A team of New York University neuroscientists has identified how two distinct growth factor families contribute to long-term memory formation, a discovery reported in the journal Neuron.
“These results give us a clearer view of memory’s architecture and specifically how molecules function together as a network to create long-term memories,” says the paper’s senior author, Thomas Carew, professor at NYU’s Center for Neural Science and dean of NYU’s Faculty of Arts and Science. “Equally important, this work advances our understanding of memory mechanisms, which is essential for developing targeted cognitive therapies for memory-related disorders.”
Growth factors (GFs) are well known for their essential role in brain development from the prenatal period through adulthood. Over time, research has shown that many growth factors originally involved in shaping the developing brain are later repurposed to support synaptic plasticity and the molecular changes required for long-term memory.
However, it has been unclear how different families of growth factors, and distinct members within those families, work together to produce the range of molecular events underlying memory formation. To address that question, the NYU research team—led by graduate student Ashley Kopec (lead author) with contributions from research scientist Gary Phillips—focused on two GF signaling systems: TrkB and TGF-βr‑II. These represent separate classes of growth factors that use different receptor systems to produce cellular effects in the nervous system.
The experiments were carried out in Aplysia californica, the California sea slug, a widely used model for studies of learning and memory. Aplysia offers particular advantages for molecular neuroscience because its neurons are much larger than those of vertebrates and it has a relatively simple neural circuit. These features make it easier to observe signaling events in identified neurons and separate subcellular compartments such as cell bodies and synapses.
To induce a simple form of threat-related memory known as sensitization, the investigators applied two mild electrical tail shocks to the animals, separated by 45 minutes. The first shock establishes a molecular “context” in the neurons of the reflex circuit; the second shock uses that context to engage the molecular mechanisms needed to consolidate a long-term memory. The team measured growth factor signaling and downstream molecular activity at both time points—Time 1 (after the first shock) and Time 2 (after the second shock)—and in different cellular compartments.
The results reveal complementary temporal and spatial roles for the two growth factor systems. Temporally, TrkB signaling is essential at Time 1 when the memory context is first set, while TGF-βr‑II signaling is not required at that stage. At Time 2, when the long-term memory is consolidated, the roles reverse: TGF-βr‑II becomes critical and TrkB signaling is no longer essential.
Spatially, the two growth factor families act in separate cellular compartments within the same neurons. In the Aplysia reflex circuit, sensory neuron cell bodies are located in a different compartment from their synaptic terminals. The study found that TrkB-dependent effects occur primarily at synapses, while TGF-βr‑II functions specifically at the neuronal cell body (soma). This compartmentalization supports a model in which local synaptic signaling and distant somatic signaling work together to generate the molecular conditions required for long-term changes.
At the molecular level, TrkB and TGF-βr‑II independently regulate distinct phases of MAPK activation, a kinase pathway important for plasticity, yet they act synergistically to control expression of key genes involved in memory, including apc/ebp. Both the early, synaptic TrkB signal and the later, somatic TGF-βr‑II signal are necessary for the formation of long-term memory in this paradigm, supporting the idea that multiple growth factor systems form an interactive molecular network during memory consolidation.
These findings refine our understanding of how growth factors contribute to learning and memory by specifying not only which molecules are required, but when and where they act within the neuron. That spatiotemporal precision is fundamental to translating molecular neuroscience into effective strategies for treating memory impairments and cognitive disorders.
Funding: This research was supported by grants from the National Institute of Mental Health (RO1 MH 041083, F31 MH 100889).
Source: James Devitt, NYU. Image source: Public domain image. Original research: Kopec AM, Philips GT, Carew TJ. “Distinct Growth Factor Families Are Recruited in Unique Spatiotemporal Domains during Long-Term Memory Formation in Aplysia californica,” Neuron, published online June 3, 2015. doi: 10.1016/j.neuron.2015.04.025
Abstract
Distinct Growth Factor Families Are Recruited in Unique Spatiotemporal Domains during Long-Term Memory Formation in Aplysia californica
Highlights
- Trials 1 and 2 recruit synaptic TrkB and somatic TGF-βr‑II signaling, respectively.
- TrkB and TGF-βr‑II act independently to regulate discrete phases of MAPK activation.
- TrkB and TGF-βr‑II act synergistically to regulate gene expression (apc/ebp).
- Both trial 1 TrkB and trial 2 TGF-βr‑II signaling are required for long-term memory formation.
Summary
Multiple growth factors have been implicated in long-term memory, yet no single factor accounts for all plastic changes involved in memory formation. Because growth factors engage convergent signaling cascades that can produce similar outcomes, attributing specific roles to individual GFs has been challenging. Using the Aplysia two-trial sensitization model, the authors demonstrate that TrkB and TGF-βr‑II are differentially recruited by trial and by subcellular location. These growth factors independently regulate MAPK activation phases and synergistically control gene expression necessary for consolidation. The study shows that trial 1 TrkB and trial 2 TGF-βr‑II signaling are both required for long-term memory, supporting a model in which growth factors act as interacting components of a complex molecular network during memory formation.