Primate research in neuroscience



Much of what we know about the human brain derives from neuroscience research on non-human primates. Given our present state of knowledge, research on primates is likely to be necessary for the foreseeable future. We know all too little about the details of how the human brain is organised for computer models of the brain to be sufficient at this stage.

Our understanding of the functioning of the nerve cell itself has been based on animals such as the rat and even invertebrates, but the nature and complexity of the organisation of these nerve cells to form different brain systems cannot be understood without studying the primate brain. The complex nature and connectivity of these neural systems is much closer to that found in the human brain in monkeys than in other animals. For example, the large cortical mantle of the brain, the cerebral cortex, is poorly developed in non-primates. And certain portions of the brain, such as the temporal and frontal lobes, which are involved in the higher cognitive functions such as perception, attention, memory and planning, are only present in primitive forms in lower animals. Although there are some aspects of cognition that may be unique to humans, there is very strong evidence for structural, functional, behavioural and neurobiological commonalities or homologies that extend across species.

The study of neurological and neuropsychiatric disorders, which generally implicate higher cognitive functions and brain structures such as the frontal lobes, depend much more on studies of primates than of other animals. For example, disorders such as depression, schizophrenia, Attention Deficit Hyperactivity Disorder, autism, drug addiction and Obsessive Compulsive Disorder all implicate malfunctioning of the frontal lobes and their interactions with other structures. This is also true of neurological conditions such as closed head injury, Parkinson's and Huntington's diseases, stroke and some dementias.


Alzheimer's disease

Alzheimer's disease is a crippling disease of old age which begins in the temporal lobe and related brain areas with accompanying cognitive deficits such as loss of memory. By using models of some of these conditions it is possible to understand better how they arise and how to treat them. It is generally impossible to model all aspects of a complex human disorder such as schizophrenia or Alzheimer's disease with animals by producing symptoms that exactly match those of the human disorder. However, it is possible to model not only some aspects of neuropathology, but also some of the behavioural and cognitive deficits. For example, in non-human primates damage to parts of the cerebral cortex and hippocampus that in humans are affected by Alzheimer's disease, produce deficits in memory that are qualitatively similar to those seen in Alzheimer's disease and can be used to assess novel anti-Alzheimer's drug therapies. One way in which studies of primates has been essential has been to determine the neuroanatomical organisation of the human brain at a microscopic level (ie the detailed 'wiring diagram' of the different systems and how they connect to one another). Many brain disorders arise because of loss of communication between different brain regions or are due to impaired function within these systems. It has proved largely impossible to understand the wiring of the human brain from post mortem studies, and studies of rodents are only of limited applicability because their brain structure is not sufficiently similar to humans. Structural brain scanning using CT or MRI cannot provide the necessary spatial resolution for specifying these connections. Therefore, it is necessary to study the anatomy of the primate brain at the microscopic level.

To study how nerve cells work to produce behaviour it is necessary to examine their firing patterns using microelectrodes that are implanted under anaesthesia. This technique does not in any way incapacitate the animal and only causes minimal discomfort. The techniques are quite similar to those used in certain human disorders such as epilepsy where it is necessary to record brain activity. The information provides us with the basis for understanding how brain systems form impressions of the world, make decisions and act appropriately. Studies using only functional imaging in humans are inadequate for fully understanding the role of the brain in cognition for several reasons: the nature and therefore the exact meaning of the imaging signals with respect to neuronal activity is incompletely understood; the spatial and temporal resolution of the signals is inadequate; and because the technique does not establish whether particular neural systems are necessary for aspects of cognition - it only shows that these systems may be active during cognition.

The most precise way of determining the causal role of particular brain structures or systems is to study the way they function when they are damaged or lesioned. In humans, inferences made about brain-behaviour relationships on the basis of lesions are extremely limited because the damage in patients arising from accidental injuries or disease processes is often diffuse or extends across several neural systems. Techniques for temporary inactivation of the human brain, such as transcranial magnetic stimulation, are also relatively gross, affecting the functioning of a number of systems and only applicable in limited circumstances. Therefore, it is necessary to study the effects of small lesions directed at discrete cells or systems, and this is best accomplished for studies of cognitive function involving the cerebral cortex and related structures in primates.

For such experiments, it is vital that the animals are stress-free and are kept in conditions that provide best practice in terms of welfare. No forms of painful aversive motivation are used, although they may have to work for some of their preferred foods. In general primates enjoy solving puzzles and interacting with computer screens.


Parkinson's disease

Although Parkinson's disease is probably not naturally present in most animals it is possible to simulate some of the symptoms of this condition. In fact, our understanding of the pathology and treatment of Parkinson's disease has depended almost entirely in studies with other animals. These have enabled us for example to discover the neurotransmitter dopamine in the brain, measure it in the human brain and show it is deficient in certain parts of the brain in Parkinson's disease. They have also enabled us to develop the successful therapy of L-dopa. However, L-dopa medication is not a perfect treatment and clinicians have been seeking other forms of treatment - based for example on transplanting stem cells into the brain or on other procedures.

One of these is subthalamic electrical stimulation. From studies of monkeys, the entire neural circuitry implicated in human Parkinson's disease has been unravelled - involving connections between for example, the frontal lobes, and the basal ganglia. Part of the problem of Parkinson's disease is that the loss of dopamine in the basal ganglia causes the motor (and cognitive) output system to seize up because certain structures become too active. These effects can be curbed however by disengaging a specific basal ganglia structure called the subthalamic nucleus. This can be done by giving this structure stimulation with tiny amounts of electrical current. This was originally shown to work in primates with some Parkinson's disease symptoms - and has recently been tried in human patients with considerable success. The patients are able to regulate the activity of this nucleus by stimulating themselves via an implanted electrode-like a heart pacemaker. The benefits are often immediately apparent and quite dramatic.


Drug addiction

It is now gradually becoming clear that chronic drug abuse may be associated with brain damage and disastrous cognitive sequelae in humans. This may make impossible the full rehabilitation of addicts, even when they are detoxified. In fact, some forms of cognitive impairment dependent on frontal lobe function (in complex decision-making) have been shown to correlate with the duration of drug abuse, for drugs such as amphetamine. It may also be true for related drugs such as MDMA (Ecstasy). However, we do not know the basis of this correlation - it may arise from some pre-existing deficit in the brain of the drug abuser. It is actually impossible to be sure whether the drug abuse has actually caused these deficits because we cannot study humans at earlier stages in their development, nor can we ever be fully aware of the variety of drugs or other life events that may have affected them. The only way to isolate and thus determine whether it is exposure to a particular drug that causes the problems is to study its effects in an experimental, controlled manner in animals.


Schizophrenia

Recent advances with gene microchip technology are showing that certain genes are expressed differently from normal in the frontal cortex of patients with schizophrenia. However, it is difficult to be sure that these potentially important clues to how the brain has become 'miswired' are actually due to a disease process, possibly arising in brain development, or are merely side-effects of treatment with drugs which are used to treat schizophrenia. The same types of gene are expressed in the monkey frontal lobes. Only by studying whether comparable drug treatments lead to the same changes can we rule out this potential artefact. In addition to this need to understand how anti-schizophrenic drugs work, it is becoming increasingly necessary to determine how such drugs may improve the impaired cognitive functions of the temporal or frontal lobes that prevent full rehabilitation, even after the psychotic symptoms have remitted.