Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal

word count: 250 16 Number of figures: 7 17 Articles in PresS. J Neurophysiol (July 15, 2015). doi:10.1152/jn.00359.2015 Copyright © 2015 by the American Physiological Society. Abstract Chronic stress is thought to impart risk for depression via alterations in brain 18 structure and function, but contributions of specific mediators in generating these changes 19 remain unclear. We test the hypothesis that stress-induced increases in corticosterone (CORT), 20 the primary rodent glucocorticoid, are the key mediator of stress-induced depressive-like 21 behavioral changes and synaptic dysfunction in the rat hippocampus. In rats, we correlated 22 changes in cognitive and affective behavioral tasks—spatial memory consolidation, anhedonia, 23 and neohypophagia—with impaired excitatory strength at temporoammonic-CA1 (TA-CA1) 24 synapses; an archetypical stress-sensitive excitatory synapse. We tested whether elevated CORT 25 was sufficient and necessary to generate a depressive-like behavioral phenotype and decreased 26 excitatory signaling observed at TA-CA1 after chronic unpredictable stress (CUS). Chronic 27 CORT administration induced an anhedonia-like behavioral state and neohypophagic behavior. 28 Like CUS, chronic, but not acute, CORT generated an impaired synaptic phenotype 29 characterized by reduced AMPAR-mediated excitation at TA-CA1 synapses, decreased GluA1 30 protein expression, and altered 5-HT1BR-mediated potentiation. Repeatedly blunting stress31 induced increases of CORT during CUS with the CORT synthesis inhibitor metyrapone (MET) 32 prevented these stress-induced neurobehavioral changes. MET also prevented the CUS-induced 33 impairment of spatial memory consolidation. We conclude that corticosterone is sufficient and 34 necessary to mediate glutamatergic dysfunction underlying stress-induced synaptic and 35 behavioral phenotypes. Our results indicate that chronic excessive glucocorticoids cause specific 36 synaptic deficits in the hippocampus, a major center for cognitive and emotional processing, that 37 accompany stress-induced behavioral dysfunction. Maintaining excitatory strength at stress38 sensitive synapses at key loci throughout cortico-mesolimbic reward circuitry appears critical for 39 maintaining normal cognitive and emotional behavior. 40 Chronic stress is thought to impart risk for depression via alterations in brain 18 structure and function, but contributions of specific mediators in generating these changes 19 remain unclear. We test the hypothesis that stress-induced increases in corticosterone (CORT), 20 the primary rodent glucocorticoid, are the key mediator of stress-induced depressive-like 21 behavioral changes and synaptic dysfunction in the rat hippocampus. In rats, we correlated 22 changes in cognitive and affective behavioral tasks—spatial memory consolidation, anhedonia, 23 and neohypophagia—with impaired excitatory strength at temporoammonic-CA1 (TA-CA1) 24 synapses; an archetypical stress-sensitive excitatory synapse. We tested whether elevated CORT 25 was sufficient and necessary to generate a depressive-like behavioral phenotype and decreased 26 excitatory signaling observed at TA-CA1 after chronic unpredictable stress (CUS). Chronic 27 CORT administration induced an anhedonia-like behavioral state and neohypophagic behavior. 28 Like CUS, chronic, but not acute, CORT generated an impaired synaptic phenotype 29 characterized by reduced AMPAR-mediated excitation at TA-CA1 synapses, decreased GluA1 30 protein expression, and altered 5-HT1BR-mediated potentiation. Repeatedly blunting stress31 induced increases of CORT during CUS with the CORT synthesis inhibitor metyrapone (MET) 32 prevented these stress-induced neurobehavioral changes. MET also prevented the CUS-induced 33 impairment of spatial memory consolidation. We conclude that corticosterone is sufficient and 34 necessary to mediate glutamatergic dysfunction underlying stress-induced synaptic and 35 behavioral phenotypes. Our results indicate that chronic excessive glucocorticoids cause specific 36 synaptic deficits in the hippocampus, a major center for cognitive and emotional processing, that 37 accompany stress-induced behavioral dysfunction. Maintaining excitatory strength at stress38 sensitive synapses at key loci throughout cortico-mesolimbic reward circuitry appears critical for 39 maintaining normal cognitive and emotional behavior. 40