A novel operant testing regimen for multi-construct cognitive characterization of a murine model of Alzheimer's amyloid-related behavioral impairment.

A common method for modeling pathological and behavioral aspects of Alzheimer's disease (AD) is the transgenic mouse. While transgenic strains are often well characterized pathologically, behavioral studies of cognitive deficits often employ a limited set of aversively motivated, spatial learning and memory tests, under brief testing periods. Here we illustrate an alternative operant behavioral methodology to provide a comprehensive characterization under repetitive testing conditions, and with appetitive motivation. In this study, we employed the commonly used Tg2576 murine model of Alzheimer's disease amyloid pathology, since it has been the subject of many previous behavioral studies. In these mice, we compared the learning of simple and complex, as well as spatial and non-spatial rules. The mice were assessed on a progressively more complex and interlocking battery of operant tasks, ranging from simple rule learning to delayed recall, as well as tests of motor and sensory ability. In general, as compared to wild type control mice, within-group variability was high in the Tg2576 mice, and deficits were most apparent in more complex discrimination tasks. Furthermore, a consistent decrease in the rate at which Tg2576 mice completed testing trials was observed, pointing to a potential motivation difference or speed-accuracy tradeoffs as a defining characteristic of this strain under these test conditions. Using sensitive adjusting retention interval procedures, it was also possible to isolate a difference in retention interval and separate it from non-mnemonic processes. Overall, these experiments demonstrate the utility of this novel operant approach for characterizing the cognitive deficits of transgenic murine models of dementia.

Intracerebroventricular administration of galanin or galanin receptor subtype 1 agonist M617 induces c-Fos activation in central amygdala and dorsomedial hypothalamus.

The neuropeptide galanin and galanin receptors are widespread throughout cortical, limbic and midbrain areas implicated in reward, learning/memory, pain, drinking and feeding. While many studies have shown that galanin produces a variety of presynaptic and post-synaptic responses, work studying the effects of galanin on neural activation is limited. The present study examined patterns of c-Fos immunoreactivity resulting from intracerebroventricular administration of galanin versus saline injection in awake rats. An initial comprehensive qualitative survey was conducted to identify regions of high c-Fos expression followed up with quantitative analysis. Galanin induced a significant increase in c-Fos levels relative to saline-treated controls in dorsomedial hypothalamus and in the central nucleus of the amygdala. This pattern of activation was also produced by galanin receptor type 1 agonist M617. The present findings confirm that galanin upregulates c-Fos activation in hypothalamic nuclei, and supports roles for galanin in central amygdala-mediated regulation of stress-responses, food intake, and Pavlovian conditioning.