Janet Menard, Ph.D. Department of Psychology, Queen's University

Mapping the neural correlates of fear and anxiety

A major focus of my research is to map the neuroantatomical and neuropharmacological correlates of fear-related behaviors in the rat. Although early theories sought to localize fear or anxiety to a specific region in the brain (e.g., amygdala or septal nucleus), evidence increasingly suggests that different fear-related behaviors have different underlying neural mechanisms (reviewed in Menard & Treit, 1999; Treit & Menard, 2000). For example, using intra-cerebral drug infusions, I was able to show that rats' defensive burying in the shock-probe burying test and their open-arm avoidance in the elevated plus-maze are differentially regulated by distinct receptor systems within the septal nucleus and dorsal hippocampus. Defensive burying (but not open-arm avoidance) is regulated by septal NMDA and 5-HT1A receptors, whereas open-arm avoidance (but not burying behavior) is regulated by hippocampal benzodiazepine and 5-HT1A receptors (Menard & Treit, 1998, 2000, 2001). Open-arm avoidance is also regulated by a population of septal non-NMDA receptors that receives glutamatergic projections from the dorsal hippocampus, and this particular projection path does not play a role in the burying (Menard & Treit 2000, 2001). Although complex, these behavioral dissociations suggest that functionally distinct, parallel pathways in the brain differentially regulate different aspects of fear or anxiety. What these different aspects are or, indeed, how these different pathways interact to promote adaptive defensive responding under different environmental contexts is not clear. What is clear is that over reliance on a single behavioral measure of 'fear' or 'anxiety' will result in a relatively impoverished account into the neurobiology of fear and anxiety.

These findings lay the groundwork for both current and future studies aimed at further elucidating the neurobiology of fear and anxiety. This work involves two inter-related approaches. First, using the septohippocampus as a starting point, I plan to continue exploring the neuroanatomy (and neuropharmacology) of rats' fear-related responses. For example, I plan to determine the involvement of various septohippocampal subregions (e.g., ventral hippocampus) and their respective input (e.g., entorhinal cortex) and output structures (e.g., anterior hypothalamus) in fear regulation. A major emphasis will be to determine the means of communication (e.g., neurochemical and neuropeptite) between structures that regulate fear expression, by using a combination of brain lesions, multi-site drug infusions and immunohistochemical techniques. Second, I plan to use a battery of behavioral tests as a means to tease out some of the aspects of fear or anxiety that may be governed by distinct circuitries in the brain. For example, some animal tests of fear expression, such as the burying test and resident intruder paradigms, measure rats' defensive responses toward a discrete threat stimulus that is clearly "present" in the animals' environment. Alternatively, other animal tests of fear expression, such as the plus-maze and cat-odor tests, involve more diffuse or "potential" threats. Current theories suggest that defensive responses to "potential" vs "present" threats are differentially represented in the brain, yet provide little by way of direct empirical support for this possibility. I plan to test this theory by determining whether responses to "present" (or "potential") threats share a similar neural basis. This type of research will permit a more refined analysis into how different circuits in the brain evaluate threatening stimuli and integrate this information into adaptive, contextually-specific defensive behavior. Ultimately, we may gain insight into how disregulation within these circuits results in aberrant levels of fearfulness.