Unlike “overt” stroke which affects the large vessels and produces paralysis or weakness, “covert stroke” arises from small vessel disease often as a result of hypertension, that eventually leads to diffuse white matter injury, small lacunar infarcts and vascular cognitive impairment (VCI). A barrier to the development of treatments for covert stroke and the associated VCI is the lack of an animal model. Such a model could pave the way for testing interventions such as exercise or drug therapies to slow or prevent cognitive decline. We describe a model of VCI that incorporates several key clinical pathological features, namely white matter damage, lacunar infarcts, dietary co-morbidity factors and cognitive impairment. We have used this model to assess novel regimens of physical activity (PA) and cognitive activity (CA) in attempts to attenuate cognitive dysfunction. In Experiment 1 we exposed 6 mo old rats to a high fat, high sugar diet (HFS) prior to permanent bilateral common artery occlusion (2-VO) under isoflurane anesthesia (4.0% induction, 2.5% maintenance) followed by topical 2.0% xylocaine. Following recovery from surgery the rats were randomized to 5 groups: Sham + control diet (n=6); Sham + HFS (N=6); 2-VO + control diet (n=12); 2-VO + HFS (n=10) and 2-VO + PA (wheel running) + CA (exposure to Hebb-Williams maze) (n=11) 5 days per week. All groups were tested on the Morris water maze 4, 8, 16 and 24 weeks post-surgery. At the end of behavioural testing rats were humanely killed under 4.0% isoflurane anesthesia by exsanguination. Perfused brains were removed and processed for quantification of hippocampal CA1 cells using unbiased stereological procedures. At 16 weeks post surgery, 2-VO animals showed significant learning and memory deficits in the Morris water maze, independent of diet. These impairments were associated with CA1 hypertrophy. Rehabilitation, consisting of PA + CA, significantly attenuated cognitive deficits at 16 and 24 weeks. Interestingly, rehabilitation also normalized hippocampal CA1 soma size (area and volume) to that of control animals, independent of cell number. These results suggest that a combination of physical and cognitive exercise may be helpful in slowing the progression of VCI. In Experiment 2, we sought to further refine this 2-VO VCI model by introducing a small lacunar stroke in the mediodorsal thalamic (MD) nucleus using intracerebral injections of Endothelin-1 (0.25µl, 400pmol/µl) in middle-aged rats (n=150) using the same anesthetic and surgical procedures as in Experiment 1. Executive function was assessed using an attention set-shifting paradigm (Birrell & Brown 2000) at intervals post-surgery. Blood pressure (BP) and glucose tolerance were examined during this time period and microvascular function was determined using 2-photon imaging. Lesions of MD resulted in deficits in extradimensional set shifting strategy while HFS animals (diet exposure of 9 months) showed impairments in intra- and extradimenional set shifting ability, elevated BP (p<0.03), altered glucose homeostasis (p<0.02) and increased blockage of red blood cells in small cerebral vessels (p<0.05). There was also white matter atrophy in HFS exposed rats (p<0.04). Results show that chronic HFS diets in middle-aged rats causes hypertension, decreased cerebrovascular compliance and white matter atrophy. These effects manifested as general impairments in set shifting ability and perseverative errors. In contrast, the MD lacunes produced a selective impairment in extradimensional set shifting. In summary, we have described an animal model of VCI that includes aspects of aging, metabolic disturbances, cardiovascular and small vessel disease. Importantly, these animals experience profound executive dysfunction following a unilateral, small (0.363 mm3) lacunar infarct in the MD, an area commonly affected in humans with small vessel disease (Longstreth et al., 1998; Carey et al., 2008). This animal model, including the co-morbidities, may be useful in developing treatment approaches to slow or offset the development of executive dysfunction arising from silent stroke.