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 semilunar granule cell (SGC) Left: Ramón y Cajal drawing of the guinea pig hippocampal dentate gyrus. A semilunar granule cell, highlighted by the arrow, is located in the inner molecular layer, right above the layer of granule cells (GC), the most common cell type in the dentate gyrus. Figure adapted from Cajal (1995).  Right: Intracellular responses of a SGC to graded stimulation in the perforant pathway (PP - main input to dentate gyrus). Note the plateau potential and the persistent firing that lasts for seconds after stimulation. A GC response is showed below for comparison. Figure modified from Larimer and Strowbridge (2010).

The semilunar granule cell (SGC)
Left: Ramón y Cajal’s drawing of the guinea pig hippocampal dentate gyrus. A semilunar granule cell, highlighted by the arrow, is located in the inner molecular layer, right above the layer of granule cells (GC), the most common cell type in the dentate gyrus. Figure adapted from Cajal (1995). Right: Intracellular responses of a SGC to graded stimulation in the perforant pathway (PP – main input to dentate gyrus). Note the plateau potential and the persistent firing that lasts for seconds after stimulation. A GC response is showed below for comparison. Figure modified from Larimer and Strowbridge (2010).

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).

Schematic of hippocampal dentate gyrus showing semilunar granule cells (SGCs) in the inner molecular layer (IML) and their projections to hilar neurons (excitatory mossy cells and inhibitory interneurons). Red indicates active neurons, dashed lines indicate inactive pathways. Open circles indicate inhibitory synapses and closed circles indicate excitatory synapses. Hilar neurons can show different patterns of activity, depending on the stimuli, modulating and refining the pattern of granule cell firing (GC), as illustrated by the scheme.  EC: entorhinal cortex; IML: inner molecular layer; GR/ML: granule cell/molecular layer. Figure slightly modified from Walker et al. 2010.

Schematic of hippocampal dentate gyrus showing semilunar granule cells (SGCs) in the inner molecular layer (IML) and their projections to hilar neurons (excitatory mossy cells and inhibitory interneurons). Red indicates active neurons, dashed lines indicate inactive pathways. Open circles indicate inhibitory synapses and closed circles indicate excitatory synapses. Hilar neurons can show different patterns of activity, depending on the stimuli, modulating and refining the pattern of granule cell firing (GC), as illustrated by the scheme. EC: entorhinal cortex; IML: inner molecular layer; GR/ML: granule cell/molecular layer. Figure slightly modified from Walker et al. 2010.

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.

Primary reference:

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:
Other references:

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

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2 responses »

  1. Martin Pyka says:

    Hi,

    this is more a kind of advertisement, but it might interest you that a 3d printed version of the hippocampus of the rat can be ordered on Shapeways:

    http://www.shapeways.com/model/1809522/hippocampus-dentate-gyrus-ca3-ca2-ca1.html

    It does not depict single neurons but it helps a lot to understand the overall shape of the hippocampus.

    Best,
    Martin

    • Kerin Higa says:

      That’s awesome, thanks for sharing! I get the Shapeways newsletters, but I never thought to look for neuroscience models! Maybe we’ll get one for our outreach program..

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