Increased aortic stiffness in the insulin-resistant Zucker fa/fa rat.

Accumulating clinical evidence indicates increased aortic stiffness, an independent risk factor for cardiovascular and all-cause mortality, in type 2 diabetic and glucose-intolerant individuals. The present study sought to determine whether increased mechanical stiffness, an altered extracellular matrix, and a profibrotic gene expression profile could be observed in the aorta of the insulin-resistant Zucker fa/fa rat. Mechanical testing of Zucker fa/fa aortas showed increased vascular stiffness in longitudinal and circumferential directions compared with Zucker lean controls. Unequal elevations in developed strain favoring the longitudinal direction resulted in a loss of anisotropy. Real-time quantitative PCR and immunohistochemistry revealed increased expression of fibronectin and collagen IV alpha 3 in the Zucker fa/fa aorta. In addition, expression of transforming growth factor-beta and several Smad proteins was increased in vessels from insulin-resistant animals. In rat vascular smooth muscle cells, 12-18 h of exposure to insulin (100 nmol/l) enhanced transforming growth factor-beta1 mRNA expression, implicating a role for hyperinsulinemia in vascular stiffness. Thus there is mechanical, structural, and molecular evidence of arteriosclerosis in the Zucker fa/fa rat at the glucose-intolerant, hyperinsulinemic stage.

Post-training excitotoxic lesions of the dorsal hippocampus attenuate forward trace, backward trace, and delay fear conditioning in a temporally specific manner.

The present study sought to determine whether post-training excitotoxic lesions of the dorsal hippocampus would disrupt retention of fear conditioned using a trace procedure. Rats were trained using one of six procedures. Forward trace conditioning consisted of 10 trials in which a 16-s tone conditional stimulus (CS) was followed by a 28-s stimulus-free trace interval and then a mild footshock unconditional stimulus (US). We used two forms of delay conditioning where the tone and footshock co-terminated. Short delay used a 16-s tone and long delay used a 46-s tone. Backward trace conditioning was the same as forward trace, except that the order of the CS and US was reversed. CS-only and US-only were similar to forward trace except that the footshock or tone, respectively, was eliminated. One day later, animals received either an N-methyl-D-aspartate (NMDA)-induced lesion of the dorsal hippocampus or sham surgery. One week later, the rats were tested for freezing to the tone in a novel context. The next day, they were tested for freezing to the original training context. Hippocampal lesioned trace conditioned rats showed significantly less freezing during the tone compared with their sham lesioned controls. The lesion did not affect freezing during the tone in delay conditioning, nor in the other training conditions. During the 1-min period after tone offset, there was a trend in all hippocampal lesioned animals toward a deficit in freezing, compared with their corresponding sham lesioned controls, although only short delay, forward and backward trace groups showed a significant deficit. Hippocampal lesions also attenuated contextual conditioning. Thus, the hippocampus is critical for the consolidation and/or expression of a trace fear conditioned stimulus.