Microsphere embolism‐induced cortical cholinergic deafferentation and impairments in attentional performance

Abstract

Ischemic events have been hypothesized to play a critical role on the pathogenesis of dementia and the acceleration of cognitive impairments. This experiment was designed to determine the consequences of microvascular ischemia on the cortical cholinergic input system and associated attention capacities. Injections of microspheres ( approximately 50 microm diameter; approximately 5000 microspheres/100 microL) into the right common carotid artery of rats served as a model of microvascular ischemia and resulted in decreases in the density of cholinergic fibers in the ipsilateral medial prefrontal cortex and frontoparietal areas. Furthermore, dense astrogliosis, indicated by glial fibrillary acidic protein (GFAP) immunohistochemistry, was observed in the globus pallidus, including the areas of origin of cholinergic projections to the cortex. Fluoro-Jade B staining indicated that loss of neurons in the cortex was restricted to areas of microsphere-induced infarcts. Attentional performance was assessed using an operant sustained attention task; performance in this task was previously demonstrated to reflect the integrity and activity of the cortical cholinergic input system. Embolized animals' performance was characterized by a decrease in the animals' ability to detect signals. Their performance in non-signal trials remained unaffected. The residual density of cholinergic axons in prefrontal and frontoparietal areas correlated with the animals' performance. The present data support the hypothesis that microvascular ischemia results in loss of cortical cholinergic inputs and impairs associated attentional performance. Microsphere embolism represents a useful animal model for studying the role of interactions between microvascular disorder and impaired forebrain cholinergic neurotransmission in the manifestation of cognitive impairments.

Nerve Growth Factor Differentially Affects Spatial and Recognition Memory in Aged Rats

“…This hypothesis is consistent with the results of experiments which demonstrated that rats are impaired in the acquisition and retention of high attentionally demanding spatial tasks [82][83][84][85][86]. In addition, studies in rodents [3,50,54] and monkeys [42,54] have demonstrated that selective loss of BF cholinergic nuclei does not disrupt mnemonic abilities but rather indicate attentional defects in learning and memory tests [36,87]. Our results may suggest that the very selective difference observed in OLT could be explained by differences in attentional processes which are enhanced due to protective action of NGF on cholinergic system.…”

Cognitive changes after surgery vs stenting for carotid artery stenosis

“…41,42 In experimental studies, injection of 50-m microspheres into rat carotid arteries resulted in cerebral injury and reduced attentional performance. 43 Manipulation of the carotid artery during surgical or endovascular revascularization causes atheroembolization with consequent silent cerebral microinfarction. 44 Transcranial Doppler monitoring has identified approximately 1000 microemboli during CAS while CEA is associated with eight to 17 times fewer microemboli.…”

Intact Memory in TGF-β1 Transgenic Mice Featuring Chronic Cerebrovascular Deficit: Recovery with Pioglitazone

“…Cerebrovascular insufficiency has been associated with cholinergic and cognitive impairments (Craft et al, 2005), prompting us to examine these parameters in TGF mice featuring cerebrovascular dysfunction. Both the total number of ChAT-positive fibers and terminals ( Figure 5A), as well as the number of perivascular ChAT terminals ( Figure 5B) were comparable between elderly TGF mice and wild-type littermates, and pioglitazone had no effect, indicating the absence of a cholinergic deficit in aged TGF mice, at least with regard to this immunohistochemical assessment.…”

“…We specifically studied arterial responsiveness and proteins regulating vascular structure or function. We also measured the neuronally driven cerebral glucose uptake (CGU) and CBF responses to whisker stimulation, the status of astrocytes involved in synaptic transmission and neurovascular coupling (Haydon and Carmignoto, 2006), cortical cholinergic innervation, not only known for its effect on cognition and CBF but also for its susceptibility to ischemia (Craft et al, 2005), and spatial memory in the Morris water maze. Our results provide new insights into the link between cerebrovascular dysfunction and dementia, and support the use of pioglitazone as a strategy to preserve the cerebral circulation in the context of advanced age, fibrosis, and antioxidant resistance, hence to potentially delay disease progression in vulnerable populations or to improve response to AD therapies.…”