Neuroimaging: CAMH Research Annual Report 2002

In the Neuroimaging Section, we aim to identify specific brain areas, neuroanatomical pathways and chemical mechanisms involved in neuropsychiatric disorders. This is done through detailed post-mortem analyses of anatomically preserved brains from animal models or human subjects. Research continues in three major areas.

Models of Depression

We are analysing brain alterations in four different models of depression, in particular the role of thyroid hormones and their receptors in brain. We continue to study models involving reactivity to stress as well as genetic models provided by collaborators from McMaster University, the University of Maryland and the Federal University of São Paulo. These analyses are complemented by similar investigations of the effects of various types of antidepressant interventions, including sleep deprivation, on the same brain systems and pathways.

In the chronic mild stress anhedonia model, we have found significant and widespread decreases in the expression of alpha1 thyroid hormone receptors in brain. When animals were treated with the antidepressant imipramine, both the behavioural deficits and brain receptor changes reverted to normal levels. These brain changes were not seen in the helplessness model of depression, suggesting that they may be associated with specific types of depressive symptoms.

Brain analyses in these models were expanded with the introduction of cDNA microarray techniques for large-scale gene screening.

We have reported upregulation and downregulation in a number of genes in the frontal cortex of animals showing vulnerability to depressive symptoms after stress. Unexpectedly, we found that a different set of genes was affected in animals showing resistance to depressive symptoms following stress.

In the sleep deprivation model, we reported the negative results of a fairly comprehensive assessment of neuropathology, using gene markers of apoptosis and autoradiographic indices of necrosis in brain. This agrees with other evidence that sleep deprivation does not induce neuronal loss.

The neuropeptide orexin has been identified as a key element in human narcolepsy. We have started to examine orexin, and have reported increases in the expression of the precursor prepro-orexin after sleep deprivation and after sleep rebound. We are currently completing in situ hybridization analyses of expression of orexin1 and orexin2 receptors after sleep deprivation.

Brain Dopamine and Movement Disorders

In collaboration with investigators from Hanover, Germany, a long-term project continues to build a comprehensive map of brain alterations in a genetic model of paroxysmal dystonia. This year we reported significant changes in glutamatergic AMPA receptors in basal ganglia as well as changes in NK-3, but not NK-1, Substance P receptors in dystonic hamster brains.

We have made significant progress in our ongoing work with a model of tardive dyskinetic syndromes induced by long-term antipsychotic treatment. In collaboration with clinical researchers from the Centre's Schizophrenia Division, we have identified and reported important differences related to role of antipsychotic dose and route of administration (continuous vs. intermittent availability) in defining the risk of late-onset dyskinetic symptoms. We have also reported early gene activation data on a modified clozapine molecule. This finding is in line with the hypothesis that dopamine D2 receptor occupancy is a key factor in defining atypicality for antipsychotic drugs. However, our current work with mice lacking dopamine D1 or D2 receptors suggests that long-term dyskinetic effects must involve other factors in addition to D2 receptor occupation

Brain Mechanisms of Compulsive Drug-Taking

For the last few years, in collaboration with a group from São Paulo, Brazil, we have been systematically investigating brain mechanisms underlying differential susceptibility to alcohol sensitization.

We have reported that animals showing differential propensity to alcoholsensitization have increased levels of D2 binding in specific areas of the limbic forebrain. We reported separately that similar changes were not seen in D1 receptors or in the dopamine transporter. We have also found and reported increased levels of nmda binding in mice showing resistance to ethanol sensitization.

In collaboration with investigators from the Biobehavioural Pharmacology and the Pharmacogenetics laboratories at CAMH, we reported localized brain changes in 3H-flunitrazepam, and 3H-muscimol binding in animals showing a differential propensity to consume alcohol. We have not observed changes in other components of the GABAa receptor system, including 3H-zolpidem and 3H-RO-154523 binding sites, and alpha1 or alpha6 receptor subunits examined by in situ hybridization.