Control of Fear/Defensive Behavior by Brain Derived Neurotrophic Factor

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Multiple studies suggest that interactions between the higher brain structures, such as cortex and hippocampus, and so called defensive circuitry, which include amygdala, hypothalamus and periaqueductal grey, modulate fear/defensive behaviors. Moreover, changes in such interaction may lead to mental illness. We have previously found that mice with the conditional knockout (KO) of Brain Derived Neurotrophic Factor (BDNF) restricted to the hippocampal area CA3 are more aggressive than their wild type (WT) counterparts. During the past fiscal year we pursued two aims. 1) Identification of mechanisms responsible for previously found changes in serotonergic system of BDNF KO mice. 2) Investigation of physiological role of the hippocampal serotonin receptor 3 (5-HTr3), which has been found to enhance aggression. To address the first aim we employed microdialysis/HPLC system for measuring levels of extracellular serotonin in various locations throughout the hippocampus. This work revealed that the decrease in 5-HT concentration occurs in the vicinity of the area CA3, but not in the locations that are far from this area. This finding indicated that BDNF effect on 5-HT level is localized even within the hippocampus. To examine local mechanism that control levels of 5-HT we used reverse microdilaysis with serotonin reuptake inhibitor citalopram, which increases level of 5-HT by suppressing 5-HT reuptake, and KCl, which increases level of 5-HT by triggering activity-dependent release of 5-HT from serotonergic terminals. The analysis revealed that gross 5-HT transporter activity and vesicular content of serotonergic terminals are not altered in KO animals. It suggests that BDNF modulates balance between 5-HT release and reuptake at the basal state, but does not alter release or reuptake capacity of serotonergic terminals. To investigate physiological role of 5-HTr3 in the hippocampus we combined genetic and pharmacological approaches to selectively modulate 5-HTr3 with specific agonist and antagonist and to record from the interneuronal subpopulation that express 5-HTr3. For the latter, we obtained transgenic mice where green fluorescent protein (GFP) is expressed under the control of 5-HTr3 promoter and allows recording from cells with 5-HTr3. One of the major physiological properties of the hippocampus is generation of oscillatory activity at certain frequencies. Oscillations at gamma frequency have been postulated to be important for both cognitive and emotional behaviors and can be modeled in the hippocampal slice. We reproduced this model in our laboratory and examined how 5-HTr3 affects gamma oscillations induced by carbachol. We discovered that 5-HTr3 agonist suppresses gamma oscillations and are trying to determine underlying mechanisms at the level of local hippocampal circuit. Preliminary finding suggest that a5-HTr3 alters afterhyperpolarization of 5-HTr3 expressing interneurons, which alters their firing patterns leading to the interference with gamma oscillations. Our future goals are to understand how oscillatory activity of hippocampus may relate to aggression and whether 5-HTr3 modulates aggression by changing hippocampal oscillations.