Material below summarizes the article A Primary Cortical Input to Hippocampus Expresses a Pathway-Specific and Endocannabinoid-Dependent Form of Long-Term Potentiation, published on July 25, 2016, in eNeuro and authored by Weisheng Wang, Brian H. Trieu, Linda C. Palmer, Yousheng Jia, Danielle T. Pham, Kwang-Mook Jung, Carley A. Karsten, Collin B. Merrill, Ken Mackie, Christine M. Gall, Daniele Piomelli, and Gary Lynch.
The hippocampus is a structure about the length of your little finger, nestled deep inside the cerebral cortex, that plays a vital role in the formation of new memories. This includes episodic memory, which is a record of a series of events placed into a narrative containing information about what you saw, the locations of the items, and the sequence in which they occurred.
People routinely perform this complex type of encoding and then use the stored episodes to recall what happened at a particular place or time. When asked about a possible encounter while walking through a building, you’ll likely replay an episode to find the answer, such as, “I came through the door, walked across the lobby, and then spotted an unusual chair next to the elevator.
Given that episodic memory is fundamental to everyday behavior, it is not surprising that brain scientists around the world are trying to understand how the hippocampus builds it.
A big and surprising clue came with the discovery by neuroanatomists years ago that the hippocampus has massive interconnections with the association areas of cortex. These regions, which comprise the majority of the human cortex, are widely held to be the sites at which the disparate parts of cognition are assembled.
Researchers then found that one of the two major input paths from the associational cortex to the hippocampus carries “what is it” information, while the other conveys ”where is it” data. Current theories propose that “when” is encoded by circuits within the hippocampus.
But how do these connections store the different pieces of an episode?
The obvious answer is that encoding happens within synaptic connections between neurons, and research over the past several decades has provided a mechanism for this. Scientists found that the contact points increase their strength when stimulated by a rhythmic pattern that mimics neuronal activity patterns that occur during learning.
Numerous studies show that this long-term potentiation (LTP) effect is required for the formation of new memory. Neuroscientists have steadily unraveled the complex chemistry responsible for LTP, something that is one of the premier accomplishments of the field.
Putting all of this together, we have a learning rhythm that engages synaptic processes that produce an astonishingly stable change in communication between hippocampal neurons. In essence, this research describes a substrate for memory.
However, almost all of the work on LTP mechanisms was conducted on only one link in hippocampal circuitry. Can we assume then that each of the features of the episode is encoded in the same way?
Results described in our eNeuro article tell us that the answer is a definitive “no.” The studies tested LTP in the “what is it” cortical input and found that potentiation differs radically from the well-established form found elsewhere in hippocampus. Remarkably, it seems that one basic element of orderly thinking is encrypted by its own special mechanism.
Relating this entirely unexpected discovery to psychology requires insights into how the new LTP is generated.
Work with several highly selective drugs and genetic mutations pointed to an exciting conclusion: The new form of LTP is triggered by the local production of cannabinoids (endocannabinoids). These small lipid messengers, which are structurally similar to the active ingredient of marijuana, are synthesized on one side of the synapse in response to patterned activity and then diffuse to the other side.
There they bind to a receptor (cannabinoid receptor 1: CB1). These effects occur throughout the brain and typically cause a transient depression of neurotransmitter release. The “‘what” input is a special case: There, and so far only there, the CB1 receptor triggers a structural reorganization leading to a lasting increase in transmitter release and greater potency for the synapse. Experiments then showed that blocking or enhancing this peculiar mechanism produces corresponding effects on the formation of long term memory for ”what” type information.
Why does only one critical pathway in the hippocampus use a singular type of LTP?
In addition to its two major cortical inputs, the hippocampus receives several much smaller connections from phylogenetically older parts of the brain. The transmitter used by one of these stimulates the production of endocannabinoids. This regulatory input is thus capable of acting as an on-off gatekeeper that allows the system to encode “what” versus “where” at different steps in an ongoing sequence, something that would be valuable in creating a proper episodic memory.
This idea helps explain why drugs that block the regulatory input — which are sometimes used in minor surgery — disrupt the encoding of “what” data into an episode.
Our results also raise new questions about the influence of cannabinoid drugs on cognitive memory. The active ingredient of marijuana targets CB1 receptors that are found throughout the brain where they are thought, for good reasons, to depress transmitter release. But CB1 receptors produce a very different, memory-positive effect in the “what” pathway.
Is it possible, then, that marijuana and related agents interfere with most types of memory formation but actually facilitate storage of specific aspects of an episode?
Replay in this instance would produce strange results with specific items being unusually sharp but with distortions about where or when they occurred. Perhaps this relates to the occasional reports of quickened mental associations and “rare creative” responses in cannabis users.
Before digging into these issues, we must first deal with the more basic question of whether marijuana actually enhances the unusual LTP found in the “what” pathway, as we found with another agent that acts on the CB1 receptor. Answers should be coming soon.
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A Primary Cortical Input to Hippocampus Expresses a Pathway-Specific and Endocannabinoid-Dependent Form of Long Term Potentiation. Weisheng Wang, Brian H. Trieu, Linda C. Palmer, Yousheng Jia, Danielle T. Pham, Kwang-Mook Jung, Carley A. Karsten, Collin B. Merrill, Ken Mackie, Christine M. Gall, Daniele Piomelli, Gary Lynch. eNeuro July 2016 DOI: 10.1523/ENEURO.0160-16.2016
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