The final section of this chapter deals with molecular genetic approaches to the neurobiology of learning. In so far as changes in behaviour are learnt (a proposition that applies as much to therapeutic interventions as to the development of disordered behaviour), understanding the neurobiology of learning encompasses almost all psychiatric practice/4,) In the future, a neurobiological understanding of the relationship between brain and mind will be possible, using the sort of approaches described below. While they are still far from making an impact on clinical practice, the potential for them to do so is very great indeed.
Animal studies of memory indicate that learning induces gene expression, which in turn leads to the growth of new synaptic connections, as explored most fully in the snail Aplysia.(73 In a typical experiment the snail is given a noxious stimulus and then develops a vigorous withdrawal response to a previously neutral or indifferent stimulus. The key finding here is that the animal's memory has at least two forms; while a single noxious stimulus gives rise to sensitization lasting minutes to hours, repetitive stimulation produces sensitization that can last days to weeks. The short- and long-term changes have different properties; long-term, but not short-term, sensitization is blocked by inhibitors of RNA and protein synthesis, and long-term sensitization involves synaptogenesis. Thus long-term changes require gene induction, which is essential for the development of new neuronal connections.
At least part of the molecular pathway involved has now been identified: cell surface receptors activate protein kinase A ( PKA) via an increase in cAMP. PKA acts in the nucleus to activate cAMP response element binding protein 1 (CREB1) and to relieve CREB2-mediated repression. One consequence is downregulation of cell adhesion molecules (in Aplysia these are termed apCAMs), decreasing the interaction of neurites and resulting in the generation of new synaptic connections.
It is now clear that the same pathway is used by other organisms; mutations in PKA or its subunits disrupt olfactory learning in the fruitfly Drosophila}71) Two forms of CREB have been identified that have complementary effects on olfactory learning in Drosophila, just as they do in Aplysia. The situation in mammals is more complex, but CREB has been identified as a key molecule in learning. Mice with a targeted mutation in the CREB gene have spatial memory deficits. (72) The animals could be conditioned to a tone and could learn to find a hidden platform in a water bath, but both skills were lost after 30 min. In other words, the deficit specifically affected long-term memory. Successful short-term training ruled out motivational sensory or motor deficits as an explanation.
The involvement of CREB in long-term memory in molluscs, flies, and mice indicates the existence of an evolutionary conserved pathway that operates in neurones. There seems little doubt that what applies at the neuronal level in molluscs, flies, and mice will apply to humans. While this is consoling, it also suggests that genetic approaches may not tell us what we would really like to know. Molecular neurobiology is very good at revealing the commonalities between species, but most psychiatrists are concerned with the behavioural repertoire that makes humans distinct. From a strictly biological point of view, that means asking what is distinctive about neural connections and activity in humans.
An answer requires that we know first how genetic effects determine neural activity, and that is now possible. The best example comes again from the study of memory, this time in the hippocampus. Pyramidal cells in the hippocampus fire when a rodent is in a restricted region, and information about the location of an animal can be estimated from the simultaneous firing patterns of many hippocampal neurones.(7 ,74) Genetic knockouts have been used to investigate the molecular basis of this phenomenon.
A modification of gene-knockout technology was used to ablate the W-methyl-D-aspartate receptors specifically from hippocampal pyramidal neurones, (75,76) resulting in impaired spatial memory. How is this genetic effect mediated? A miniaturized multi-electrode recording device was used to examine the firing patterns of hippocampal neurones. Fairly normal place cell activity was observed, but there were significant alterations in the size and quality of place fields. Cells with overlapping fields tend not to fire at the same time, giving incorrect signals about the animal's position and impairing its spatial memory. Thus genetically determined changes in synaptic plasticity are linked to both electrophysiological and behavioural impairments. This experiment demonstrates for the first time how genetic influences on cognitive processes can be interpreted as acting at the level of a neural system (spatial memory) and not just on its cellular components (neurones).
Thus, while molecular neurobiology has not yet progressed to the point of explaining how neural activity determines behaviour, it has begun to give us a molecular description of a neural system. Does this mean that we can expect similar advances in our understanding of other neural systems? A moment's reflection will show that successful application of genetic approaches requires that the neurobiology of the system is already well worked out. Consider again the example of the CREB gene in long-term memory/72)
CREB proteins are not specific to the hippocampus. Indeed, they are widely distributed throughout the tissues of the body and involved in so many fundamental cellular processes that it is surprising that the CREB knockout mouse is viable. Thus the knockout experiments, while strongly supporting the view that CREB is required for long-term memory, raise another question. Why, contrary to our expectations, are the effects of the knockout apparently so specific?
The answer probably lies in the fact that specific effects arise because there is considerable redundancy in most genetic systems; another gene can at least partly take over the role of a missing or abnormal gene. However, such an answer raises new problems. If phenotypes arise due to the partial rescue of mutant, to what do we attribute the effect? Is it simply a reduced effect from a single gene acting in many different brain systems, is it complete absence of gene effect in one brain system (where isoforms cannot compensate), or is it the accumulated, and presumably unpredictable, result of compensatory mechanisms? As yet, we do not have definitive answers to these questions.
The important observation here is that genetic approaches on their own do not tell us how genes shape behaviour. In fact they often raise more questions than they answer, and this has implications for the hopes placed in positional cloning as a method of unravelling the biology of the mind. Accessing the neural correlates of mood disorders and psychosis or normal behavioural and cognitive traits appears possible by using the positional candidate cloning strategies described above. But, even with the genes in our hand, we may be no wiser about what they do. The detailed functional assays described above for memory have only been possible because so much was already known about its anatomical, cellular, and molecular basis.
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