The long-term goal of this project is to develop and use a clinically relevant animal model of aggressive behavior. We hypothesize that low serotonin-induced aggression is associated with (1) changes in other emotional behavior and (2) increased membrane excitability in amygdala neurons. Impulsive-aggressive humans reportedly have low anxiety and are less sensitive to fear-conditioning. Similar to humans, it is proposed that anxious behaviors and fear-learning are correlated with aggression and low serotonin levels. In addition, aggression has been suggested to result from epilepsy-like processes in limbic areas. One limbic structure, the amygdala, has well-defined roles in both epilepsy and emotion, and seizure activity that involves the amygdala may be associated with aggression in humans. Thus, cellular mechanisms of neuronal excitability in the amygdala may have a functional role in aggressive behavior. Supporting this idea are clinical studies showing anti-aggressive effects of anticonvulsants in prison inmates and psychiatric patients. In this project rats are chronically treated with PCPA, a competitive inhibitor of serotonin synthesis, to significantly inhibit serotonin synthesis. Low serotonin is widely-implicated in aggression in many species. Aggressive behavior is quantified using a simple test of rodent aggression characterized by easily recognized, stereotypical behaviors. Preliminary data have shown that aggressive behavior in this model is inhibited by the anticonvulsant phenytoin, as others have shown with human aggression.
The specific aims of this project are to (1) define the salient independent variables required to model impulsive aggression, and to examine the relationship between aggression, low brain serotonin, and changes in amygdala-dependent emotional behaviors such as anxiety and fear-learning; and (2) compare amygdala neuron membrane properties and neurotransmission in control and aggressive animals using whole cell voltage-clamp.An animal model is developed that shares behavioral, neurochemical, and pharmacological similarities with impulsive-aggression in humans. Also, the neural correlates of aggression are investigated using cellular physiological methods never before used to study aggressive behavior. This innovative proposal examines basic biological mechanisms of aberrant emotional behavior that are relevant to human psychopathology. By developing this animal model, future research efforts can yield important insight into the cellular neurobiology of complex emotional behaviors such as aggression, and may have important clinical implications for the treatment of psychiatric disorders involving inappropriate aggression such as bipolar disorder, borderline personality disorder or antisocial personality disorder.
| Hughes, Cathryn R; Keele, N Bradley (2006) Phenytoin normalizes exaggerated fear behavior in p-chlorophenylalanine (PCPA)-treated rats. Epilepsy Behav 9:557-63 |
| Keele, N Bradley (2005) The role of serotonin in impulsive and aggressive behaviors associated with epilepsy-like neuronal hyperexcitability in the amygdala. Epilepsy Behav 7:325-35 |
