A novel pathway regulates memory and plasticity via SIRT1 and miR-134. SIRT1, a mammalian homologue of the yeast Sir2 protein, plays a complex role in various biological processes, including aging, oxidative stress, metabolism, and circadian rhythms. Recent studies suggest that SIRT1 is involved in normal brain physiology and neurological disorders. This study reveals that SIRT1 modulates synaptic plasticity and memory formation through a microRNA-mediated mechanism. Activation of SIRT1 enhances, while its loss-of-function impairs, synaptic plasticity. These effects are mediated by post-transcriptional regulation of CREB expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit miR-134 expression via a repressor complex containing the transcription factor YY1. Unchecked miR-134 expression following SIRT1 deficiency results in down-regulated expression of CREB and BDNF, thereby impairing synaptic plasticity. These findings demonstrate a novel role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signaling, in which SIRT1 has a direct role in regulating normal brain function, distinct from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of CNS disorders. The study used mutant mice lacking SIRT1 catalytic activity in a brain-specific manner (SIRT1Δ) to evaluate the physiological role of SIRT1 in learning and memory. SIRT1Δ mice exhibited significant decreases in freezing behavior and memory performance in various tasks, including associative memory, novel object recognition, and spatial learning. These results show that SIRT1 has an important role in several forms of memory. Additionally, SIRT1Δ mice showed deficits in long-term potentiation (LTP), a key mechanism of synaptic plasticity, indicating that SIRT1 is required for synaptic plasticity. The brains of SIRT1Δ mice had a normal anatomy, but experiments using an antibody against synaptophysin (SVP) revealed significant decreases in SVP immunoreactivity in the hippocampal striatum radiatum, as well as reduced SVP protein content in the SIRT1Δ hippocampus. These results suggest that SIRT1 regulates synapse formation, synaptic plasticity, and memory formation. Brain-derived neurotrophic factor (BDNF) and cAMP response binding protein (CREB) are two genes that play critical roles in synaptic plasticity and modulating synapse formation. Both mRNA and protein levels of BDNF were significantly decreased in SIRT1Δ hippocampal compared with controls. CREB binds to several BDNF promoters and plays a key role in the activity-dependent regulation of BDNF expression. The study found that CREB binding to BDNF promoters was reduced in SIRT1ΔA novel pathway regulates memory and plasticity via SIRT1 and miR-134. SIRT1, a mammalian homologue of the yeast Sir2 protein, plays a complex role in various biological processes, including aging, oxidative stress, metabolism, and circadian rhythms. Recent studies suggest that SIRT1 is involved in normal brain physiology and neurological disorders. This study reveals that SIRT1 modulates synaptic plasticity and memory formation through a microRNA-mediated mechanism. Activation of SIRT1 enhances, while its loss-of-function impairs, synaptic plasticity. These effects are mediated by post-transcriptional regulation of CREB expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit miR-134 expression via a repressor complex containing the transcription factor YY1. Unchecked miR-134 expression following SIRT1 deficiency results in down-regulated expression of CREB and BDNF, thereby impairing synaptic plasticity. These findings demonstrate a novel role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signaling, in which SIRT1 has a direct role in regulating normal brain function, distinct from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of CNS disorders. The study used mutant mice lacking SIRT1 catalytic activity in a brain-specific manner (SIRT1Δ) to evaluate the physiological role of SIRT1 in learning and memory. SIRT1Δ mice exhibited significant decreases in freezing behavior and memory performance in various tasks, including associative memory, novel object recognition, and spatial learning. These results show that SIRT1 has an important role in several forms of memory. Additionally, SIRT1Δ mice showed deficits in long-term potentiation (LTP), a key mechanism of synaptic plasticity, indicating that SIRT1 is required for synaptic plasticity. The brains of SIRT1Δ mice had a normal anatomy, but experiments using an antibody against synaptophysin (SVP) revealed significant decreases in SVP immunoreactivity in the hippocampal striatum radiatum, as well as reduced SVP protein content in the SIRT1Δ hippocampus. These results suggest that SIRT1 regulates synapse formation, synaptic plasticity, and memory formation. Brain-derived neurotrophic factor (BDNF) and cAMP response binding protein (CREB) are two genes that play critical roles in synaptic plasticity and modulating synapse formation. Both mRNA and protein levels of BDNF were significantly decreased in SIRT1Δ hippocampal compared with controls. CREB binds to several BDNF promoters and plays a key role in the activity-dependent regulation of BDNF expression. The study found that CREB binding to BDNF promoters was reduced in SIRT1Δ