AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

Abstract

Both the formation of long-term memory (LTM) and dendritic spine growth that serves as a physical basis for the long-term storage of information require de novo protein synthesis. Memory formation also critically depends on transcription. Adenosine monophosphateactivated protein kinase (AMPK) is a transcriptional regulator that has emerged as a major energy sensor that maintains cellular energy homeostasis. However, still unknown is its role in memory formation. In the present study, we found that AMPK is primarily expressed in neurons in the hippocampus, and then we demonstrated a time-dependent decrease in AMPK activity and increase in mammalian target of rapamycin complex 1 (mTORC1) activity after contextual fear conditioning in the CA1 but not CA3 area of the dorsal hippocampus. Using pharmacological methods and adenovirus gene transfer to bidirectionally regulate AMPK activity, we found that increasing AMPK activity in the CA1 impaired the formation of long-term fear memory, and decreasing AMPK activity enhanced fear memory formation. These findings were associated with changes in the phosphorylation of AMPK and p70s6 kinase (p70s6k) and expression of BDNF and membrane GluR1 and GluR2 in the CA1. Furthermore, the prior administration of an mTORC1 inhibitor blocked the enhancing effect of AMPK inhibition on fear memory formation, suggesting that this negative regulation of contextual fear memory by AMPK in the CA1 depends on the mTORC1 signaling pathway. Finally, we found that AMPK activity regulated hippocampal spine growth associated with memory formation. In summary, our results indicate that AMPK is a key negative regulator of plasticity and fear memory formation.

Intermittent metabolic switching, neuroplasticity and brain health

“…Recent findings suggest that AMPK also mediates adaptive responses of neuronal networks to IMS. Daily treadmill training in rats results in activation of AMPK in hippocampal cells 87 , and pharmacological inhibition of AMPK enhances contextual fear memory in mice 88 . AMPK activity is increased in response to fasting and is required for fasting-induced dendritic spine formation and synaptic functional plasticity in hypothalamic arcuate nucleus neurons 89 .…”

EphB2 in the Medial Prefrontal Cortex Regulates Vulnerability to Stress

“…Locomotor activity was measured using the open field test as previously described (Han et al, 2015;Xue et al, 2015). Briefly, the apparatus consisted of a 42 × 42 × 42 cm 3 square arena that was divided into 25 equal squares (8.4 × 8.4 cm 2 ) on the floor of the arena.…”

“…The Golgi-Cox impregnation procedure was based on a previous study (Han et al, 2015;Restivo et al, 2005). The mice were perfused with 0.9% saline, and the brains were removed and placed in Golgi-Cox solution (1.04% potassium dichromate, 1.04% mercury chloride, and 0.83% potassium chromate, dissolved in double-distilled water) at room temperature for 14 days.…”

“…The locations of the cannulae are shown in Supplementary Figure S8. Additionally, the brains were coronally sectioned at 20 μm using a sliding microtome, and the brain slices were counterstained with DAPI and examined using an Olympus BX53 fluorescent microscope to evaluate enhanced green fluorescent protein expression in the mPFC and OFC (Han et al, 2015;Xue et al, 2015). Mice with misplaced cannulae were excluded from the statistical analysis.…”

Calpain-GRIP Signaling in Nucleus Accumbens Core Mediates the Reconsolidation of Drug Reward Memory

“…The injectors were kept in the cannula for 1 additional minute to allow for drug diffusion into the tissue. The injectors were then removed and the stylets were replaced (Khoutorsky et al, 2013;Han et al, 2016).…”