Francis Crick‘s astonishing hypothesis (1995) is that “You, your joys and your sorrows, your memories and your ambitions, your sense of personal identity and free will, are in fact no more than the behavior of a vast assembly of nerve cells and their associated molecules.” Actually, more than a hypothesis, this is the basis of modern neuroscience. Understanding how the tiny cells in our brains can generate everything that is in our mind is what motivates the research of Dr. Ben Strowbridge, a professor of Neuroscience and Physiology/Biophysics at Case Western University. Dr Strowbridge is particularly interested in the mechanisms that neurons use to remember things.
Dr. Strowbridge majored in Biology at MIT in 1984, when he started to develop his passion for neurons and their amazing properties. He received his PhD in Neuroscience in Gordon Shepherd’s laboratory at Yale University, studying local circuits that mediate neural activity in neocortex. Later, he moved to the University of Washington, first as a postdoc with Philip Schwartzkroin, and then as an Assistant Professor, before moving to his currently lab at Case Western in 1998, where he has been investigating the neural circuits in the hippocampus, the brain region that is crucial for the generation of many kinds of memory (he has also been interested in understanding how neurons process and generate the sense of smell, but this is subject for another day).
Dr. Strowbridge has been studying one particular type of memory called short-term memory (or working memory), which is the kind of memory that allow us to remember what we did seconds or minutes ago and, in this way, make sense of the world as a continuous story. Most of these things we will later forget, like what we ate for breakfast this morning, or that phone number that we memorized for a couple of seconds and that disappeared from ours minds seconds later.
As Francis Crick said, this kind of memory also needs to be physically stored somewhere inside our brains, during the time of seconds or minutes that it lasts. The most famous theory, first proposed by Donald Hebb, states that short-term memories can be stored by reverberating activity circulating through networks of neurons that fades after a certain period of time (Hebb 1949). Another possibility is that some neurons with exquisite properties would be able to fire persistently during many seconds after the end of the stimulus and, in principle, could store information during this period of time.
Dr. Strowbridge and a graduate student in his lab, Philip Larimer, decided to look at the circuits in a specific part of the hippocampus called dentate gyrus. Using slices of the rat brain, they started looking for some cellular and/or network mechanism into this brain region that would allow the storage of information for periods of at least a few seconds. Since they were working with brain slices in vitro, Larimer and Strowbridge (2010) had more control of what is going on and could use electrophysiology to record the activity of specific neurons while stimulating axons at precise locations.
Despite looking for reverberating activity at neural networks, which would support Hebb’s theory, what they found was that a specific neuron called semilunar granule cells (SGC) showed plateau potentials and remained firing for seconds after the end of the stimulus. Interestingly, this cell was first described by our godfather Santiago Ramón y Cajal about a century ago and was almost neglected since then.
The firing properties of this cell was then characterized and demonstrated to depend on NMDA receptors and specific voltage gated calcium channels. After characterizing the SGC, Dr. Strowbridge and colleagues also demonstrated that downstream neurons in the hilus of the dentate gyrus receive inputs from SGCs and showed SGC dependent persistent firing. Furthermore, they showed that the activity of these hilar neurons varies, depending on the site of the stimulating electrode, but is reliable at a specific site. In other words, the persistent firing of these cells can discriminate between different stimuli, based on their site of origin, and also on their temporal sequence (Larimar and Strowbridge 2010; Hyde and Strowbridge 2012).
Therefore, Dr. Strowbridge and colleagues have demonstrated that specific cells in the hippocampal dentate gyrus, the SGCs, and their downstream neurons in the hilus have the potential to store the information related to short-term memory in their persistent firing activity patterns.
In spite of all short-term memory work, use a bit of your long-term memory and don’t forget to join us this Tuesday April 7, 2014 at 4:00PM at CNCB Large Conference Room to hear more about this story from Dr. Ben Strowbridge in his talk entitled “Cellular mechanisms of short-term mnemonic representations in the dentate gyrus in vitro”.
Leonardo M. Cardozo is a first year student in the UCSD Neurosciences Graduate Program. He is currently rotating at Dr. Massimo Scanziani’s lab, investigating if long-range projections can also originate from inhibitory neurons, which would be able to control cortical excitability not only locally, but also at distant sites, coordinating activity across the brain.
Larimer P. & Strowbridge B.W. (2009). Representing information in cell assemblies: persistent activity mediated by semilunar granule cells, Nature Neuroscience, 13 (2) 213-222. DOI: 10.1038/nn.2458
Cajal S.R.Y. (1995). Histology of the Nervous System of Man and Vertebrates. Oxford University Press.
Crick F.H.C. (1995). The Astonishing Hypothesis: The Scientific Search For The Soul. Touchstone.
Hebb D. (1949). The Organization of Behavior. John Wiley & Sons.
Hyde R.A. & Strowbridge B.W. (2012). Mnemonic representations of transient stimuli and temporal sequences in the rodent hippocampus in vitro. Nature Neuroscience 15 (10) 1430-1438. DOI: 10.1038/nn.3208
Walker M.C., Pavlov I., Kullmann D.M. (2010). A ‘sustain pedal in the hippocampus? Nature Neuroscience 13 (2) 146-148. DOI: 10.1038/nn0210-146