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

The influence of early-life adversity on the neural regulation of fear and anxiety

Individuals abused or neglected in early childhood are at greater risk for developing stress-related psychopathologies, including depression, anxiety and aggression-related disorders in later life (Widom, 1989; Heim and Nemeroff, 2001). Similarly, parental 'neglect' in the rat is associated with long-lasting increases in vulnerability to stress (Liu et al., 1997; Francis et. al., 1999). Thus, adult offspring of mother rats that display low levels of maternal licking/grooming of pups (Low LG) are behaviorally more fearful and display greater hypothalamic-pituitary-adrenal activity in response to stress, relative to offspring of High LG mothers. Interestingly, these effects are associated with differences receptor binding and gene expression in limbic regions implicated in stress and fear reactivity (e.g., Liu et. al., 2000; Caldji et al., 1998; Menard & Meaney, 2001). The current proposal aims to directly address whether natural variations of maternal care in the rat are similarly associated with individual differences in aggression in adulthood.

Low levels of serotonin (5-HT) have long been associated with increased levels of aggression in both human and rodent populations (e.g., Kavoussi et al., 1997; van Erp and Miczek, 2000). Pharmacological agents that increase serotonergic activity, such as 5-HT1A and 5-HT1B receptor agonists, as well as 5-HT reuptake inhibitors, effectively reduce aggressive behavior in rodents and humans (e.g., Miczek et al., 1998; Olivier and Mos, 1986). These actions appear to be mediated, at least in part, by increased serotonergic activity in the lateral septum. For example, intra-septal infusions of a 5-HT1B receptor agonist suppressed rats' aggressive responses in the resident intruder paradigm (Cologer-Clifford et al, 1997). As well, higher levels of aggression have been associated with lower levels of 5-HT immunoreactive varicosities and fibers within the lateral septum (DeLeon et al., 2002; Delville et al., 1998).

Neo-natal adversity in rat appears to alter the development of neuronal systems that regulate 5-HT activity. For example, maternal separation in the first two weeks of life has been associated with persistent increases in corticotrophin releasing factor (CRF) receptor binding in the raphe nuclei (Ladd et al., 1996). CRF neurotransmission in the raphe decreases the firing rate of serotonin (5-HT) cells (Kirby et al., 2000), which could result in lower levels of 5-HT release in forebrain structures during periods of stress. Adult rats exposed to maternal separation in early life also display greater suppression of raphe 5-HT cell firing in response to the selective 5-HT reuptake inhibitor citalopram (Arborelius et al., 2000). Although these findings hint that early-life adversity might lead to higher levels of aggression in later life (i.e., by reducing 5-HT activity), this possibility has yet to be directly tested. Thus, one goal of the current proposed research is to assess the influence of natural variations of maternal care on aggressive behavior in adulthood. A second goal is to correlate any observed group differences in aggression with alterations in serotonergic innervation patterns in the lateral septum.