In recent years, the work in our lab has revealed that behaviors long known to be supported by prefrontal function, in fact, draw upon activity from a broad network of brain areas, including not only the prefrontal cortex but also the hippocampus, basal ganglia, and certain thalamic nuclei. These structures are anatomically connected in a way that is conserved across rodents, humans and non-human primates, suggesting a shared mammalian network underlying the forebrain control of behavior. Its relation to the regulation of neurotransmitters, such as dopamine, makes it central not only to understanding executive function, but also to schizophrenia and other brain-behavior disorders in humans. Our research is focused on understanding the functional anatomy of this circuitry. Our recent studies have examined the function and connections of the hippocampus, which we now believe is at least as important as the prefrontal cortex for the inhibitory control of behaviour. For example, like humans with disinhibitory syndromes (e.g., psychopaths, alcoholics, patients with hyperkinesis), rats with hippocampal lesions are impulsive, antisocial, and emotionally unaroused. In our current work, we focus on recent advances in molecular and genetic manipulation afforded by rat CRE lines and cell specific viruses that form the basis for cellular and functional differentiation. Below we discuss current projects in the lab that make use of these methods.
Transsynaptic organization of fronto-temporal circuits
Lesions to the hippocampus can have specific effects on decision-making, inhibitory control, emotion, social interaction, and a range of other behavioral variables. This is because the medial temporal lobe is a critical component of a wide range of cortical circuits implicated in cognitive behaviors. For example, the medial prefrontal, orbital, retrosplenial and cingulate cortex all receive direct input from the hippocampus. This input is not, however, directly reciprocated through monosynaptic projections, suggesting a possible unidirectional influence. A true understanding of brain function at the systems neuroscience level rests on a clear picture of the underlying neuroanatomy. In the laboratory, we approach the study of anatomical circuits using polysynaptic tracing methods. To this end, neurotropic viruses are useful alternatives to traditional tracers, first because they are self-amplifying, and second, their infection crosses synapses in either the retrograde or anterograde direction. This allows us to identify a series of two, three or more neurons that form serial synaptic connections with each other. These neuroanatomical studies serve to guide experiments in which specific components of frontotemporal pathways are manipulated.
Cognitive-emotional functions of the frontal-hippocampal system
In behavioral neuroscience, perturbing neural activity in specific brain regions, and observing changes in social, emotional and cognitive behavior allows us to infer the potential function of the inactivated region. The permanent nature of a lesion allows researchers to model the effect of long-term brain damage in humans, and the capacity for recovery with pharmacological treatments. On the other hand, temporary inactivation or stimulation of specific brain areas using designer drugs like DREADDS or light sensitive proteins like channelrhodopsin provide the opportunity to modulate neural activity over shorter time scales. In combining these multiple approaches, our aim is to establish how a broad range of forebrain structures, and their highly specific functional interconnections, contribute to aspects of cognition and emotion. Paramount to this research is the capacity to isolate and quantify specific behaviors. Through computer controlled assays, we’re able to perform fine-grained analyses on a range of established cognitive and social behaviors in animals. We are also in the process of developing new paradigms, such as social interactive games and puzzles in order to investigate the influence of abnormal cognition on the formation of socioemotional relationships.
Establishing the neurochemical mechanisms of cognitive function
Classical neurotransmitters are key players in executive function, along with their role in emotion, arousal and reward. A key step in determining how these neuromodulators control behaviour is to profile, and ultimately manipulate, the expression of genes known to regulate selective neurotransmitter receptors. We are particularly interested in the neuropeptides that exist with nearly all monoaminergic and cholinergic neurons. Although lower in concentration than classical neurotransmitters, neuropeptides are potent at correspondingly lower concentrations and are thus in a position to strongly influence brain function. For example, neuropeptides can serve as powerful mediators of neuronal signalling and likely modulate activity of prefrontal, hippocampal, and thalamic neurons innervated by brainstem nuclei including the locus coeruleus and ventral tegmental area. We are currently exploring how manipulating the expression of certain neuropeptides such as galanin and neuropeptide Y regulate cognitive functions by controlling mood, arousal and our memories.