Purpose: Stroke is the third leading cause of death and permanent disability in the United States, often producing long-term cognitive impairments, which are not easily recapitulated in animal models. The goals of this study were to assess whether: (1) the endothelin-1 (ET-1) model of chronic stro ke produced discernable cognitive deficits; (2) a spatial operant reversal task (SORT) would accurately measure memory deficits in this model; and (3) bone-marrow-derived mesenchymal stem cells (BMMSCs) could reduce any observed deficits. Methods: Rats were given unilateral intracerebral injections of vehicle or ET-1, a stroke-inducing agent, near the middle cerebral artery. Seven days later, they were given intrastriatal injections of BMMSCs or vehicle, near the ischemic penumbra. The cognitive abilities of the rats were assessed on a novel SORT, which was designed to efficiently distinguish cognitive deficits from potential motoric confounds. Results: Rats given ET-1 had significantly more cognitive errors at six weeks post-stroke on the SORT, and that these deficits were attenuated by BMMSC transplants. Conclusions: These findings indicate that: (1) the ET-1 model produces chronic cognitive deficits; (2) the SORT efficiently measures cognitive deficits that are not confounded by motoric impairment; and (3) BMMSCs may be a viable treatment for stroke-induced cognitive dysfunction.

The effects of the dopamine D1 receptor agonist, SKF-38393, on the levels of mRNAs encoding for the proto-oncogene c-fos and the GABA-synthesizing enzyme glutamate decarboxylase (GAD65) were measured by in situ hybridization histochemistry in the striatum of adult rats depleted of dopamine as neonates. c-fos mRNA levels exhibited a prominent increase following the acute systemic administration of SKF-38393 in dopamine-depleted but not in normal rats. Double-labeling in situ hybridization histochemistry using a radioactive c-fos probe and a digoxigenin-labeled preproenkephalin (PPE) cRNA probe indicated that c-fos mRNA levels were increased by SKF-38393 exclusively in a subpopulation of PPE-unlabeled neurons. Dopamine-depleted rats exhibited an increase in GAD65 mRNA levels relative to control rats. Acute administration of SKF-38393 did not alter GAD65 mRNA levels in control or in dopamine-depleted rats. Our results demonstrate that an acute administration of a D1-receptor agonist induces c-fos but not GAD65 gene expression in a subpopulation of presumed striato-nigral/entopeduncular neurons. They also suggest that the D1-dependent behavioral plasticity exhibited by adult rats depleted of dopamine as neonates is not the result of an altered activation of the two subpopulations of striatal efferent neurons.

The effects of 6-hydroxydopamine (6-OHDA)-induced lesions of the dorsal noradrenergic bundle (DNB) were assessed in animals trained in a task designed to measure sustained attention, or vigilance. Infusions of 6-OHDA reduced frontal cortical noradrenaline contents but did not significantly affect striatal and hypothalamic noradrenaline contents. The performance of lesioned animals did not differ significantly from sham-lesioned controls. The performance of both the lesioned and sham-lesioned animals was impaired by the presentation of a visual distractor and by a decrease in the probability for a signal. The results from this study largely coincide with the results from previous studies on the effects of noradrenergic lesions on various aspects of attention. In contrast to the attentional functions assessed in this experiment, the ability to detect and select stimuli that are associated with activation of sympathetic functions is hypothesized to be sensitive to the effects of DNB lesions.