Abstract
Caloric restriction by fasting has been implicated to facilitate synaptic plasticity and promote contextual learning. However, cellular and molecular mechanisms underlying the effect of fasting on memory consolidation are not completely understood. We hypothesized that fasting-induced enhancement of synaptic plasticity was mediated by the increased signaling mediated by CREB (cAMP response element binding protein), an important nuclear protein and the transcription factor that is involved in the consolidation of memories in the hippocampus. In the in vivo rat model of 18 h fasting, the expression of phosphorylated CREB (pCREB) was examined using anti-phospho-CREB (Ser133) in cardially-perfused and cryo-sectioned rat brain specimens. When compared with control animals, the hippocampus exhibited up to a twofold of increase in pCREB expression in fasted animals. The piriform cortex, the entorhinal cortex, and the cortico-amygdala transitional zone also significantly increased immunoreactivities to pCREB. In contrast, the amygdala did not show any change in the magnitude of pCREB expression in response to fasting. The arcuate nucleus in the medial hypothalamus, which was previously reported to up-regulate CREB phosphorylation during fasting of up to 48 h, was also strongly immunoreactive and provided a positive control in the present study. Our findings demonstrate a metabolic demand not only stimulates cAMP-dependent signaling cascades in the hypothalamus, but also signals to various limbic brain regions including the hippocampus by activating the CREB signaling mechanism. The hippocampus is a primary brain structure for learning and memory. It receives hypothalamic and arcuate projections directly from the fornix. The hippocampus is also situated centrally for functional interactions with other limbic cortexes by establishing reciprocal synaptic connections. We suggest that hippocampal neurons and those in the surrounding limbic cortexes are intimately involved in the metabolism-dependent plasticity, which may be essential and necessary for successful achievement of adaptive appetitive behavior.
Highlights
The family of CREB transcription factors are involved in a variety of biological processes including the development and plasticity of the nervous system (Mayr and Montminy, 2001; Pittenger et al, 2002)
We observed a significant increase of phosphorylated form of CREB (pCREB) expression in the arcuate nucleus in the fasted rats for 18 h (Figure 1)
The present study demonstrated that (1) major limbic cortexes of the rat brain, the hippocampus, the entorhinal cortex, the piriform cortex, and the amygdalo-cortical zone, responded to an increased metabolic demand (18 h of fasting) by stimulating the activity of CREB increasing the expression level of pCREB; (2) the magnitude of increase in the pCREB expression in response to increased metabolic demand varied among the limbic cortexes; and (3) an intrinsic level of CREB activities, measured by the expression level of pCREB in control animals, varied among different limbic cortexes exhibiting a structure-specific level of CREB homeostasis
Summary
The family of CREB (cAMP response element-binding protein) transcription factors are involved in a variety of biological processes including the development and plasticity of the nervous system (Mayr and Montminy, 2001; Pittenger et al, 2002). Identification of a phosphorylated form of CREB (pCREB) is a reliable assay for predicting the occurrence of functional plasticity, learning, and memory in neurons. The magnitude of the expression of pCREB changes depending on the metabolic demand (Sheriff et al, 1997). The expression of pCREB increases in the orexigenic peptide-producing neurons in the arcuate nucleus (Morikawa et al, 2004; Shimizu-Albergine et al, 2001). The elevated expression of pCREB persists until feeding is initiated and metabolic balance is restored. This suggests that CREB is constitutively active in the arcuate nucleus of the hypothalamus during starvation
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