Neurofibrillary pathology [paired helical filaments (PHFs)] formed by the microtubule-associated protein tau in a hyperphosphorylated form is a major hallmark of Alzheimer's disease and related disorders. The process of tau phosphorylation, thought to be of critical importance for PHF formation, and its potential link to neurodegeneration, however, is not understood very well, mostly because of the lack of a physiological in vivo model of PHF-like tau phosphorylation. Here we describe the formation of highly phosphorylated tau, containing a number of PHF-like epitopes in torpor during hibernation. PHF-like phosphorylation of tau was not associated with fibril formation and was fully reversible after arousal. Distribution of PHF-like tau followed a consistent pattern, being most intense in the entorhinal cortex, hippocampus, and isocortical areas. Within the hippocampus, a particularly high labeling was seen in CA3 pyramidal cells. Somewhat lesser reactivity was present in CA1 neurons while dentate gyrus granule cells were not reactive. Formation of PHF-like tau in CA3 neurons was paralleled by the regression of synaptic contacts of the mossy fiber system terminating on CA3 apical dendrites. Mossy fiber afferentation was re-established during arousal, concomitantly with the decrease of PHF-like tau in CA3 neurons. These findings implicate an essential link between neuronal plasticity and PHF-like phosphorylation of tau. The repeated formation and degradation of PHF-like tau might, thus, represent a physiological mechanism not necessarily associated with pathological effects. Hibernation will, therefore, be a valuable model to study the regulation of PHF-like tau-phosphorylation and its cell biological sequelae under physiological in vivo conditions.

Properties of the circadian and annual timing systems are expected to vary systematically with latitude on the basis of different annual light and temperature patterns at higher latitudes, creating specific selection pressures. We review literature with respect to latitudinal clines in circadian phenotypes as well as in polymorphisms of circadian clock genes and their possible association with annual timing. The use of latitudinal (and altitudinal) clines in identifying selective forces acting on biological rhythms is discussed, and we evaluate how these studies can reveal novel molecular and physiological components of these rhythms.

Many species express endogenous cycles in physiology and behavior that allow anticipation of the seasons. The anatomical and cellular bases of these circannual rhythms have not been defined. Here, we provide strong evidence using an in vivo Soay sheep model that the circannual regulation of prolactin secretion, and its associated biology, derive from a pituitary-based timing mechanism. Circannual rhythm generation is seen as the product of the interaction between melatonin-regulated timer cells and adjacent prolactin-secreting cells, which together function as an intrapituitary "pacemaker-slave" timer system. These new insights open the way for a molecular analysis of long-term timing mechanisms.