Laboratory of neurobiology of hedonic and addictive behaviours
Principal Investigator: Dr. Francesco Leri
There is preliminary evidence that several brain regions, systems and genes that regulate hedonic homeostasis are involved in modulating responses to incentive and aversive stimuli, and that similar biochemical systems regulate intake and seeking of chemical (drugs of abuse) and natural rewards (sugars). My program of research is funded by two different granting agencies, and it investigates the neurobiology of behaviors motivated by various incentives and aversive stimuli, with the goal of identifying common substrates that may then be targeted to treat conditions such as binge eating, depression, and drug abuse.
The research funded by NSERC is aimed at studying basic mechanisms of motivated behavior. More specifically, it has been proposed that reinforcing stimuli strengthen behavior because they enhance “consolidation” of memories of events in which they were encountered. Memory consolidation refers to biological processes by which the labile neural representation of a memory that exists immediately after its formation changes over time into a relatively permanent representation. The “memory enhancing” hypothesis of reinforcers generates three testable predictions. First, different reinforcers should strengthen behavior through actions on overlapping neurochemical systems of memory consolidation. Second, because these neurochemical systems overlap, there should be behavioural interactions between different reinforcers. Finally, in the mammalian brain, interacting neurochemical systems converge into a primary “pathway” of memory consolidation. To test these predictions, male Sprague-Dawley rats are trained to associate particular actions (pressing a lever during self-administration) or environmental stimuli (a white chamber during place conditioning), with the delivery of various reinforcers. Following training, the memories of these associations are measured by assessing the persistence of the learned actions, or the frequency of approach to the environmental stimuli, in the absence of reinforcers.
We employ pharmacological and neurobiological methods to study systems of memory consolidation engaged by saccharin, fructose, glucose, heroin, oxycodone and cocaine. These reinforcers have been selected because, although they have different effects on the body and on the brain, they are all self-administered by rats. The “sweets” are self-administered intraorally and the drugs intravenously. Rats are also trained in a dual self-administration procedure, and behavioural interactions are characterized during various tests in the presence and absence of one or both reinforcers. Finally, neuro-pharmacological methods (implantation of infusion cannulas and micro dialysis probes) are employed to explore the interaction between dopamine and noradrenaline; two systems that likely contribute to a pathway of memory consolidation activated by all reinforcing and aversive stimuli.
Funded by the Ontario Brain Institute, my laboratory at Guelph is part of the Canadian Biomarker Integration Network in Depression.
Human depression is a complex and heterogeneous illness that cannot be captured by any single animal model. As such, animal models can achieve construct, face and predictive validity only by focussing on particular features of the human disease. Furthermore, by investigating the validity of particular animal models, it is possible to test hypotheses about neurobiological bases of human disease, and explore effectiveness of possible treatments.
The studies in rats performed in my laboratory focus on two cardinal symptoms of depression: anhedonia and psychomotor retardation. The general hypothesis is that biological differences predict the effects that antidepressant treatments will have on behavioral responses to uncontrollable stress. To test the hypothesis, male and female Sprague-Dawley rats are exposed to uncontrollable stressors (delivered in avoidance chambers or injections of 2-deoxy-glucose to produce rapid cellular hypoglycemia). Control groups escape and avoid the aversive stimuli in the avoidance chambers, or receive vehicle. Animals are treated with various doses of acute and/or chronic antidepressants. Behaviours testes include: intraoral self-administration of sweetened liquid, intravenous self-administration of heroin, oxycodone, and cocaine, taste reactivity to the same liquid, investigation of a novel conspecific (i.e., unlearned social preference), preference for a place associated with the investigation of a conspecific (i.e., socially learned preference), avoidance of a place associated with the administration of 2DG, horizontal and vertical movements, inactivity and stereotypy. At the conclusion of behavioural testing, plasma is sampled to measure corticosterone, and the pre-frontal cortex, amygdala, hippocampus, dorsal and ventral striatum are extracted to measure expression of particular genes (dopamine and opioid receptors, brain derived neurotrophic factor), or to measure patterns of global gene expression via DNA microarrays.