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Research @ Cardiff University

From brain to behaviour - unravelling the biological basis of learning and memory

Summer 2010

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Psychologists, behavioural geneticists and neurologists are working together to understand the fundamental mechanisms of learning and memory. Their work has implications for understanding how brain function and structure change, for example as we get older, as well as better informing the management of a wide range of neurological conditions from Alzheimer's disease to drug addiction and schizophrenia.

Beyond Pavlov

Animals, including people, readily learn links between events that occur close together in time and space. The classic example of animal learning comes from Pavlov's demonstration that dogs that were fed immediately after hearing a bell began to salivate in advance of the food when the bell was rung. This 'associative learning' mechanism may also play a crucial role in how people distinguish between similar faces as well as how we learn to like and dislike particular foods.

And it appears that the way in which rodents drink is particularly informative with respect to how much they like what they are drinking. "Rats tend to produce few, but rather long, bouts of licks when they like a solution they are drinking but the length of the bouts decreases while the number of bouts can increase with a less palatable solution," explains Dr Dominic Dwyer.

Using this technique, Dr Dwyer is shedding light on the underlying biological basis of complex disorders such as depression and schizophrenia. "Drugs like PCP induce some of the cognitive effects of schizophrenia, but they do not produce changes in how animals like and dislike foods," explains Dwyer. "This suggests that different symptoms of schizophrenia - cognitive and emotional effects - are caused by separate biological mechanisms."

He has also found that animals come to dislike the taste of foods that they associate with illness. Interestingly, animals will avoid consuming foods paired with the unpleasant side effects of drugs such as amphetamine but they still enjoy the taste of those foods.

"This research suggests that your reactions to foods which make you feel sick are different to those that make you worried," says Dwyer.

Like man, like rat

If you were asked to judge the similarity of a 'torch' and a 'rope' you might say that the two things are not similar at all. If, however, the same question was posed in the context of 'things taken on camping trips' you would most probably have judged them to be more related.

"People's judgements about whether two stimuli are associated with one another are not solely determined by their physical properties," explains Professor Rob Honey. "Rather they are influenced by the context in which the judgement is made."

This flexibility in similarity judgements has been contrasted with the seemingly inflexible judgements of similarity evident in the rest of the animal kingdom, where similarity is simply assumed to reflect the physical properties of stimuli. However, in a BBSRC-funded project, Professor Rob Honey together with Professor Ulrike Hahn and PhD student James Close have discovered that rats show an analogous form of flexibility. Moreover, the theoretical analysis for how this flexibility can be stimulated in rats has the potential to provide an account for the same finding in people.

Pay attention bird brain

Professor John Pearce FRS is using an ingenious new technique to explore where animals will direct their attention when they are learning about changes in their environment. Much of his current research is focussed on homing pigeons, whose remarkable vision makes them ideal for studying changes in attention during complex learning tasks.

"The term 'bird brained' is a bit of a misnomer. At least in some respect, pigeons display considerable intelligence," says Pearce. "For example, they are capable of remembering hundreds of different photographs, and of forming something akin to concepts. The experiments in our test chambers are revealing, not surprisingly, that pigeons attend to stimuli that signal the delivery of important events such as food or water, but they also pay attention when they can't work out what a stimulus is signalling."

This last finding is in keeping with the highly cited Pearce-Hall theory. A parallel series of experiments with rats is revealing that, despite the obvious differences between the two species, the same principles of attention appear to apply to both of them. It is also highly likely that the principles extend to humans. For instance, advertisements on the television hold our attention by keeping the viewer uncertain about the nature of the product being advertised until as late as possible.

The main purpose of Pearce's research is to identify a general set of principles specifying where an animal will direct its attention. Once these principles are clear he intends to identify the neural mechanisms responsible for changes in attention, and this is the basis of a new project funded by BBSRC with Professor Mark Good.

Brain stimulation

In a similar vein, BBSRC David Phillips Fellow Dr Chris Chambers is exploiting a combination of experimental techniques to understand neural mechanisms of selective attention, awareness and cognitive control in the human brain.

"Even though attention is traditionally considered as a universal process, we have found that transcranial magnetic stimulation (TMS) can reveal remarkable brain specialisations for different components, such as attending to colour or spatial location, and to a light or touch to the hand. We are also finding that TMS can shed light on the role of the mysterious prefrontal cortex, distinguishing between higher aspects of cognitive function such as impulse control and working memory."

"Having recently established simultaneous TMS and MRI in Cardiff, we are looking at exciting times ahead. In the longer term, our hope is that new insights into the basic biological mechanisms of attention and cognition will have implications for the wide range of cognitive deficits that accompany brain injury and disease," says Chambers.

