Chronic stress causes long term changes in neural circuits that may underlie symptoms of depression. The CA3 subfield of the hippocampus is one of these important neural circuits because it is the induction site for the oscillatory neuronal activity seen during many different behavioral states. This neural activity has been correlated with cognitive functions. The neurons that comprise the circuit are regulated by 5HT projections from the median raphe. Recent evidence indicates that 5HT postsynaptic receptor-effector mechanisms are altered by stress. These postsynaptic changes may be responsible for the long-term alterations in CA3 neural activity following stress. The long term goal is to elucidate the cellular substrates for alterations in CA3 hippocampal function induced by stress. The working hypothesis is that one of the cellular mechanisms underlying stress induced changes in the CA3 hippocampal circuit is a change in the 5HT modulatory input. Intracellular recording techniques in hippocampal brain slice preparations will be used to record CA3 neural activity.
Specific aim 1 : To characterize postsynaptic 5-HT receptor-mediated responses in CA3 pyramidal cells. Hypothesis: 5-HT concentration response curve characteristics and second messenger systems linked to the 5-HT-1A , 5-HT-4 and 5-HT-7 receptors will not be the same.
Specific aim 3 : To determine the effects of 5-HT and CA3 oscillatory activity as induced by carbachol. Hypothesis: Selective activation of isolated 5-HT receptors will differentially modulated carbachol induced oscillatory activity.
Specific aim 3 : To determine the effects of stress on postsynaptic 5-HT receptor-mediated responses, carbachol induced oscillatory activity and 5-HT modulation of carbachol induced oscillatory activity. Two different behavioral stress paradigms will be used, i.e., forced swimming and inescapable restraint as well as a treatment group that has endogenous levels of the stress hormone corticosterone controlled. It is expected that the modulatory effects of the three protocols can be discriminated because the nature and duration of the stressors are vastly different. Together these studies will systematically examine multiple mechanisms for stress induced changes in the neural circuitry of the CA3 subfield. These mechanisms may underlay many of the debilitating symptoms and cognitive deficits seen in depression and stress related disorders. Understanding these mechanisms may also provide important information for the development of new treatments for depression and stress related disorders.
