In his epic poem Visions of the Daughters of Albion, William Blake asks: “Where goest thou O thought? To what remote land is thy flight?” More than two centuries later, memory remains as one of the enduring mysteries of neuroscience, and despite decades of intensive research using modern techniques, we still have no answer to the questions posed by Blake.
Traditionally, memory has been regarded as consisting of several distinct processes or storage systems. Short-term memory (sometimes referred to as working memory) stores information that is required for the task at hand, but is severely limited in its capacity and duration. Long-term memory serves as a relatively permanent store of information, and information from the short-term store can be transferred to it by the process of rehearsal.
This distinction still holds true, but most of the research to date has focused on long-term memory. The prevailing view is that memories are encoded over long periods of time by the strengthening of connections in distributed networks of nerve cells, and we now have some understanding of the underlying mechanisms. However, very little is known about how nerve cells encode information for short periods of time.
Now researchers have identified a cellular memory mechanism whereby single neurons in the prefrontal cortex of mice can maintain persistent activity for short periods of time, much like a computer’s random access memory (RAM), which temporarily stores data to improve the machine’s performance. They suggest that this mechanism underlies working memory, and that their findings may lead new treatments for drug addiction, and other conditions in which working memory and decision-making processes are disrupted.
In the study, Donald Cooper and his colleagues investigated the functional properties of nerve cell proteins called metabotropic glutamate receptors (mGluRs). The word metabotropic denotes the mechanism of action of these receptors. mGluR molecules are embedded in the cell membrane and associated with a G-protein, which is tethered to that part of the receptor which is exposed to the inside of the cell. Binding of the neurotransmitter glutamate to the receptor causes uncoupling of the G-protein, which then activates various biochemical signalling cascades, known as second messenger systems, within the cell.
mGluRs and other metabotropic receptors mediate slow neurotransmission, because the signalling pathways they activate take many seconds or minutes to exert their effects on a cell. This mechanism differs from that of the ion channel proteins responsible for generating nervous impulses. Although ion channels are also activated by the binding of a neurotransmitter molecule, they are deactivated within approximately one thousandth of a second; this quick inactivation is essential for the proper functioning of the neuron, as it enables the cell to generate trains of up to 1,000 electrical impulses per second.
The researchers used a technique called patch-clamping to electrically stimulate single neurons in slices of prefrontal cortex dissected from the mouse brain, while at the same time recording their responses to the stimulation. This involves impaling each cell with two microelectrodes. One of these (the stimulating electrode) can be used to inject a solution of ions into the cell. Because the solution carries a current, this alters the electrical properties of the cell by activating membrane proteins which are sensitive to changes in the membrane voltage. The other electrode is attached to a tiny patch of membrane on the outside of the cell, and forms a tight seal, so that the flow of currents through proteins in the membrane, which changes in response to the applied current, can be measured.
In these experiments, small currents which would not normally lead to a nervous impulse were found to elicit stable, low frequency electrical activity in the cells, which persisted for up to a minute after the injection of the current had ceased. When the experiments were repeated using cells from mutant mice lacking mGluR1, the same activity was still observed, ruling out the involvement of this receptor subtype. Then, by using chemicals which either inhibit or enhance other receptors, the researchers determined that the mGluR5 receptor subtype was responsible for the novel activity that they had observed. Further investigation revealed that the activity of this receptor is reduced by the neurotransmitter dopamine, via a second messenger system which involves a molecule called protein kinase A (PKA).
The prefrontal cortex is involved in cognitive processes such as attention, decision-making and working memory, and chronic use of cocaine and other psychostimulants adversely affects this part of the brain. This causes impairments in the cognitive functions it performs – for example, cocaine addicts are known to choose immediate rewards which carry high risks. Cooper’s group had previously found that repeated administration of cocaine and short-term withdrawal from the drug leads to increased PKA activity in neurons of prefrontal cortex. They therefore investigated if the drug would have any effect on mGluR5 activity and, sure enough, found that short-term cocaine withdrawal significantly reduced its ability to convert small electrical stimuli into a stable train of nervous impulses.
Studies carried out on monkeys in the 1970s revealed that neurons in the prefrontal cortex become active in working memory tasks, during the “delay period” which follows the presentation of a stimulus but precedes the behavioural response elicited by it. They are therefore believed to transiently encode information that is relevant to the tasks, and this study describes a candidate mechanism by which they do so. The new findings suggest that cells in layer 5 of the prefrontal cortex function as a temporary memory storage buffer, by converting brief stimuli into neuronal activity which persists for about one minute and then decays over a period of several seconds.
As well drug addiction, disruption of the interactions between mGluR5 and dopamine receptors is implicated in schizophrenia and attention deficit disorder (ADD). Drugs which enhance mGluR1 activity may therefore maintain the transient memory traces thought to be encoded in these cells, and possibly enable patients with these conditions to remain focused on what they are doing, ignore their impulses and make better decisions.
Sidiropoulou, K. et al (2009). Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity. Nat. Neurosci. DOI: 10.1038/nn.2245.