NEONATAL BRAIN DEVELOPMENT

NEONATAL BRAIN DEVELOPMENT
When mammals are born, they have to pass through a narrow birth canal, which places a practical limit on neonatal head size. But this does not necessarily limit ultimate brain size, so long as further brain development can take place after birth. This is not too much of a problem for human infants, whose particularly helpless state at birth is made feasible by parental care. Small animals like rats can hide their young safely away in holes. So, like humans, the young can be born immature without incurring excess risk. In contrast, herbivores that inhabit open grassland may need to be able to run with the herd within minutes, or at most a few hours, of their birth. Such creatures could not afford a long postnatal period of general brain development. This problem has been solved in a different way by the kangaroo, which is born very early in its development but remains protected in the safety of its mother’s pouch, where it continues to develop until it is capable of independent movement. Our own protracted postnatal development not only allows us to grow a bigger brain (the adult brain is around four times the size of a new-born baby’s brain). It also ensures that our brain continues to develop while we are interacting with our environment. So each person’s brain will, to a certain extent, be adapted to the circumstances of their lives. Survival of the most useful The first sign of what will become the brain appears very early in human gestation. By the end of the second week, a neural plate made up of precursor neurons can be identified. By the end of the first month, a primitive brain has already formed. Like other parts of the body, the brain develops when cells migrate to the appropriate place. Those cells have to know how to differentiate into the right kinds of eventual cell types, and when to stop differentiating. But brain development requires more than cells simply knowing how to get to the right place and what to do when they are there. For this particular organ, a high level of competitiveness is involved. During development, connections in the brain respond to what is going on. We start off with many more potential neurons than will eventually survive. Neurons compete to make connections with their targets, and it is the connections that are actually used which seem to have a better prospect of survival. Unsuccessful neurons die, through a process of programmed cell death, called apoptosis. If one set of neurons fails to make its normal connections, then another set of opportunist neurons may colonize the vacant space.

The NMDA receptor

The NMDA receptor
One key element in LTP is a particular subtype of glutamate receptor, the NMDA receptor. Calcium entry into the cell is one of the triggers for the development of LTP. The NMDA receptor controls a calcium ion channel that is both transmitter dependent and voltage dependent. This means that even when the NMDA receptor is activated by glutamate, no calcium will pass into a cell through the NMDA-controlled channel unless the target cell has also recently been depolarized. So NMDA dependent LTP can only develop in a cell that has been depolarized and then receives a further input – exactly the conditions that apply during a burst of high frequency stimulation. The mechanism underlying this dual sensitivity to neurotransmitter levels and voltage levels is remarkably simple. It turns out that in cells at their normal resting potential, a positively charged magnesium ion is held in the channel by the electrostatic gradient across the cell membrane. If the NMDA receptor is activated, so that the channel could, in principle, be opened, the inflow of calcium is blocked by the magnesium ion. Once the cell is depolarized, nothing holds the magnesium ion in place, so it can diffuse into the extracellular fluid. If the NMDA receptor is again activated at this point, the ion channel opens and, with the magnesium block removed, calcium can pour into the cell, triggering the series of events that leads to LTP. Of course, as the cell repolarizes, the magnesium ion is drawn back into position once more. The LTP system, particularly in the hippocampus, has been a focus of intense research activity. Rat experiments have shown the blockade of the NMDA receptor by the drug AP5 prevents the development of LTP, and at the same time appears to prevent the normal operation of hippocampus-dependent spatial memory (Morris et al., 1986). More recently still, psychological studies of ‘knockout’ mice, genetically engineered so they can no longer show LTP in the hippocampus, have also shown striking failures of hippocampus-dependent spatial memory tasks, that neatly parallel the effects on LTP (e.g. Reisel et al., 2002). If we can combine these new techniques in molecular biology with sophisticated behavioural analysis, we will have ways to study the relation between brain and cognition at a finer level of detail than has ever been possible before. So we have seen that the adult nervous system is highly modifiable: our brains change in accordance with our experiences. Is the development of our brains modified by the environment too?

