ABSTRACT:The cytokine interleukin-1 (IL-1) is produced by peripheral immune cells as well as glia and neurons within the brain; it plays a major role in immune to brain communication and in modulation of neural, neuroendocrine, and behavioral systems during illness. Although previous studies demonstrated that excess levels of IL-1 impaired memory processes and neural plasticity, it has been suggested that physiological levels of IL-1 are involved in hippocampal-dependent memory and long-term potentiation (LTP). To examine this hypothesis, we studied IL-1 receptor type I knockout (IL-1rKO) mice in several paradigms of memory function and hippocampal plasticity. In the spatial version of the water maze test, IL-1rKO mice displayed significantly longer latency to reach a hidden platform, compared with wild-type controls. Furthermore, IL-1rKO exhibited diminished contextual fear conditioning. In contrast, IL-1rKO mice were similar to control animals in hippocampal-independent memory tasks; i.e., their performance in the visually guided task of the water maze and the auditory-cued fear conditioning was normal. Electrophysiologically, anesthetized IL-1rKO mice exhibited enhanced paired-pulse inhibition in response to perforant path stimulation and no LTP in the dentate gyrus. In vitro, decreased paired-pulse responses, as well as a complete absence of LTP, were observed in the CA1 region of hippocampal slices taken from IL-1rKO mice compared with WT controls. These results suggest that IL-1 contributes to the regulation of memory processes as well as short-and long-term plasticity within the hippocampus. These findings have important implications to several conditions in humans, which are associated with long-term defects in IL-1 signaling, such as mutations in the IL-1 receptor accessory protein-like gene, which are involved in a frequent form of X-linked mental retardation.

Neurons, astrocytes, and blood vessels are organized in functional “neurovascular units” in which the vasculature can impact neuronal activity and, in turn, dynamically adjust to its change. Here we explored different mechanisms by which VEGF, a pleiotropic factor known to possess multiple activities vis-à-vis blood vessels and neurons, may affect adult neurogenesis and cognition. Conditional transgenic systems were used to reversibly overexpress VEGF or block endogenous VEGF in the hippocampus of adult mice. Importantly, this was done in settings that allowed the uncoupling of VEGF-promoted angiogenesis, neurogenesis, and memory. VEGF overexpression was found to augment all three processes, whereas VEGF blockade impaired memory without reducing hippocampal perfusion or neurogenesis. Pertinent to the general debate regarding the relative contribution of adult neurogenesis to memory, we found that memory gain by VEGF overexpression and memory impairment by VEGF blockade were already evident at early time points at which newly added neurons could not yet have become functional. Surprisingly, VEGF induction markedly increased in vivo long-term potentiation (LTP) responses in the dentate gyrus, and VEGF blockade completely abrogated LTP. Switching off ectopic VEGF production resulted in a return to a normal memory and LTP, indicating that ongoing VEGF is required to maintain increased plasticity. In summary, the study not only uncovered a surprising role for VEGF in neuronal plasticity, but also suggests that improved memory by VEGF is primarily a result of increasing plasticity of mature neurons rather than the contribution of newly added hippocampal neurons.

To examine the effects of exposure to post-weaning pre-puberty (juvenile) stress on the emotional and cognitive abilities in response to exposure to stress in adulthood, we first exposed rats to a platform stress at the age of 28 d. Two months later the rats were exposed to acute swim stress. Rats exposed to both stressors showed a higher level of anxiety (as measured both in open-field and startle response tests) than controls or rats exposed to either the juvenile or the adulthood stressor. In the Morris water-maze, rats that were exposed to both juvenile and adulthood stress performed better than the other groups. In a second experiment we verified that the effect of the juvenile stress was indeed age-dependent. One group was exposed at the age of 26-28 d and again at the age of 60 d (juvenile + adulthood stress); the other group was exposed to the first stressor at the age of 60-62 d and to the second at the age of 90 d [adulthood (60) + adulthood (90) stress]. Juvenile + adulthood stress had a significantly greater effect than exposure to stress twice in adulthood, on anxiety level and on the performance in the water-maze. Finally, in a third experiment we found that the juvenile+adulthood stress group swam faster and tended to explore the central area more than the other groups--a finding that could explain their better performance on the first trial of the spatial task. These results indicate that an exposure to a relatively brief juvenile stressful experience has profound and long-lasting effects on the ability to cope with stress in adulthood.