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Sex Differences in the Effects of Acute and Chronic Stress and Recovery after Long-Term Stress on Stress-Related Brain R

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Sex Differences in the Effects of Acute and Chronic Stress and Recovery after Long-Term Stress on Stress-Related Brain R

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    1. Sex Differences in the Effects of Acute and Chronic Stress and Recovery after Long-Term Stress on Stress-Related Brain Regions of Rats By: Stacy Zeigler

    2. Who Cares? Women more vulnerable to stress-related psychopathologies Depression twice as frequent

    3. CREB and BDNF CREB= cAMP response element-binding protein BDNF? TrkB receptor? MEK-ERK pathway? RSK2? CREB phosphorylation on ser133

    4. Regulation via antidepressant drugs As seen here, many signaling factors can lead to the phosphorylation of CREB CREB directly binds to CRE (on serine 133) MEK= mitogen-activated protein kinase (blocks ERK?) ERK= extracellular signal-regulated protein kinase RSK 1-3= Ribosomal S6 kinases Kinases phosphorylate protein substrates such as CREB CREB binds to cAMP responsive element (CRE) in DNA?DNA regulation Regulation via antidepressant drugs As seen here, many signaling factors can lead to the phosphorylation of CREB CREB directly binds to CRE (on serine 133) MEK= mitogen-activated protein kinase (blocks ERK?) ERK= extracellular signal-regulated protein kinase RSK 1-3= Ribosomal S6 kinases Kinases phosphorylate protein substrates such as CREB CREB binds to cAMP responsive element (CRE) in DNA?DNA regulation

    5. Oestradiol=this is what testosterone can be broken down to in the brain Oestradiol=this is what testosterone can be broken down to in the brain

    6. Actually memory formation 1- NT released 2- kinase and phosphatase activities equilibrium at synapse 3- retrograde transport from synapse to nucleus 4- nuclear transcription factor activation 5- gene expression 6- chromatin alteration and epigenic changes in gene expression 7- synaptic capture of newly synthesized gene products 8- protein synthesis 9- synaptic growth and formation of new synapses 10- synapse activation 11- self-perpetuating mechanisms and molecular basis of memory persistenceActually memory formation 1- NT released 2- kinase and phosphatase activities equilibrium at synapse 3- retrograde transport from synapse to nucleus 4- nuclear transcription factor activation 5- gene expression 6- chromatin alteration and epigenic changes in gene expression 7- synaptic capture of newly synthesized gene products 8- protein synthesis 9- synaptic growth and formation of new synapses 10- synapse activation 11- self-perpetuating mechanisms and molecular basis of memory persistence

    7. Simplified Shows neural circuits that may contribute to depressive symptoms Most depression research focused on hippocampus and prefrontal cortex (PFC)Simplified Shows neural circuits that may contribute to depressive symptoms Most depression research focused on hippocampus and prefrontal cortex (PFC)

    8. Stress

    9. Reduced BDNF mediated partly by excessive glucocorticoids, which could interfere with normal transcriptional mechanisms, like CREB, that control BDNF expressionReduced BDNF mediated partly by excessive glucocorticoids, which could interfere with normal transcriptional mechanisms, like CREB, that control BDNF expression

    10. Sex Differences in the Effects of Acute and Chronic Stress and Recovery after Long-Term Stress on Stress-Related Brain Regions of Rats

    11. Functions Hippocampus and dAAC Learning, memory, attention, conflict monitoring, pain, pleasure, decision making Hippocampus and PFC Implicated in depression Hippo and PFC- implicated as key sites of neuropathology in depressionHippo and PFC- implicated as key sites of neuropathology in depression

    12. Sex Differences… Mechanisms underlying sex differences in stress-related depression Methods- males/females in each group 1) No footshock 2) 6 footshocks on day 42 3) Footshocks daily for 3 weeks then no footshocks for 3 weeks 4) Footshocks daily for 3 weeks; next 3 weeks alternating days of footshocks 2-4= on day 43 rats exposed to light with no shocks (then killed 2 hrs/30 min after) 2 hrs= 3 rats per group; used with isoflurane anesthesia 30 min= 5 rats per group; decapitated2 hrs= 3 rats per group; used with isoflurane anesthesia 30 min= 5 rats per group; decapitated

    13. Shocked with randomized starting time unpredictable 10 second light signal preceded each shock Examined rat brains Immunohistochemistry analysis ELISA and western blot

    14. Immunohistology in CA1, CA2, CA3, PVT (paraventricular nucleus of the thalamus), amygdala (BLA, LA, BMA= basomedial amygdala?) BDNF levels measured in dendate gyrus (red circle ?) -via ELISAImmunohistology in CA1, CA2, CA3, PVT (paraventricular nucleus of the thalamus), amygdala (BLA, LA, BMA= basomedial amygdala?) BDNF levels measured in dendate gyrus (red circle ?) -via ELISA

    15. ACAd (anterior cingulate area- dorsal), ILA (infralimbic area) BDNF measured in PL (prelimbic area)= red circle -via ELISAACAd (anterior cingulate area- dorsal), ILA (infralimbic area) BDNF measured in PL (prelimbic area)= red circle -via ELISA

    16. Males pCREB in acute and chronic stress groups decreased CREB in CA2 of acute and chronic stress decreased Females No significant changes of pCREB or CREB in stress

    17. Males- expression of pCREB and CREB in control, acute and chronic stress group Arrows pointing to patches (clearly observed in chronic group) Males- expression of pCREB and CREB in control, acute and chronic stress group Arrows pointing to patches (clearly observed in chronic group)

    18. Males- No positive staining in patches and background of these patches was bright which is different from surrounding tissue patches may be due to necrosis and/or apoptosis; in ACAd may be due to loss of glial cells Females- ILA and ACAd no significant change in CREB or pCREB levels No patches shown (not shown)Males- No positive staining in patches and background of these patches was bright which is different from surrounding tissue patches may be due to necrosis and/or apoptosis; in ACAd may be due to loss of glial cells Females- ILA and ACAd no significant change in CREB or pCREB levels No patches shown (not shown)

    19. No morphological abnormalities in either group No morphological abnormalities in either group

    20. Neither group showed morphological abnormalitiesNeither group showed morphological abnormalities

    21. PL of PVC Males show higher baseline BDNF level in DG than femalesPL of PVC Males show higher baseline BDNF level in DG than females

    22. Discussion Rat brains response to stress is different Male/female Recovery! reversible Antidepressants Shown to increase CREB and pCREB levels in amygdala (Burton et al. 2007) Recovery following stress restores pCREB, CREB, BDNF to baseline in males and femalesRecovery following stress restores pCREB, CREB, BDNF to baseline in males and females

    23. BDNF Regulation Regulated by other factors other than pCREB and CREB Other studies Nuclear factor of activated T cells (Graef et al. 2003) mRNA= biphasic time course Protein= monophasic 4 different RNA transcripts encode for same BDNF protein Possible uncoupling of BDNF transcriptional and translational mechanisms

    24. So… Don’t stress out!!!

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