Stress diminishes regulatory control of behavior by the prefrontal cortex (PFC); while heightening subcorticalmediation of habits. Project 2 of this consortium will examine the molecular' and cellular basis of RFCdysfunction during acute and chronic stress, with the aim of identifying hovel therapeutic targets. Previousresearch has found that stress impairs PFC funetibh through 1) excessive production of CAMP via dopamihe(DA) D1 and nOrepinephririe (KlE) beta! receptors, and 2) NE alpha-1-activation of phosphbtidyl inositoi (PI)DAG-prOtein kihase C (PKC) signaling, suppressing PFC cell firing. The proposed research will furtherexplore the signaling cascades contributing to PFC dysfunction by examining the role of the IP3-Ca2+component of PI signaling. Consistent with this possibility, in vitro recordings from PFC neurons show thatrP3-mediatedihterharCa2+ release opens SKchannels thereby suppressing PFC cell excitability, theproposed research will examinei whether this rhechahisnrcontributes to stress-induced PFC dysfunction at 3levels:
Aim 1 will use in vitro recordings and Ca2+ fluorescence imaging of PFC pyramidal neurons toexamine the cellular basis of the PI cascade, Aim 2 will extend these results to in vivo recordings of PFCneurons in animals performing working merhbry tasks, and Aim 3 will test whether PFC cognitive functionscan be protected from stress by blocking IPS receptors or SK channels.
Aim 3 will also assess agents thatcan be administered to humans. We will test whether blocking alpha-1 and beta Kl'E receptors with carvedilolprotects PFC function from stress. If successful in animals, carvedilol can be tested in humEins exposed tostress in Project 9; We will also test the role of endbcanrtabanoids (eCB) in stres^induCed PFC dysfunctionas an extension of Project 5. Because eCBs depend on DAG and Ca2+, this work is diredtly relevant to PIsignaling. We will test whether pharmacological manipulation of eCB signaling with Rimbnabant ahdURB597 alters PFC physiology and cbghitibn as a prelude to possible human testing in Project 9. Finally,Aim 4 will determine whether PI signaling contributes to spine loss on PFC neurons during chronic stress.PKC phosphorylation of MARCKS disrupts actin, which may contribute tb spine loss. We will test whetherChronic PKC inhibition with Chelerythrine protects PFC neurons from spine loss. As chelerythrine is in pfeclinicaldevelopment, this may provide another strategy for increasing PFC regulation of behavior in humans.
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