperative testing, performance was also examined in the same multiple ratio schedule without the cues, to confirm that the cues continued to influence performance in the task. Finally the ability to learn the meaning of cues during reversal was also assessed.
The second experiment assesses attentional function using a test of covert orienting (analogous to the test for humans developed by Posner (1980)). The covert orienting task is capable of detecting a variety of attentional impairments including difficulty in the covert engagement, maintenance, disengagement and shifting of attention (Posner & Petersen, 1990). The task used a choice reaction time test, with peripheral visual cues preceding peripheral visual targets to which the rat was required to make a lateralised response.
Damage to mediofi-ontal cortex in the rat has impaired performance in a task demanding sustained attention (Muir et al., 1996). Furthermore, Parkinson’s disease and droperidol (a dopamine antagonist) have been demonstrated to reduce the effect of invalid cues in humans (Clark et al., 1989; Wright et al., 1990; Yamada et al., 1990) and monkeys (Witte et al., 1992). Wright et al. (1990) and Yamada et al. (1990) have speculated that a failure to maintain attention in the covert orienting task is due to prefrontal dopamine depletion.