Empirical tests of the functional significance of amygdala-based modulation of hippocampal representations: evidence for multiple memory consolidation pathways

This series of experiments evaluated the effects of amygdala damage on the acquisition and long-term retention of variants of the water task, and tested the hypothesis that the amygdala is an essential neural system for consolidation of hippocampal memories. In Experiment 1, rats with large, neurotoxic lesions of the amygdala (AMYG) showed normal acquisition on the standard spatial version of the water task, as well as normal retention and decay rate profiles on the 24-h and 30-day retention probes. In Experiment 2, AMYG rats showed normal one-trial place learning abilities and could retain this one-trial information over a 24 h delay. Experiment 3 showed that the amygdala lesions used in this study were functionally significant because AMYG rats, from Experiment 2, showed impairments in a discriminative fear conditioning to context paradigm. Experiment 4 was a critical test of the idea that the amygdala is a decisive locus for consolidation of hippocampal memories. AMYG rats were trained to sub-asymptotic levels of performance on the standard version of the water task. Following each training session, the subjects were given a post-training peripheral injection of D-amphetamine. A probe test revealed that normal subjects and AMYG rats showed similar post-training memory improvement effects. Taken together, the results show that hippocampal memory consolidation processes do not require amygdala modulation. Arguments for an alternative view are presented suggesting that there are multiple memory consolidation pathways, one of which may depend on amygdala neural circuitry.     

The same dorsal root ganglion neurons innervate uterus and colon in the rat

The purpose of this study was to determine whether primary sensory neurons that innervate the uterus receive convergent input from the colon. To test this, in the rat, cell bodies of colonic and uterine dorsal root ganglia were retrogradely labeled with fluorescent tracer dyes microinjected into the colon/rectum and bilaterally into the uterine horns. Ganglia were harvested, cryoprotected and cut into 20 microm slices to identify positively stained cells for fluorescent microscopy. Up to 5% of neurons were colon-specific or uterus-specific, and 10-15% of labeled ganglion neurons innervate both viscera in the L1, L2, L6 and S1-S3 levels. These results suggest a novel form of visceral sensory integration in the dorsal root ganglion that may underlie comorbidity of many functional pain syndromes.     

Vitamin C reduces spatial learning deficits in middle-aged and very old APP/PSEN1 transgenic and wild-type mice

Alzheimer's disease is a progressive and fatal neurodegenerative disease characterized by a build up of amyloid β (Aβ) deposits, elevated oxidative stress, and deterioration of the cholinergic system. The present study investigated short-term cognitive-enhancing effects of acute intraperitoneal (i.p.) Vitamin C (ascorbate) treatment in APP/PSEN1 mice, a mouse model of Alzheimer's disease. Middle-aged (12 months) and very old (24 months) APP/PSEN1 bigenic and wild-type mice were treated with ascorbate (125 mg/kg i.p.) or the vehicle 1 h before testing on Y-maze spontaneous alternation and Morris water maze tasks. Very old mice performed more poorly on cognitive tasks than middle-aged mice. Ascorbate treatment improved Y-maze alternation rates and swim accuracy in the water maze in both wild-type and APP/PSEN1 mice. Aβ deposits and oxidative stress both increased with age, and acetylcholinesterase (AChE) activity was significantly reduced in APP/PSEN1 compared to wild-type mice. However, the short course of acute ascorbate treatment did not alter Alzheimer-like neuropathological features of plaque deposition, oxidative stress, or AChE activity. These data suggest that ascorbate may have noötropic functions when administered parenterally in high doses and that the mode of action is via an acute, pharmacological-like mechanism that likely modulates neurotransmitter function.     

Systemic nanoparticle paclitaxel (nab-paclitaxel) for in-stent restenosis I (SNAPIST-I): a first-in-human safety and dose-finding study

BACKGROUND: Paclitaxel-eluting stents inhibit restenosis; however, this technology has drawbacks (e.g., stent thrombosis, requirement for long-term antiplatelet therapy, and cost--particularly for patients with multivessel disease). Systemic treatment with a novel 130-nm, albumin-bound particle form of paclitaxel (nab-paclitaxel) has been shown to reduce restenosis in animals. HYPOTHESIS: This study was designed to establish the safety and optimal dose of systemic nab-paclitaxel for reducing in-stent restenosis in humans. If well tolerated, systemic nab-paclitaxel may be used with any available bare-metal stent and at potentially lower cost than drug-eluting stents. METHODS: Patients received nab-paclitaxel 10, 30, 70, or 100 mg/m(2) intravenously after stenting of a single de novo lesion >or= 3 mm in diameter. Study endpoints included safety and major adverse cardiac events (MACE) at 2 and 6 months. RESULTS: Data were obtained for all 23 enrolled patients (mean age 66 +/- 10 years, 74% men, 26% with diabetes). No significant adverse events (AE) were attributable to nab-paclitaxel at 10 or 30 mg/m(2). Moderate neutropenia, moderate sensory neuropathy, and mild to moderate, reversible alopecia occurred only at doses of 70 and 100 mg/m(2); therefore, doses of 70 mg/m(2) or higher were considered unacceptable in this patient population. No MACE were reported at 2 months. At 6 months, 4 target lesion revascularizations (TLR) for restenoses were reported (2 each in the 10- and 100-mg/m(2)-dose groups). CONCLUSIONS: Systemic nab-paclitaxel was well tolerated at doses below 70 mg/m(2) in this group of patients; no unexpected AE were noted. Additional studies are under way to explore intravenous and intracoronary administration of nab-paclitaxel.     

