mPFC’s role in stress and anxiety

1. Prostaglandin E2-Mediated Attenuation of MesocorticalDopaminergic Pathway Is Critical for Susceptibility toRepeated Social Defeat Stress in Mice

2. mPFC’s role in stress and anxiety • provides an interface between limbic and cortical structures • regulates the stress-induced activity of the hypothalamus-pituitary-adrenal (HPA) axis • Synaptic connections with nucleus accumbens • Suppress action of amygdala via glutamatergic efferents stimulating GABAergic neurons of the amygdala • Under normal conditions of fear suppression (acute stress) • the mPFC is activated and inhibits amygdala output • Chronic stress • Reduction in medial PFC inhibition of the amygdala  amygdala takes control

4. Evidence linking mPFC to psychiatric disorders • decrease in apical dendritic material in the anterior cingulate region of mPFC in depressed patients • Stimulation of mPFC neurons supresses depression-like behavior • Depression and anxiety associated with hyperactivity of amygdala • Electrical stimulation of NAc relieves depressive symptoms • Decrease of c-Fos, FosB or ΔFosB expression in glutamatergic neurons of medial PFC • Decreased expression of immediate-early gene products suggests decrease of neuronal activation in brain region

6. Prostaglandin E2 (PGE2) • NSAIDs have therapeutic effects in major depression • EP1 is present at GABAergic terminals onto midbrain dopamine neurons • EP1 stimulation potentiates inhibitory synaptic inputs

7. How are PGs generated in the Brain? • gene coding for the P2X7 receptor (P2X7R) is located on a susceptibility locus associated with major depressive disorder • ATP is usually released from damaged cells as a result of oxidative stress • relatively high (mM) ATP concentrations are needed to elicit PGE2 production • Repeated social defeat • Prenatal stress increased IL1β mRNA levels in the hippocampus of rats • Increased Iba1-immunoreactive microglial cells • IL1β is known to decrease the affinity of corticosteroid receptors in the hippocampus • increased activity of HPA axis observed in adulthood • studies have reported elevated blood glucocorticoids in MDD patients as well as decreased levels PGE2?

8. P2X7 Deficient vs Wild type Mice • P2X7/ mice exhibited significantly lower immobility time than WT mice, as revealed by a genotype main effect • P2X7 mice appeared more anxious in elevated pulse maze • Decreased C-Fos in basolateral amygdala and dentate gyrus

9. Materials and Methods • Mice • EP1, EP2 EP3-deficient mice • EP4 Crerecombinase mice • EP4-deficientpatent ductusarteriosus (blood vessel ductusarteriosus (to lungs) doesn’t close) • COX-1 and 2 deficient • Repeated social defeat stress • 7-week old male mice introduced to aggressor 10 min daily for 10 days • Social interaction test • Control and defeated mice in open field chamber for 150 seconds • Elevated Plus maze • Control and defeat mouse in maze for 10 min • Dopaminergic lesion • 6-Hydroxydopamine

11. PGE2 Measurement in Subcortical Region

14. Production of PGE2s by microglia • Quantitative RT-PCR • No change in [COX-1 mRNA] after repeated social defeat • Constitutively expressed COX-1microglia activation • COX-1 activity suppressed under normal conditions?

15. EP1-deficiency

18. Attenuation of MesocorticalDopaminergic Pathway • EP1 located at GABAergic synaptic inputs to midbrain dopamine neurons • Stimulation of EP1inhibition of dopamine neurons • Susceptibility to repeated defeat • C-Fos expression in VTA measured • First social defeat=increase in c-FOS in VTA • Attenuated upon 10th defeat • Recent studies have shown a greater degree of c-Fos, FosB or ΔFosB expression in glutamatergic neurons of mPFC of resilient mice following chronic predator or social defeat stress. • Increased expression of these immediate-early gene products would suggest increased neuronal activation in this brain region, which might represent a pro-resilience adaptation.

20. Dopamine Turnover • Emotional behaivor • Dopamine-innervated • mPFC • NAc • Ratio of DOPAC/HVA to dopamine • mPFC • First social defeatincrease turnover • 10th defeat attenuated turnover • NAc • Smaller initial turnover but still attenuated after repeated defeat • EP1-deficiency turnover attenuation didn’t occur in mPFC but still occurred in NAc • EP1 involved in attenuation upon repeated stress not involved in stress-induced activation

25. Susceptible • Susceptibility receptors • EP1 • P2X7 • Resilient • Active mesocorticaldopaminergic pathway • Decreased EP1 action • Decreased P2X7 action

26. References • Tanaka, Kohei, TomoyukiFuruyashiki, et al. Prostaglandin E2-Mediated Attenuation of MesocorticalDopaminergic Pathway Is Critical for Susceptibility To Repeated Social Defeat Stress in Mice. Journal of Neuroscience. (2012). 32 4319-4329. • Durrenberger, Pascal, Edna Grunblatt, et al. Parkinson's Disease. (2012): 1-16. • Boucher , A, JC Arnold, et al. Resilience and redueced C-Fos Expression in P2X7 Recetor Knockout Mice Exposed to Repeated Forced Swim Test. Neuroscience. 189. (2011): 170-177. • Russo, S. Murrough, J. et al. Neurobiology of resilience. (2012). Nature Neuroscience 15, 1475-1485. • Furuyashiki, T. Roles of Dopamine and Inflammation-Related Molecules in Behavioral Alterations Caused by Repeated Stress. Journal of Pharmacology Science. (2012) 120 63-69