One of the central dogmas of neuroscience, which persisted for much of the history of the discipline, was that the adult human brain is immalleable, and could not change itself once fully developed. However, we now know that this is not the case: rather than setting like clay placed into a mould, the brain remains pliable, like a piece of putty, so that each new experience makes a lasting impression upon it.
This phenomenon, referred to as synaptic (or neural) plasticity, involves reorganization of the connections between nerve cells, and is arguably the most important discovery in modern neuroscience. It is well established, from research carried out in the past 20 years or so, that the brain can adapt itself to any circumstance; this therefore opens up the possibility of therapies for a wide variety of neurological conditions.
Until now, it was thought that such reorganization is restricted to small numbers of connections within discrete areas of the brain. But new research published yesterday in the journal Current Biology now provides the first evidence that local modifications to small numbers of connections can induce global changes in brain connectivity.
In his seminal 1949 book The Organization of Behavior, the Canadian neuropsychologist Donald Hebb postulated a mechanism by which experience can result in learning, by impinging upon the connections between nerve cells in the brain:
Let us assume that the persistence or repetition of a reverberatory activity (or “trace”) tends to induce lasting cellular changes that add to its stability…When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.
Hebb had remarkable foresight – decades later, researchers found evidence for the mechanism he has proposed. Now referred to as long-term potentiation (LTP), this mechanism has since become the most intensively studied in modern neuroscience,and is widely believed to be the cellular basis of learning and memory, although this is yet to be proven unequivocally.
LTP can be induced experimentally, and this is most often done in slices of tissue from the hippocampus, a part of the brain which is known to be crucial in memory formation. This is done by using a microelectrode to apply high frequency stimulation to axons in the perforant path, which project from the entorhinal cortex and constitute the main synaptic input into the hippocampal formation. At the same time, the cells in the hippocampus which receive those inputs are also stimulated. Subsequently, stimulation of the perforant path alone elicits an enhanced (or “potentiated”) response in the downstream cells. This can be measured using a recording electrode, and can last for as long as several months.
LTP is thus defined as the persistent strengthening of a connection between two nerve cells following simultaneous stimulation of both cells. This definition is essentially the same as that out forward by Hebb, but modern techniques have enabled researchers to analyse LTP in more detail, and to elucidate the molecular mechanisms by which communication between the neurons in a potentiated synapse is enhanced. Some studies have pointed to an increase in the amount of neurotransmitter molecules released by the cell generating the signal, while others suggest that there is an increase in the concentration of receptors in the membrane of the cell receiving the signal.
The extent to which each of these processes contributes to to synaptic strengthening is still the subject of debate, but it is likely that both are involved, and that different forms of LTP are dependent upon these mechanisms to different extents. One molecule that is known to be essential for LTP induction is the NMDA receptor. In its resting state, this receptor is blocked by a magnesium ion which nestles in the pore, and which is only removed by a change in the membrane voltage. Activation of the receptor therefore requires not only a change in membrane voltage, but also binding of the neurotransmitter glutamate. These unique properties make the NMDA receptor an ideal candidate for inducing the early stages of LTP, because it will only when a cell receives two simultaneous inputs.
In the new study, Santiago Canals of the Max Planck Institute for Biological Cybernetics in Tübingen and his colleagues used the same protocol to induce LTP. But while the vast majority of researchers have investigated LTP in slices of hippocampal tissue, this study involved observing LTP in live animals. To do this, the researchers first anaesthetized 14 rats, then made small openings in the animals’ skulls so that electrodes could be implanted into the hippocampus. The electrodes were fixed to the sides of the opening in the skull with dental cement and plastic screws. The rats were then fitted into a custom-made fMRI-compatible frame which prevented them from moving their heads, and placed in the scanner. In this way, the researchers could induce LTP in their experimental animals and simultaneously monitor the global changes in brain activity induced by it.
Following induction of LTP, stimulation of neurons in the perforant path was found to activate cells in the hippocampus which receive inputs from them, as measured by an increase in blood flow to that region of the brain. Unexpectedly though, it also led to increased activity in the subiculum and entorhinal cortex, areas which surround the hippocampus, and to activation of these same regions in the opposite hemisphere. In fact, the acitivty in the opposite hemisphere was found to be higher than that of the activity of cells in the hemisphere in which LTP had been induced. But the effects went even further afield than the hippomcampus and adjacent regions – activation of neurons in the prefrontal cortex, nucleus accumbens and olfactory nucleus was also observed. Application of MK-801, a compound which blocks the NMDA receptor, inhibited this activity, confirming that it was occurring in response to the LTP induced in the perforant path-hippocampus synapses.
Earlier studies have shown that LTP induces a series of biochemical changes within individual neurons. These can eventually lead to structural changes in the microscopic organization of neurons which enable the potentiated connections to persist for longer periods of time. Cells can not only strengthen existing synapses, but they can form de novo connections, by sprouting new dendritic spines, the tiny finger-like projections at which synapses are located. However, these changes have until now been thought to occur only at the level of single potentiated synapses.
This new research provides the first evidence that the local modifications in synaptic connections induced by LTP lead to long-lasting changes in the activity of a diffuse network of brain regions, and even to facilitated communication between the two hemispheres. The fMRI data showed that hippocampal LTP recruits higher order association areas, as well as regions involved in emotions and others subserving different sensory modalities, all of which are known to be involved in memory formation.
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Canals, S. et al (2009). Functional MRI Evidence for LTP-Induced Neural Network Reorganization. Curr. Biol. 519: 398-403. DOI: 10.1016/j.cub.2009.01.037