"Long before it's in the papers"
January 28, 2015


Molecules may “anchor” memories in the brain

Nov. 21, 2006
Courtesy University of Utah
and World Science staff

Our brains nail down mem­o­ries by us­ing spe­cial pro­tein mo­le­cules as an­chors that streng­th­en nerve cell con­nec­tions, a study sug­gests.

These con­nec­tions, called sy­n­apses, “are in a con­s­tant state of flux. They are ex­chang­ing mo­le­cules all the time,” said Paul Bress­loff of the Uni­ver­si­ty of Utah in Salt Lake City.

Deep in­side the brain, a neu­ron pre­pares to trans­mit a sig­nal to its tar­get. This im­age won the U.S. Na­tion­al Sci­ence Foun­d­a­tion's Sci­ence & En­gi­neer­ing Vis­u­al­i­za­tion Chal­lenge im­age com­pe­ti­tion last year. (Cred­it: Gra­ham John­son Med­i­cal Me­dia).

“So how can they be the seat of mem­o­ries that can last a life­time? Part of the an­s­wer is that there are an­chors in­side the sy­n­apse.” These hold in place other pro­teins that de­ter­mine the strength of con­nec­tions, he ar­g­ued, which in turn help form and re­tain mem­o­ries.

The re­search, he said, is also rel­e­vant to learn­ing and Alz­hei­mer’s dis­ease. That ill­ness is thought to in­volve, at least in part, a mal­func­tion in pro­tein move­ments in syn­apses.

Bresloff and a co-author de­tailed their work in the Nov. 22 is­sue of The Jour­nal of Neu­ro­science. Both au­th­ors are math­e­mati­cians, not bi­ol­o­gists. But Bressloff said he’s not wor­ried about pos­si­ble skep­ti­cism from sci­en­tists who may ar­gue that it will take ex­per­i­ments, not math­e­mat­i­cal the­o­ries, to prove his point.

“The­ory can be a real­i­ty check [on] ex­per­i­ments just as much as the oth­er way around,” wrote Bress­loff, a mem­ber of the uni­ver­si­ty’s Brain In­s­ti­tute, in an e­mail. 

On the sub­ject that his stu­dy co­vers, he added, there’s al­ready “an over­whelm­ing amount of ex­per­i­men­tal da­ta, much of which ap­pears to be con­tra­dic­to­ry.”

Bressloff said the big de­bate on con­scious­ness is, “can it be ex­plained simp­ly in terms of a bunch of nerve im­pulses in the brain? In my opin­ion, the an­swer has to be yes”—and his find­ings re­in­force that. “If you change the pat­tern of nerve im­pulses, then that changes the mem­o­ries, be­hav­ior and feel­ings. … What de­ter­mines that pat­tern of nerve im­pulses is a mix­ture of stim­u­li we are re­ceiv­ing from the out­side world and the strength of con­nec­tions be­tween nerve cells.”

The strength of these links de­ter­mines who we are, he ar­g­ued.

A syn­apse, the junc­tion be­tween nerve cells or neu­rons, has three parts: an end or “ax­on” of the trans­mit­ting cell; a mi­cro­scop­ic gap be­tween cells; and a mush­room-shaped “den­dritic spine,” which is part of the re­ceiv­ing cell.

What we learn and re­mem­ber is be­lieved to be dis­trib­ut­ed across many syn­apses, Bress­loff said. Some mem­o­ries, such as a per­son’s face, may rely on just a few syn­apses; oth­er mem­o­ries may be dis­trib­ut­ed across many.

While a nerve cell has on­ly one ax­on to trans­mit out­go­ing sig­nals, it has many branch-like struc­tures called den­dri­tes. Each den­drite, in turn, branches in­to twig-like pro­tru­sions known as den­d­rit­ic spines. A nerve cell may have 10,000 den­drit­ic spines, each of which is part of a syn­apse. So the cell can get sig­nals from that many oth­er nerve cells.

Nerve cells fire elec­tric im­pulses. When an im­pulse ar­rives at the syn­apse, it trig­gers the re­lease of chem­i­cals called neurotrans­mitters. These cross the syn­apse and at­tach or “bind” to pro­teins on the den­drit­ic spine, called re­cep­tors. These help the sig­nal con­ti­nue on the oth­er side.

A key neurotrans­mitter, glu­ta­mate, binds to pro­teins known as AMPA re­cep­tors, em­bed­ded in the den­drit­ic spines on the re­ceiv­ing cells. These re­cep­tors are one of two re­cep­tor types known to play a cru­cial role in learn­ing and mem­o­ry, Bresloff said. The AMPA re­cep­tors, he added, are held in the mem­brane cov­er­ing the cell by oth­er mo­le­cules called scaf­fold­ing pro­teins. 

Ear­li­er re­search in­di­cates learn­ing and mem­o­ry de­pend on the strength of syn­apses. Bress­loff said a syn­apse’s strength de­pends not on­ly on how much neu­ro­trans­mitter the up­stream cell sends, but on oth­er fac­tors, in­clud­ing the num­ber of re­cep­tors like AMPA.

Bress­lof­f studied how syn­apse strength re­lates to the num­ber of AMPA re­cep­tors, which helps de­ter­mine the strength of a trans­mitted cur­rent.

