We Know How to Create and Erase Memories on Demand

Researchers at University of California, San Diego (UCSD) have found an interesting way to manipulate the creation and deletion of memories stored in a mouse model by taking advantage of previous knowledge regarding Long Term Potentiation (LTP) and Long Term Depression (LTD).2 A synapse is defined as a connection between two neurons that enable one neuron to transmit an electrical or chemical signal to another. LTP and LTD are two major functions that permit long term alterations of neurological properties and affect synaptic efficiency to permit the formation of learning and memory. By introducing a relative increase or decrease in synaptic strength through the application of LTP and LTD respectively, memories can be created and erased.

Long term potentiation is defined as an increase in synaptic strength that is correlated with the onset of learning. LTP will strengthen a synapse by trafficking more receptors to the postsynaptic membrane of the receiving neuron. The receptor, named AMPA-R, allows an influx of cations, notably sodium and potassium, into the cell when activated by neurotransmitters. After LTP has occurred, a responding neuron will have more available receptors to bind neurotransmitters, explaining the increase in synaptic strength. LTP will occur when a strong stimulus, often referred to as a strong tetanus, is applied to the presynaptic neuron. Overall, application of a strong tetanus to a presynaptic neuron will cause an increase in synaptic strength, indicating the storage of new memories. On the other hand, Long Term Depression is a relative decrease in synaptic strength that is indicative of forgetting. LTD occurs when AMPA-Rs are internalized from the postsynaptic membrane to the cytoplasm of the neuron. A decrease in the density of receptors on the membrane will cause a depression in synaptic strength. LTD will occur on the synaptic terminal through application of a low tetanus for longer periods of time on the synaptic terminal. This dull and elongated stimulus will initiate the endocytosis of receptors, weakening the synaptic strength.

Navabi and Fox from the Manilow Lab at UCSD were able to induce LTP and LDP on demand through the use of optogenetics, an increasingly popular modern use of light to manipulate cell activity with spatial and temporal precision. Certain neurons that have been genetically manipulated to express photoreceptors are precisely activated or deactivated by the onset and offset of light exposure. The rats were trained to associate an optogenetically driven input (ODI) stimulation (conditioned stimulus) with a foot shock (unconditioned stimulus), such that ODI stimulation alone would generate fear in the animal. The ODI stimulation was specifically generated on auditory nuclei projecting to the lateral amygdala, a subregion of the brain associated with the processing of fear. Before training, the rats first learned to continuously press a lever for the release of their food. It has been widely acknowledged that rodents will freeze when in a state of fear. Thus, researchers were able to imply that the rats were in a state of fear when the number of lever presses decreased because freezing would cause rats to stop pressing the lever. The normalized decrease in lever presses depicted in the paired condition for Figure 2a and Figure 2b follow similar patterns. This indicates that association of ODI stimulation to the foot shock was as efficient as traditional methods of associating a tone to an unconditioned stimulus, such as a foot shock.

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Figure 2a. Rats learned to associate a tone with a foot shock, indicated through the decrease in lever presses in the paired condition when compared to the unpaired condition (n=5) b. The tone is replaced with optogenetic stimulation of auditory nuclei projecting to the lateral amygdala (n=8). The data indicates that optogenetically driven input stimulation was also associated with a foot shock.2

After successfully defining the ODI stimulation as a conditioned stimulus, learning can be assumed to have occurred through the decrease in lever presses. Researchers then exposed the same animals to an optically generated LTD, generated through low frequency optical stimulation for a long period of time. The onset of LTD caused no change in lever presses during ODI stimulation, indicating a lack of fear in the animal and a loss in the associative memory the mice previously had. The mice were no longer fearful of ODI stimulation and did not freeze with its onset. The researchers then reintroduced LTP through high frequency optical stimulation and found that the animal relearned to associate ODI stimulation with a tail shock, as shown with the decreased amount of lever presses.

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Figure 3. Areas in blue denote times of ODI stimulation. Pairing the optogenetic stimulation to the tail shock led to a decrease in lever presses. LTD protocol caused forgetting to occur, indicated through an increase in lever presses. LTP protocol reintroduced the learned association and lever presses decreased. (n=12)2

These findings confirm the important function of LTP and LTD for associative learning. LTP permits the onset of learning while LTD accounts for loss in a memory. The paired use of optogenetics with LTP or LTD allowed researchers to create and erase memories on demand. These findings are exciting in an advancing world of medical technology, but questions regarding the applicability of this model on the more complex memory of human beings have yet to be answered.

References:

  1. Purves, Dale. Neuroscience. Oxford University Press, 2018.
  2. Nabavi, Sadegh, et al. “Engineering a Memory with LTD and LTP.” Nature, vol. 511, no. 7509, Jan. 2014, pp. 348–352., doi:10.1038/nature13294.

Feel free to email me with questions and comments at mal036@ucsd.edu!

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