Neurons Take the Path More Traveled
Nicholas Gans
12/12/2016
As humans, we experience life linearly through time, physically living only in the moment. We have the capacity, however, to remember the past, and to think about the future.
This ability to conceptualize time, and form a generalized image of ourselves through our memories gives rise to the concept of personality. Personality, defined as a person’s behavior over time that give rise his or her individual character, is what makes each of us who we are regardless of environment and situation. Daniel Kahneman (2010), the founder of behavioral economics, would argue each of our personalities and identities are product of our current ‘experiencing selves’ and our past ‘remembering selves.’ And if our experiencing self is largely impacted by our memory, it can be said that one’s memory is truly who they are and know themselves to be.
So by what mechanism do we form memories, exhibit patterns of behavior, and integrate each moment that we experience into our personality? These behavioral and psychological properties have a biological and further molecular basis. Long term potentiation (LTP) and long term depression LTD, are forms of synaptic plasticity by which after repeated stimulation (for LTP, and lack thereof for LTD) from a presynaptic neuron, the same activation yields a greater (for LTP, or weaker for LTD) postsynaptic potential. LTP and LTD are the foundation for how experience and perception induce lasting neuronal changes in an organism; LTP and LTD are necessary for processes such as habituation, learning, memory, and behavioral adaptation.
While these processes occur in all brain areas, much of what researchers know about LTP is from studying the hippocampus. The hippocampus is part of the limbic system and is the brain’s memory integration center. It extensively involved in spatial navigation and response inhibition. It is a unique part of the brain in that neurogenesis persists here well into adulthood. The glutamatergic pathway involving the CA1, CA3, EC (entorhinal cortex), and dentate gyrus is the main subject of interest in studying LTP and LTD. Many of these studies employ the technique tetanus, in which repeated high frequency stimulation from the EC and/or CA3 regions results in a single-pulse EPSP in the CA1 region, inducing LTP.
The pertinent neurotransmitter receptors involved in this system are the NMDA and AMPA glutamate receptors. Activation of these receptors increases postsynaptic Na+ and K+ permeability. Sufficient NMDAR activation also increases Ca2+ permeability by expelling an Mg2+ ion from the receptor’s voltage gated channel. If high enough voltage is reached to open the channel and allow the influx of calcium into the postsynaptic neuron, then secondary signaling pathways are activated which trigger the transcription of CREB (and associated genes) to produce neurotrophins, phosphorylate proteins, and activate kinases. These secondary signaling pathways (in LTP) induce conformational changes in the postsynaptic neuron: increasing the expression of NMDAR, optimizing the synapse structure for increased efficiency, and even inducing synaptogenesis.
In order to study the relationship between LTP and memory, researchers stop LTP through various methods and observe the effects on memory. Via genetic manipulation, protein synthesis inhibitors, and receptor antagonists, studies have shown that consolidation or reconsolidation can be diminished or prevented. These interventions prevent the flow of Ca2+ into the post synaptic neurons and thus prevent the Long Term Potentiation or Depression of a recently experienced or recalled event. NMDAR antagonists such as AP5, ethanol, DXM, ketamine, and propranolol have been extensively studied for this property, and have been shown to be extremely effective methods of fear extinction. In previous studies, rats were who were conditioned to fear tones paired to a shock did not exhibit freezing (a behavior that indicates fear in rats) if they were administered an NMDA antagonist during consolidation (Burgos-Robles et al., 2007). Beyond single event consolidation prevention, these drugs may also be beneficial if used as a therapy for a multitude of cognitive disorders.
There are promising studies utilizing these drugs to treat fear (Davis, M., 2011), depression (Dang, Y.H. et al., 2014), and post-traumatic stress disorder (PTSD). Shigeto Yamamoto et al. demonstrated their promising findings involving D-cycloserine in Rat Models in the Journal Nature in 2007: “Behavioral analyses indicated that SPS is an appropriate animal model of PTSD and that DCS may be effective in the treatment of PTSD. These findings suggest that DCS, irrespective of its mechanistic involvement in the enhancement of fear extinction, may help to reverse hippocampal plasticity, and thus reverse the NMDA compensatory alterations.” There has since been a surge of new research on the potential use of ketamine and other NMDA antagonists for PTSD.
In addition to the knowledge that drugs like receptor antagonists and protein synthesis inhibitors provide, much can be understood about the important role of the NMDA receptors by examining diseases that disrupt their function. In her book Brain on Fire, Susannah Cahalan shares her “Month of Madness,” with the rare disease NMDA autoimmune encephalitis which recruits the victim’s antibodies to target the NR1 subunit of the NMDAR. She experienced severe memory loss, altered personality, hallucinations, mood swings, seizures, and described herself as being turned back into a child. These receptors which are necessary for LTP and LTD, are clearly an essential biological ingredient in our personality. Without LTP, we lose the ability to learn, self-identify, and remember, all crucial aspects of what make us human.
References
Burgos-Robles, Anthony, et al. "Consolidation of fear extinction requires NMDA receptor
dependent bursting in the ventromedial prefrontal cortex." Neuron 53.6 (2007): 871-880.
Cahalan, S. (2012). Brain on Fire: My Month of Madness. New York: Simon and Schuster.
Dang, Y. H., Ma, X. C., Zhang, J. C., Ren, Q., Wu, J., Gao, C. G., & Hashimoto, K. (2014).
Targeting of NMDA receptors in the treatment of major depression. Current pharmaceutical design, 20(32), 5151-5159.
Davis, Michael. "NMDA receptors and fear extinction: implications for cognitive behavioral
therapy." Dialogues Clin Neurosci 13.4 (2011): 463-74.
Eichenbaum, H. (2011). The Cognitive Neuroscience of Memory: An Introduction (2nd ed.).
Boston, MA: Oxford University Press.
Kahneman, D. (2010). The riddle of experience vs. memory. TED2010. Web.
https://www.ted.com/talks/daniel_kahneman_the_riddle_of_experience_vs_memory
Yamamoto, S., Morinobu, S., Fuchikami, M., Kurata, A., Kozuru, T., & Yamawaki, S. (2008).
Effects of single prolonged stress and D-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD. Neuropsychopharmacology, 33(9), 2108-2116.
Disclaimer: This was used in an assignment at Lehigh University in a Cognitive Neurosience Course. Please let me know if there are any errors, typos, formatting problems, or issues with this post.