The impact of major surgery on blood coagulation factors and thrombin generation

We studied the blood coagulation system of 14 patients with metastatic malignancies before and after they had undergone major surgery. In addition to measuring a battery of coagulation factors, we assessed the function of the system with assays of whole blood thrombin generation. With the exceptions of factor VIII (fVIII), which increased, and fibrinogen and fIX, which did not change, the activities of all the pro- and anticoagulant proteins were significantly lower postoperatively. However, the thrombin generating capacity of the system was relatively preserved. Although the integral of thrombin activity over time was lower after surgery, the mean peak thrombin concentration was unchanged and the time to clot formation was shortened. Similar changes could be reproduced by lowering the concentrations of pro- and anticoagulant factors together in control blood samples. Therefore, simultaneous reductions in pro- and anticoagulant proteins postoperatively worked to maintain the functional integrity of the blood coagulation system.     

Clinical risk scoring beyond initial troponin values: results from a large, prospective, unselected acute chest pain population

BACKGROUND: Risk stratifying the diverse group of patients who present to hospital with chest discomfort remains challenging. Current clinical risk models, typically derived from selected populations, are limited by their relative complexity and the absence of a well-defined role of troponin. OBJECTIVE: To derive a simple clinical risk score from a large, unselected population of patients with chest discomfort and to delineate the prognostic value of an initial troponin measurement. METHODS: Prospective, consecutive data were collected from patients who presented to a tertiary care hospital. Multivariate analysis was used to identify variables predictive of the primary end point: death, nonfatal myocardial infarction or revascularization at 30 days. Integer values were assigned, generating a risk score to quantify individual patient risk. RESULTS: Among 1054 patients, predictor variables included ST-segment deviation (strongest predictor -- assigned two points), male sex, prior congestive heart failure, three or more cardiac risk factors and prior acetylsalicylic acid use (one point each). There was a progressive increase in events with increasing total score (P<0.0001), with a 15-fold gradient from scores of 0 to 4 and greater. Although a negative troponin measurement was associated with fewer events for all scores, patients with higher scores remained exposed to substantial risk. A negative initial troponin measurement conferred a negative predictive value of 97.3% (95% CI 93.7% to 99.1%) among patients with a risk score of 0. CONCLUSION: Significant 30-day events occurred in patients with elevated risk scores, despite negative initial troponin measurements, emphasizing the importance of clinical risk stratification. This simple clinical risk score, in conjunction with a single troponin I measurement, facilitates triage of patients who present to hospital with chest discomfort.     

A complex associative structure formed in the mammalian brain during acquisition of a simple visual discrimination task: dorsolateral striatum, amygdala, and hippocampus

A review of empirical evidence supporting the multiple memory systems view of the organization of learning and memory in the mammalian brain is presented as a powerful component of a broader foundation of basic scientific information necessary for understanding human behavior. However, it is argued that there are significant gaps in our knowledge about these different learning and memory systems, how they interact with one another, and how they interact with the rest of the brain. To demonstrate how little we know about these complex processes, this article reviews recent evidence showing the complexity of associative structure formed during the acquisition of a simple visual discrimination task. The results show that the dorsolateral striatum is necessary for the acquisition of this task but that both the amygdala and hippocampus incidentally acquire and store information during this training period. A new experiment is also presented showing that rats with complete or partial (dorsal vs. ventral) hippocampal lesions show a retrograde amnesic effect on the simple visual discrimination task despite the fact that these same lesions produce no impairment in the anterograde direction. Evidence is presented in support of one interpretation of this effect suggesting that the retrograde amnesia occurs, at least in part, because the hippocampus acquires a context-specific inhibitory association during original training. Although this representation is not required for acquisition of the task in the anterograde direction, removal of this representation has a disruptive effect on expression of the task.     

Did natural selection for increased cognitive ability in humans lead to an elevated risk of cancer?

Despite the overall genetic similarity that exists between humans and chimpanzees, the species are phenotypically distinct. Among the most notable distinctions are differences in brain size and cognitive abilities. Previous studies have shown that significant differences in gene expression exist between the human and chimpanzee brain. Integration of currently available gene expression data with known metabolic and signaling pathways indicates that the expression of genes involved in the programmed cell death of brain neurons is significantly different between humans and chimpanzees and predictive of a reduced level of neuron apoptosis in the human brain. This pattern of expression is generally maintained in other human organs suggesting that apoptosis is reduced in humans relative to chimpanzees. We propose that a decreased rate of programmed neuron death may have been a consequence of selection for increased cognitive ability in humans. Since reduced apoptotic function is associated with an increased risk of cancer and related diseases, we hypothesize that selection for increased cognitive ability in humans coincidently resulted in an increased risk of cancer and other diseases associated with reduced apoptotic function.