Reports from the forefront of neurological research were featured at Neuroscience 2008, the 38th annual meeting of the Society for Neuroscience, held November 15–19 in Washington, DC. More than 31,000 attendees from around the world gathered to exchange perspectives, engage in professional development, and share updates on cutting-edge lines of investigation. [Editor’s Note: Abstracts presented at the Society for Neuroscience meeting do not undergo the peer review process. Therefore, results presented at the meeting are preliminary and are subject to change upon publication.]

Frida Ekholm Pettersson, Uppsala University, Uppsala, Sweden, described experiments suggesting that amyloid-beta protofibrils may be a promising target for drug therapy in Alzheimer’s disease (AD). She and her coworkers found that levels of soluble protofibrils were elevated in the brains of transgenic mouse models of AD, even before the deposition of amyloid plaque. Moreover, higher protofibril levels correlated with greater degrees of early cognitive impairment. Additional work using Tris-buffered saline extracts from AD human brains revealed that levels of protofibrils in the cortex were comparable to those observed in the transgenic mouse model. In contrast, protofibril levels in extracts from healthy control brains were below the level of detection.

Chronic stress is known to cause dendritic remodeling in the hippocampus, likely due to a loss of dendritic spines. Investigators have now demonstrated, for the first time, that acute stress has similar effects, according to Tallie Baram, University of California at Irvine. She explained that adult transgenic mice exposed to a 5-hour period of restraint and noise stress exhibited a rapid decrease in dendritic spine density. Notably, such reductions in spine density did not occur in mice infused with NBI 30775, a selective antagonist of the corticotropin-releasing hormone (CRH) receptor CRFR1, 30 minutes prior to the induction of stress. Previous experiments had shown CRH to be released in the hippocampus in response to stress, leading to rapid spine loss as well as activation of CRFR1 on pyramidal neurons, which could be blocked by selective CRFR1 antagonism. The recent study further elucidated the role of CRH through the use of 2-photon live imaging, which revealed that spine retraction increased within minutes following infusion of the peptide to organotypic cultures of hippocampus. This observation suggests that selective acceleration of spine retraction may be the mechanism by which CRH promotes dendritic spine loss in the presence of stress.

Other workers have discovered that the hippocampus actually shrinks in response to chronic stress. Fred J. Helmstetter, University of Wisconsin, Milwaukee, described a study in which Long-Evans rats underwent 6 hours of restraint and immobilization, including lack of access to food or water, daily for 21 days. Comparison of T1-weighted brain images obtained on magnetic resonance imaging before and after the period of stress revealed that hippocampal volume decreased by approximately 3%. No volume changes were noted in other brain structures or in the adrenal gland. The animals exposed to chronic stress also exhibited decreases in food intake and body weight compared to controls, which were likewise deprived of food and water for 6 hours per day but were not restrained or immobilized. Dr. Helmstetter pointed out that the link between stress and decreased hippocampal volume has been controversial despite suggestions of such a correlation in patients with posttraumatic stress disorder, such as combat veterans. Because experimental imaging studies exploring the causal link between stress and hippocampal changes are not feasible in humans, the results of this animal study are of particular interest.

Data from animal models of Parkinson’s disease (PD) have demonstrated that nicotine prevents dopaminergic deficits when administered before, but not after, nigrostriatal insult, according to Neeraja Parameswaran, Parkinson’s Institute, Sunnyvale, CA. In view of the fact that the incidence of PD is consistently lower in tobacco users, previous investigations had sought to pinpoint the component responsible for this apparent neuroprotective effect. This work had identified nicotine as a likely candidate. Subsequent studies confirmed decreases in dopaminergic deficits when nicotine was administered prior to toxic insult in animal models of PD. Still unknown, however, is whether nicotine might also be beneficial if administered after insult.

To shed light on this question, Dr. Parameswaran and colleagues observed the effects of administering nicotine before or after brain lesioning in both rat and monkey models. In rats, nicotine pretreatment attenuated lesioninduced striatal dopaminergic deficits (including decreases in striatal dopaminergic transporter) and reductions in the expression of nicotinic receptors. No such benefits were evident when nicotine was administered for several weeks beginning 2 weeks after lesioning. Similarly, markers of nigrostriatal damage (such as dopamine levels) and expression of presynaptic nicotinic receptors partially improved in monkeys pretreated with nicotine but not in those treated 2 months after lesioning. The investigators concluded that nicotine is neuroprotective rather than “neurorestorative.”