MAPPING FEAR MEMORY

Identification and selective targeting of neuronal networks underlying memory

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 Obiettivo del progetto (Objective)

'Among the most fundamental questions in modern biology is how we learn and remember. Using novel genetic tools, we can now ask fundamental questions not previously possible about how the brain encodes memories. For instance, how many neurons are required for learning? Are the network requirements similar in different brain regions? And, probably most intriguingly, how is a neuron that is part of a memory trace different from its neighboring neurons? In other words, what is the cellular and molecular basis of a memory?

Using Pavlovian fear conditioning, decades of elegant experiments have mapped the anatomical location of the engram for learned fear. However, at the cellular and molecular level, little is known about the physiology of individual neurons that encode a memory. Our recent results suggest a path forward, using novel genetic tools in mice that permit targeted manipulations of genes with both spatial and temporal-specificity. In particular, using genetic manipulations of proteins absolutely required for associative learning, we now have the potential to restrict the network space in which neuronal plasticity can occur, permitting the characterization of individual neurons responsible for encoding a specific memory.

Our experiments will focus on understanding the fundamental rules by which memories are organized within the brain. Specifically, we will use the immediate-early gene Arc to map neurons active during fear conditioning at single-cell resolution. Next, we plan to define the minimum neural network requirements for establishing a fear memory. Finally, we will investigate the learning-related changes in molecular, structural, and systems-level plasticity of individual neurons of the memory trace.

Importantly, the results of these studies will not only expand our mechanistic understanding of the neurobiology of memory, but could also provide opportunities for clinical translation into cognitive neuropsychiatric disorders.'

Introduzione (Teaser)

The precise neurobiological mechanisms underlying learning and memory are still largely unknown. An EU-funded project utilised several novel techniques to explore the specific molecular and cellular networks implicated in forming and maintaining memories.

Descrizione progetto (Article)

Understanding how we learn and retain information on a molecular level is of great importance in diagnosing, treating and preventing many disorders characterised by cognitive impairment. The project 'Identification and selective targeting of neuronal networks underlying memory' (MAPPING FEAR MEMORY) used genetically modified mice to target proteins and neuronal networks implicated in fear learning and memory.

Scientists first explored the importance of neuronal excitability during memory formation and maintenance. They found that increased excitability in a molecularly defined subset of neurons within the lateral amygdala enhanced neuronal recruitment during fear learning, but is not a primary neurophysiological mechanism influencing the long-term maintenance of fear memories. They concluded that neuronal excitability is relevant in the formation but not the retention of memory.

Another study examined LSL-CaMKII transgenic mice. CaMKII is a protein kinase long known to contribute to memory formation and consolidation. During this experiment, the CaMKII protein kinase was initially disrupted. Scientists then injected the mice with tamoxifen to reinstate the function of the CaMKII protein in defined populations of neurons.

This method allowed scientists to determine the minimally sufficient neural network necessary to encode fear memory. They found that both amygdala- and hippocampal-dependent learning require the CaMKII protein at the time of learning. The regulation of CaMKII differentially influenced behavioural tasks dependent on the hippocampus versus the amygdala.

To find out which parts of the brain are involved in memory formation and storage, scientists used a second transgenic mice species, the Arc-dVenus reporter mice. These mice express the dVenus fluorescent protein whenever Arc transcription is induced within a neuron. The experiments demonstrated that fear conditioning significantly increases both the number of neurons expressing Arc, as well as the strength of glutamatergic synaptic input onto these cells. Morevoer, the experiments provided an independent confirming under physiological conditions that neuronal excitability is a primary regulator of neuronal recruitment in the lateral amygdala during learning.

While these novel experimental techniques are still in a pre-clinical phase, they provide a first step in highlighting key neurobiological targets in the prevention and treatment of memory-related disorders. Morevoer, other neuroscientists are now able to use these techniques to further knowledge of the molecular and cellular mechanisms involved in learning and memory.