Chambers is also leading advances in the application of TMS to cognitive neuroscience, where a critical issue is the control of TMS intensity. Together with his team in the Cardiff University Brain Research Imaging Centre (CUBRIC), Chambers has found that the extent of cortical activity during TMS is steeply related to the distance between the scalp and the cortex. Even a difference of 1mm in the scalp-cortex distance between different sites can have a measurable and reliable effect on TMS-evoked behaviour. They have therefore developed a linear scaling method for calibrating the intensity of TMS according to scalp-cortex distance, enabling more precise and comparable stimulation of different regions. In collaboration with Dr Mark Stokes at the University of Oxford, they are also developing a neurological atlas for TMS that combines thousands of anatomical MRI scans to map the scalp-cortex distance across the entire brain.

Making connections

Dr Seralynne Vann has been studying the mammillary bodies (MBs), two small, spherical structures at the base of the brain whose role in memory may have been underestimated for many years.

"The mammillary bodies were largely ignored as researchers became distracted by an over-arching role for the hippocampus in long-term memory, yet they have been implicated in memory since the late 1800s," explains Vann. "We know that damage to the MBs, caused by a lack of thiamine to the brain or through years of alcohol abuse, can lead to Korsakoff's syndrome, a condition characterised by severe memory loss. However, there is still no clear consensus on what the functions of the MBs are or how they interact with other brain structures to support memory."

With the support of a BBSRC David Phillips Fellowship, Dr Vann studied the link between MB damage and memory impairment. Her work with clinical groups of patients revealed reduced MB volume to be consistently related to poor memory. By using a combination of convergent approaches she confirmed that MBs are also important for spatial memory in rats and, indeed, necessary for the hippocampus to function properly.

"These findings have led to a re-assessment of the classic temporal lobe-medial diencephalic memory models as well as a renewed focus on the 'limbic midbrain' for memory," says Vann, who was recently awarded a Wellcome Trust Senior Research Fellowship to take her research forward.

The value of a better understanding of the mammillary bodies is underlined by their vulnerability in conditions such as Korsakoff's syndrome, colloid cysts, Alzheimer's disease and schizophrenia. Understanding both normal and abnormal mammillary body function is essential for determining how these conditions impair memory and how that loss might be restored.

Making and breaking habits

Imagine how much more difficult life would be if, for example, every time you made a cup of tea you had to consciously think about every minute step of the process. Our ability to perform everyday tasks without effortful thinking is the result of practice, where, over time, repeated behaviours become fluid and relatively automatic habits.

Habits are important for normal functioning and contribute to brain and behavioural economy; allowing us, where the world is relatively unchanging, to perform routine tasks without effortful thought, whilst at the same time retaining the ability to adapt flexibly when things change.

Understanding which brain structures are involved in the development of habits and, consequently, what happens when the balance between habitual and effortful or 'goal-directed' behaviours is upset could further our understanding of aspects of drug addiction, obsessive compulsive disorder, Tourette's syndrome and autism, where individuals often exhibit rigid and repetitive behaviour patterns and an inability to show behaviours appropriate to their context.

By developing a novel virtual maze environment, to study the behaviour of rats in the presence of different environmental cues, Dr Josephine Haddon and Professor Simon Killcross (now at the University of New South Wales, Australia), examined the transition between habitual and goal-directed actions.

"We know that environmental cues play a key role in both the formation of memories and drug addiction," explains Haddon. "Now we have a tractable model to study behaviour in a more naturalistic setting - and the rats love it!"

"What's more," adds Professor Lawrence Wilkinson, "We can take our research to new levels: we know key brain structures involved in learning habits; we can measure levels of neurotransmitters such as dopamine; and in new work we are examining which genes are involved, and the epigenetic mechanisms underlying the changes to gene function related to habit formation and expression."

Where are my keys?

What if, whenever you tried to remember where you had left your keys, every place you had ever left your keys came to mind?

In order to remember something, you obviously need to recall the relevant information, but it is just as important to avoid recalling irrelevant information.

Using a combination of brain imaging techniques to track changes in neural activity in real time, Dr Ed Wilding has explored how successful remembering involves recalling some kinds of information whilst inhibiting others.

"We have shown that people automatically inhibit irrelevant information when trying to remember, and how well you can inhibit irrelevant information predicts how good your memory is," says Wilding. "We now have a clearer idea of the roles that inhibition plays in memory retrieval. This is important for understanding why memory abilities can decline with increasing age, because our capacity for inhibition also declines as we get older."

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