The M1 muscarinic agonist CI-1017 was administered intravenously to aging rabbits on a daily basis before and during hippocampally dependent trace eyeblink conditioning sessions. Circulating levels ...of CI-1017 were significantly related to the drug dose. The drug was found to significantly increase the rate and amount of learning in a dose-dependent manner with no significant effects on the amplitude, area, or latency of conditioned responses. There was no evidence of pseudoconditioning at the highest drug concentration, and the minimally effective dose produced only mild and temporary hypersalivation as a side effect. CI-1017 (10 microM) was also found to increase the excitability of CA1 pyramidal neurons recorded from hippocampal slices from young and aging naive rabbits as measured by changes in spike-frequency adaptation and the postburst afterhyperpolarization. These biophysical changes were reversed with either atropine (1 microM) or pirenzepine (1 microM). These results suggest that M1 agonists ameliorate age-related learning and memory impairments at least in part by reducing the afterhyperpolarization and spike-frequency adaptation of hippocampal pyramidal neurons and that M1 agonists may be an effective therapy for reducing the cognitive deficits that accompany normal aging and/or Alzheimer's disease.
The perirhinal cortex (PRh) is an area in the medial temporal lobe that receives inputs from the ventral visual stream, and projects to the entorhinal cortex, hippocampus, and the lateral prefrontal ...cortices. There is already preliminary evidence to suggest that the PRh is important to support the normal development of recognition memory (Weiss & Bachevalier, 2016; Zeamer et al., 2015). However there remain significant questions regarding the degree to which perceptual difficulties, retarded familiarity processes, impaired working memory, and difficulty resolving proactive interference may have contributed to the impaired performance of the Neo-PRh monkeys on the recognition tasks reported earlier. This dissertation presents three manuscripts that describe an attempt to clarify these issues. Study 1 provides evidence that neonatal PRh lesions had a significant impact on the development of familiarity mechanisms, but spared visual perception. Study 2 provides evidence that the same Neo-PRh lesions did not alter working memory processes per se, but rather increased the tendency to make perseverative errors. Study 3 provides evidence that impaired cognitive flexibility was a likely source of the increased perseverative errors made by Neo-PRh monkeys when performing WM tasks with proactive interference. Taken together, data from these studies advance our understanding of the fundamental cognitive processes that were impacted by the Neo-PRh lesions by highlighting the critical role this area plays in the development of recognition memory and executive function.
The hippocampus is importantly involved in learning and memory, and is severely impacted by aging. In
in vitro hippocampal slices, both the post-burst afterhyperpolarization (AHP) and spike-frequency ...accommodation are reduced in hippocampal pyramidal neurons after hippocampally-dependent trace eyeblink conditioning, indications of increased cellular excitability. The AHP results from the activation of outward potassium currents, including sI
AHP and muscarinesensitive I
M. The AHP is significantly increased in aging hippocampal neurons, potentially contributing to age-associated learning deficits. Compounds which reduce the AHP and spike-frequency accommodation could facilitate learning in normal aging or in age-associated dementias such as Alzheimer's disease. The cholinesterase inhibitor metrifonate enhances trace eyeblink conditioning by aging rabbits and reduces the AHP and accommodation in hippocampal CA1 neurons in a dose-dependent manner. These reductions are mediated by muscarinic cholinergic transmission as they are blocked by atropine. Hippocampal neurons from metrifonate treated but behaviorally naive rabbits were more excitable and not desensitized to the effects of metrifonate since the AHP and accommodation were further reduced when metrifonate was bath applied to the neurons. These observations suggest that the facilitating effect of chronic metrifonate on acquisition of hippocampally dependent tasks is mediated at least partially by increasing the baseline excitability of CA1 pyramidal neurons. The issue of whether learning can be facilitated with muscarinic cholinergic agonists, in addition to cholinesterase inhibitors, was addressed by training aging rabbits during intravenous treatment with the M
1 agonist CI1017. A dose-dependent enhancement of acquisition was observed, with rabbits receiving 1.0 or 5.0 mg/ml CI1017 showing comparably improved learning rates as those receiving 0.5 mg/ml or vehicle. Sympathetic side effects, mainly excess salivation, were seen with the 5.0 mg/ml dose. Post-training evaluations suggested that the effective doses of CI1017 were enhancing responsivity to the tone conditioned stimulus. These studies suggest that muscarinic cholinergic neurotransmission is importantly involved in associative learning; that learning in aging animals may be facilitated by enhancing cholinergic transmission; and that the facilitation may be mediated through actions on hippocampal neurons.
Screening of individuals who have a high risk of pancreatic ductal adenocarcinoma (PDAC), because of genetic factors, frequently leads to identification of pancreatic lesions. We investigated the ...incidence of PDAC and risk factors for neoplastic progression in individuals at high risk for PDAC enrolled in a long-term screening study.
We analyzed data from 354 individuals at high risk for PDAC (based on genetic factors of family history), enrolled in Cancer of the Pancreas Screening cohort studies at tertiary care academic centers from 1998 through 2014 (median follow-up time, 5.6 years). All subjects were evaluated at study entry (baseline) by endoscopic ultrasonography and underwent surveillance with endoscopic ultrasonography, magnetic resonance imaging, and/or computed tomography. The primary endpoint was the cumulative incidence of PDAC, pancreatic intraepithelial neoplasia grade 3, or intraductal papillary mucinous neoplasm with high-grade dysplasia (HGD) after baseline. We performed multivariate Cox regression and Kaplan-Meier analyses.
During the follow-up period, pancreatic lesions with worrisome features (solid mass, multiple cysts, cyst size > 3 cm, thickened/enhancing walls, mural nodule, dilated main pancreatic duct > 5 mm, or abrupt change in duct caliber) or rapid cyst growth (>4 mm/year) were detected in 68 patients (19%). Overall, 24 of 354 patients (7%) had neoplastic progression (14 PDACs and 10 HGDs) over a 16-year period; the rate of progression was 1.6%/year, and 93% had detectable lesions with worrisome features before diagnosis of the PDAC or HGD. Nine of the 10 PDACs detected during routine surveillance were resectable; a significantly higher proportion of patients with resectable PDACs survived 3 years (85%) compared with the 4 subjects with symptomatic, unresectable PDACs (25%), which developed outside surveillance (log rank P < .0001). Neoplastic progression occurred at a median age of 67 years; the median time from baseline screening until PDAC diagnosis was 4.8 years (interquartile range, 1.6–6.9 years).
In a long-term (16-year) follow-up study of individuals at high-risk for PDAC, we found most PDACs detected during surveillance (9/10) to be resectable, and 85% of these patients survived for 3 years. We identified radiologic features associated with neoplastic progression.
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