LTP and LTD

LTP and LTD
Although there are many ways to modulate neuronal function, they are not usually linked to specific psychological functions. But neuromodulators neurochemicals that indirectly affect neuronal activity, usually by modifying response to other chemical neurotransmitters paracrine non-classical effects of neurotransmitters that may not be released at the synapse, and/or whose receptors are not located at the synapse neurocrine classical neurochemical action of transmitters that are released at the axon terminal to affect specialized receptor sites across the synaptic cleft there is one form of synaptic modifiability that has led researchers to make striking and specific claims, presenting it as a possible neural basis for some forms of learning or the ability to lay down new memories. The first crucial observation was made by electrophysiologists studying the responses of cells in the hippocampus, a structure that is crucial in memory processing. They found that the size of the neuronal response to a single pulse of electrical stimulation at a given intensity could be increased, in a long-lasting way, by giving a relatively brief burst of high frequency stimulation. By comparing the size of the response to a single pulse before and after this high frequency series of pulses, researchers showed beyond doubt that neuronal responsiveness had increased. This change is called longterm potentiation, or LTP. It is now clear that LTP can be seen in many structures in the brain, and not only those thought to be associated with memory. It is highly likely, though, that LTP always reflects experience-dependent changes in neuronal functioning, whether in the sensitization produced by painful stimuli, or in perceptual development in the visual cortex, or in the laying down of memory traces in the brain. It has also become clear that there is a complementary process – long-term depression, or LTD – which describes a decrease in neuronal response. The ability either to increase or to decrease synaptic connectivity as appropriate offers maximum flexibility for adjusting neuronal function.


[Tim Bliss (1940– ) and Terje Lømo (1935– ) first reported the phenomenon of long-term potentiation. The plausibility that a strengthening of synapses might underlie memory storage increased tremendously when the phenomenon of long-term potentiation (LTP) was discovered by these two researchers. In the 1970s, Bliss and Lømo noticed that if they applied a few seconds of high frequency electrical stimulation to certain neurons in the rabbit hippocampus, synaptic transmissions to those neurons would increase in amplitude. More surprisingly, this enhancement seemed to be long-lasting, sometimes persisting for weeks (Bliss & Lømo, 1973). This phenomenon has since been termed long-term potentiation, or LTP. In the twenty years since its discovery, a great debate has raged among neuroscientists about whether this LTP might be the crucial mechanism underpinning learning and memory.]

Neuromodulators and hormones

Neuromodulators and hormones
A still further level of complexity is provided by non-classical neurotransmitter substances. Some of these are released by neurons like the conventional neurotransmitters already described, but they can have longer-lasting actions and (like paracrine neurotransmitters) act at greater distances from their release sites. Some may have no directly measurable effects on their targets, but they may change the target neuron’s responsiveness to its other classical neurotransmitter inputs. There is a more or less indefinable boundary between these substances – often called neuromodulators – and hormones. For example, cholecystokinin (CCK) is a peptide that is released as a hormone by the duodenum (part of the digestive tract), but is also released like a neurotransmitter from dopaminergic neurons in the brain, where it modifies the responses of dopamine autoreceptors. So the same molecule can operate as a neuromodulator in the brain and as a hormone in the gut. Hormones are molecules that are released into the bloodstream from specialized endocrine glands (such as the pituitary gland or the adrenal gland) and can therefore, in principle, act anywhere in the body. For hormones, specificity of action results from the presence of chemically specific receptors on the target structures that are bathed by the bloodstream. The hormonal receptors are activated when the hormones pass by in the blood. Hormones can affect neuronal function in a similar way to neuromodulators, changing sensitivity to other inputs and altering the release of neurotransmitters.

Paracrine effects

Paracrine effects
Target neurons can also have receptors located outside the specialized synaptic region. They are presumably activated either by neurotransmitter that escapes from the synaptic cleft, or perhaps by a transmitter that is itself released outside specialized synaptic regions.

These extra-synaptic routes for chemical communication are sometimes called paracrine systems, as opposed to the more classical neurocrine routes. Their existence adds yet further subtleties to neuronal activity. It is possible that, under certain neuronal conditions, overflow from the synaptic cleft becomes more likely. This overflow could then differentially activate these non-classical paracrine communication routes, potentially producing qualitatively different actions on the target structures.

Autoreceptors

Autoreceptors
We have so far described transmitter being released by the pre-synaptic neuron, crossing the synaptic cleft, binding to postsynaptic receptors, and shortly afterwards being deactivated. In fact, by no means all receptor sites are located on the post-synaptic membrane. Surprisingly, some axons have receptors for their own neurotransmitter – autoreceptors. For example, there are dopaminergic cells with dopamine autoreceptors on their axons. These can be activated by the dopamine that their own cells release, to provide a local, negative feedback loop, which can inhibit the cell from further firing. So input neurons can modify their own activity while activating their post-synaptic targets.

Autoreceptors

Autoreceptors
We have so far described transmitter being released by the pre-synaptic neuron, crossing the synaptic cleft, binding to postsynaptic receptors, and shortly afterwards being deactivated. In fact, by no means all receptor sites are located on the post-synaptic membrane. Surprisingly, some axons have receptors for their own neurotransmitter – autoreceptors. For example, there are dopaminergic cells with dopamine autoreceptors on their axons. These can be activated by the dopamine that their own cells release, to provide a local, negative feedback loop, which can inhibit the cell from further firing. So input neurons can modify their own activity while activating their post-synaptic targets.