Xun Tu

All Publications

• Neuroendocrine circuit for sleep-dependent growth hormone release. Cell Ding, X., Hwang, F. J., Silverman, D., Zhong, P., Li, B., Ma, C., Lu, L., Jiang, G., Zhang, Z., Huang, X., Tu, X., Tian, Z. M., Ding, J., Dan, Y. 2025

  Abstract

  Sleep is known to promote tissue growth and regulate metabolism, partly by enhancing growth hormone (GH) release, but the underlying circuit mechanism is unknown. We demonstrate how GH release, which is enhanced during both rapid eye movement (REM) and non-REM (NREM) sleep, is regulated by sleep-wake-dependent activity of distinct hypothalamic neurons expressing GH-releasing hormone (GHRH) and somatostatin (SST). SST neurons in the arcuate nucleus suppress GH release by inhibiting nearby GHRH neurons that stimulate GH release, whereas periventricular SST neurons inhibit GH release by projecting to the median eminence. GH release is associated with strong surges of both GHRH and SST activity during REM sleep but moderately increased GHRH and decreased SST activity during NREM sleep. Furthermore, we identified a negative feedback pathway in which GH enhances the excitability of locus coeruleus neurons and increases wakefulness. These results elucidate a circuit mechanism underlying bidirectional interactions between sleep and hormone regulation.

  View details for DOI 10.1016/j.cell.2025.05.039

  View details for PubMedID 40562026

• Local autocrine plasticity signaling in single dendritic spines by insulin-like growth factors. Science advances Tu, X., Jain, A., Parra Bueno, P., Decker, H., Liu, X., Yasuda, R. 2023; 9 (31): eadg0666

  Abstract

  The insulin superfamily of peptides is essential for homeostasis as well as neuronal plasticity, learning, and memory. Here, we show that insulin-like growth factors 1 and 2 (IGF1 and IGF2) are differentially expressed in hippocampal neurons and released in an activity-dependent manner. Using a new fluorescence resonance energy transfer sensor for IGF1 receptor (IGF1R) with two-photon fluorescence lifetime imaging, we find that the release of IGF1 triggers rapid local autocrine IGF1R activation on the same spine and more than several micrometers along the stimulated dendrite, regulating the plasticity of the activated spine in CA1 pyramidal neurons. In CA3 neurons, IGF2, instead of IGF1, is responsible for IGF1R autocrine activation and synaptic plasticity. Thus, our study demonstrates the cell type-specific roles of IGF1 and IGF2 in hippocampal plasticity and a plasticity mechanism mediated by the synthesis and autocrine signaling of IGF peptides in pyramidal neurons.

  View details for DOI 10.1126/sciadv.adg0666

  View details for PubMedID 37531435

  View details for PubMedCentralID PMC10396292

• Dual Regulation of Spine-Specific and Synapse-to-Nucleus Signaling by PKCδ during Plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience Colgan, L. A., Parra-Bueno, P., Holman, H. L., Tu, X., Jain, A., Calubag, M. F., Misler, J. A., Gary, C., Oz, G., Suponitsky-Kroyter, I., Okaz, E., Yasuda, R. 2023; 43 (30): 5432-5447

  Abstract

  The activity-dependent plasticity of synapses is believed to be the cellular basis of learning. These synaptic changes are mediated through the coordination of local biochemical reactions in synapses and changes in gene transcription in the nucleus to modulate neuronal circuits and behavior. The protein kinase C (PKC) family of isozymes has long been established as critical for synaptic plasticity. However, because of a lack of suitable isozyme-specific tools, the role of the novel subfamily of PKC isozymes is largely unknown. Here, through the development of fluorescence lifetime imaging-fluorescence resonance energy transfer activity sensors, we investigate novel PKC isozymes in synaptic plasticity in CA1 pyramidal neurons of mice of either sex. We find that PKCδ is activated downstream of TrkB and DAG production, and that the spatiotemporal nature of its activation depends on the plasticity stimulation. In response to single-spine plasticity, PKCδ is activated primarily in the stimulated spine and is required for local expression of plasticity. However, in response to multispine stimulation, a long-lasting and spreading activation of PKCδ scales with the number of spines stimulated and, by regulating cAMP response-element binding protein activity, couples spine plasticity to transcription in the nucleus. Thus, PKCδ plays a dual functional role in facilitating synaptic plasticity.SIGNIFICANCE STATEMENT Synaptic plasticity, or the ability to change the strength of the connections between neurons, underlies learning and memory and is critical for brain health. The protein kinase C (PKC) family is central to this process. However, understanding how these kinases work to mediate plasticity has been limited by a lack of tools to visualize and perturb their activity. Here, we introduce and use new tools to reveal a dual role for PKCδ in facilitating local synaptic plasticity and stabilizing this plasticity through spine-to-nucleus signaling to regulate transcription. This work provides new tools to overcome limitations in studying isozyme-specific PKC function and provides insight into molecular mechanisms of synaptic plasticity.

  View details for DOI 10.1523/JNEUROSCI.0208-22.2023

  View details for PubMedID 37277178

  View details for PubMedCentralID PMC10376934

• Rac1 is a downstream effector of PKCα in structural synaptic plasticity. Scientific reports Tu, X., Yasuda, R., Colgan, L. A. 2020; 10 (1): 1777

  Abstract

  Structural and functional plasticity of dendritic spines is the basis of animal learning. The rapid remodeling of actin cytoskeleton is associated with spine enlargement and shrinkage, which are essential for structural plasticity. The calcium-dependent protein kinase C isoform, PKCα, has been suggested to be critical for this actin-dependent plasticity. However, mechanisms linking PKCα and structural plasticity of spines are unknown. Here, we examine the spatiotemporal activation of actin regulators, including small GTPases Rac1, Cdc42 and Ras, in the presence or absence of PKCα during single-spine structural plasticity. Removal of PKCα expression in the postsynapse attenuated Rac1 activation during structural plasticity without affecting Ras or Cdc42 activity. Moreover, disruption of a PDZ binding domain within PKCα led to impaired Rac1 activation and deficits in structural spine remodeling. These results demonstrate that PKCα positively regulates the activation of Rac1 during structural plasticity.

  View details for DOI 10.1038/s41598-020-58610-6

  View details for PubMedID 32019972

  View details for PubMedCentralID PMC7000694