In­di­vid­u­al re­cep­tors con­stantly are re­cy­cled or “traf­ficked” in and out of the syn­apse, he said. How can the ever-changing syn­apse help re­tain learn­ing and mem­o­ries? He creat­ed a math­e­mat­i­cal sim­u­la­tion to de­scribe re­cep­tor move­ments based on the idea that the re­ceiv­ing, mush­room-shaped den­drit­ic spine has two com­part­ments. One looks like the mush­room cap; it’s where scaf­fold­ing pro­teins pin re­cep­tors in place so they can re­ceive glu­ta­mate’s chem­i­cal sig­nal. The sec­ond com­part­ment is like the mush­room’s stalk.

Bress­loff used equa­tions to de­scribe how quick­ly re­cep­tors leave or en­ter a syn­apse by go­ing be­tween the “cap” and “stalk.” The equa­tions sug­gested that the big­gest fac­tor in strength­en­ing syn­apses was the scaf­fold­ing pro­teins. “You can’t just shove a bunch of new AMPA re­cep­tors to the sur­face be­cause they will just go away again,” he said; “you need to keep them there.” What we remem­ber and learn is in ef­fect, he ar­gued, an­chored to nerve cells.

* * *

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Our brains nail memories in place by using certain protein molecules as anchors to pin other proteins in place, strengthening connections between nerve cells, a study suggests. These connections, called synapses, “are in a constant state of flux. They are exchanging molecules all the time,” said Paul Bressloff of the University of Utah. “So how can they be the seat of memories that can last a lifetime? Part of the answer is that there are anchors inside the synapse that keep proteins in place, and these proteins help determine how strong a synapse is, which in turn contributes to forming and retaining memories.” The research is relevant to memory learning and Alzheimer’s disease, he added. This condition is believed to involve, at least in part, a breakdown in the normal movement of proteins within synapses. Bresloff and a co-author detailed their work in the Nov. 22 issue of The Journal of Neuroscience. Both are mathematicians, not biologists. But Bresloff said he’s not worried about possible skepticism from scientists who think experiments, not mathematical theories, are needed to prove his point. “Theory can be a reality check [on] experiments just as much as the other way around,” wrote Bresloff, a member of the university’s Brain Institute, in an email. On this subject, he added, there’s “an overwhelming amount of experimental data, much of which appears to be contradictory.” Bressloff said the big debate on consciousness is, “can it be explained simply in terms of a bunch of nerve impulses in the brain? In my opinion, the answer has to be yes” – an answer reinforced by his findings. “If you change the pattern of nerve impulses, then that changes the memories, behavior and feelings. … What determines that pattern of nerve impulses is a mixture of stimuli we are receiving from the outside world and the strength of connections between nerve cells.” “Our knowledge and memories are determined by these connections in the brain. Who we are is determined by” their strength. A synapse, the junction between nerve cells or neurons, has three parts: the end or “axon” of the upstream nerve cell, the microscopic gap between nerve cells, and a mushroom-shaped “dendritic spine,” which is part of the downstream nerve cell. What we learn and hold in our memory is believed to be distributed across many synapses, Bressloff said. Some memories, such as a person’s face, may be held by just a few synapses, while other memories may be distributed across a large number, he adds. While a nerve cell has only one axon to transmit outgoing signals, it has numerous structures called dendrites, which are like branches of a tree. Each dendrite, in turn, branches into twig-like dendritic spines. A single nerve cell may have 10,000 dendritic spines, and each spine is part of a synapse. So a single nerve cell can receive signals from that many other nerve cells. Nerve cells fire electric impulses. When an impulse from one arrives at the synapse, it triggers the release of chemicals called neurotransmitters. These cross the synapse and attach or “bind” to proteins on the dendritic spine, called receptors. A key neurotransmitter, glutamate, binds to proteins known as AMPA receptors, embedded in the dendritic spines on the receiving end of nerve cells. These receptors are one of two receptor types known to play a crucial role in learning and memory, Bresloff said. The AMPA receptors, he added, are held in the membrane covering the cell by other molecules called scaffolding proteins. Earlier research indicates learning and memory depend on the strength of synapses. Bressloff said a synapse’s strength depends not only on how much neurotransmitter is released by the upstream nerve cell, but on other factors, including the number of receptors like AMPA. Bressloff’s study focused on how synapse strength relates to the number of AMPA receptors, which is critical in determining the strength of a transmitted current. Individual receptors constantly are recycled or “trafficked” in and out of the synapse, he said. So how can an ever-changing synapse help retain learning and memories? Bressloff constructed a mathematical simulation that used calculus equations to describe the movement of receptors in and out of the synapse. The simulation was based on the notion that the downstream part of a synapse – the mushroom-shaped dendritic spine – has two compartments. The first looks like the mushroom cap. It’s where the receptors are pinned in place by scaffolding proteins so they can receive glutamate’s chemical signal from the upstream cell. The second compartment is like the mushroom’s stalk. Bressloff used equations to describe four processes that determine how quickly receptors leave or enter a synapse by moving between the cap- and stalk-like parts of the spine. The equations suggested that the most important factor in strengthening synapses was the presence of scaffolding proteins that hold receptor proteins in place so they can receive signals. For synapses to strengthen, “you can’t just shove a bunch of new AMPA receptors to the surface because they will just go away again,” Bressloff said. “You need to keep them there.” So what we remember and learn is in effect, he argued, anchored to nerve cells in our brain.