Neuronal memory allocation

Memory allocation is a process that determines which specific synapses and neurons in a neural network will store a given memory. Although multiple neurons can receive a stimulus, only a subset of the neurons will induce the necessary plasticity for memory encoding. The selection of this subset of neurons is termed neuronal allocation. Similarly, multiple synapses can be activated by a given set of inputs, but specific mechanisms determine which synapses actually go on to encode the memory, and this process is referred to as synaptic allocation.. Memory allocation was first discovered in the lateral amygdala by Sheena Josselyn and colleagues in Alcino J Silva's laboratory. Memory allocation is a process that determines which specific synapses and neurons in a neural network will store a given memory. Although multiple neurons can receive a stimulus, only a subset of the neurons will induce the necessary plasticity for memory encoding. The selection of this subset of neurons is termed neuronal allocation. Similarly, multiple synapses can be activated by a given set of inputs, but specific mechanisms determine which synapses actually go on to encode the memory, and this process is referred to as synaptic allocation.. Memory allocation was first discovered in the lateral amygdala by Sheena Josselyn and colleagues in Alcino J Silva's laboratory. At the neuronal level, cells with higher levels of excitability (for example lower slow afterhyperpolarization) are more likely to be recruited into a memory trace, and substantial evidence exists implicating the cellular transcription factor CREB (cyclic AMP responsive element-binding protein) in this process. Certain synapses on recruited neurons are more likely to undergo an enhancement of synaptic strength (known as Long-term potentiation (LTP)) and proposed mechanisms that might contribute to allocation at the synaptic level include synaptic tagging, capture, and synaptic clustering. Neuronal allocation is a phenomenon that accounts for how specific neurons in a network, and not others that receive similar input, are committed to storing a specific memory. The transcription factor cAMP response element-binding protein (CREB) is a well-studied mechanism of neuronal memory allocation. Most studies to date use the amygdala as a model circuit, and fear-related memory traces in the amygdala are mediated by CREB expression in the individual neurons allocated to those memories. CREB modulates cellular processes that lead to neuronal allocation, particularly with regards to dendritic spine density and morphology. Many of the memory mechanisms studied to date are conserved across different brain regions, and it is likely that the mechanisms of fear-based memory allocation found in the amygdala will also be similarly present for other types of memories throughout different brain regions. Indeed, Sano and colleagues in the Silva lab showed that CREB also regulates neuronal memory allocation in the amygdala. CREB may be activated by multiple pathways. For example, the cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) pathways appear to participate in neuronal allocation. When activated by the second messengers such as cAMP and calcium ions, enzymes such as PKA and MAP kinase can translocate to the nucleus and phosphorylate CREB to initiate transcription of target genes. PKA inhibitors can block the development of long-lasting LTP, and this is accompanied by a reduction in the transcription of genes modulated by the CREB protein. Metaplasticity is a term describing the likelihood that a given stimulus will induce neuronal plasticity, based on the previous activity experienced by that neuron. Several studies provide evidence that neurons receiving “priming activity” (such as neurotransmitters, paracrine signals, or hormones) minutes to days prior will show a lower threshold for induction of long term potentiation (LTP). Other studies find that activation of NMDARs can also raise the stimulation threshold for induction of LTP. Thus, similar inputs on groups of neurons may induce LTP in some but not others based on prior activity of those neurons. Signaling mechanisms implicated in these metaplastic effects include autophosphorylation of αCaMKII, changes in NMDA receptor subunit composition, and activation of voltage-dependent calcium channels. These metaplastic effects regulate memory destabilization and reconsolidation. Synaptic allocation pertains to mechanisms that influence how synapses come to store a given memory. Intrinsic to the idea of synaptic allocation is the concept that multiple synapses can be activated by a given set of inputs, but specific mechanisms determine which synapses actually go on the encode the memory. Allocation of memories to specific synapses are key to determining where memories are stored. Synaptic activity can generate a synaptic tag, which is a marker that allows the stimulated spine to subsequently capture newly transcribed plasticity molecules such as Arc. Synaptic activity can also engage the translation and transcription machinery. Weak stimulation can create synaptic tags but will not engage the translation and transcription machinery, whereas strong stimulation will create synaptic tags and also engage the translation and transcription machinery. Newly generated plasticity-related proteins (PRPs) can be captured by any tagged synapses, but untagged synapses are not eligible to receive new PPs. After a certain time period, synapses will lose their tag and return to their initial state. Furthermore, the supply of new PRPs will deplete. The tags and new PRPs must overlap in time to capture the PRPs.