We propose to examine the role of adrenergic signaling in synaptic plasticity, learning and memory using mouse molecular genetics. Specifically, we have created mice that are unable to synthesize norepinephrine (NE) and epinephrine due to a targeted disruption of the dopamine B-hydroxylase (Dbh) gene. Homozygotes (Dbh-/-) completely lack NE; however NE can be restored rapidly in vivo and in vitro using the synthetic amino acid precursor of NE (DOPS). This model has several advantages over prior pharmacologic approaches, including completeness of effect, specificity for NE, and reversibility. Prior studies using various techniques have often generated conflicting results with regard to the roles of NE in synaptic plasticity, learning and memory. Some studies have suggested a role for NE in the formation of emotional (aversive) memories. To test this possibility, we have begun to characterize the ability of Dbh-/- mice to learn and remember an aversive event using fear conditioning. Preliminary results indicate a specific deficit in the consolidation of contextual but not cued memory, suggesting hippocampal function may be altered in the absence of NE. For this reason we have begun to examine synaptic plasticity in the hippocampus. Preliminary results from these studies suggest that the late phase of long-term potentiation in region CAl is deficient. Because other studies have suggested a critical role of synaptic plasticity in region CAl for learning and memory, we propose to examine whether intracellular signaling pathways implicated in learning and memory are altered in region CAl following stimuli that elicit the late phase of LTP in vitro, and following fear conditioning in vivo. Finally, we will test whether compensation for the absence of NE occurs during development, and whether dopamine released from the adrenergic terminals of Dbh-/- mice can substitute at least partially for NE. These goals will be achieved through the use of a second mouse model (Th-/-/Dat-Th+/-) that should lack DA as well as NE in the adrenergic neurons specifically. Some of these mice will be raised with NE present (by supplying L-DOPA pre- and postnatally). L-DOPA will then be withdrawn in half prior to using the mice in the above studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH063352-01A1
Application #
6477670
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Asanuma, Chiiko
Project Start
2002-07-01
Project End
2006-03-31
Budget Start
2002-07-01
Budget End
2003-03-31
Support Year
1
Fiscal Year
2002
Total Cost
$351,559
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Thomas, Steven A (2015) Neuromodulatory signaling in hippocampus-dependent memory retrieval. Hippocampus 25:415-31
Young, Matthew B; Thomas, Steven A (2014) M1-muscarinic receptors promote fear memory consolidation via phospholipase C and the M-current. J Neurosci 34:1570-8
Zhang, Lei; Ouyang, Ming; Ganellin, C Robin et al. (2013) The slow afterhyperpolarization: a target of ?1-adrenergic signaling in hippocampus-dependent memory retrieval. J Neurosci 33:5006-16
Maison, Stéphane F; Usubuchi, Hajime; Vetter, Douglas E et al. (2012) Contralateral-noise effects on cochlear responses in anesthetized mice are dominated by feedback from an unknown pathway. J Neurophysiol 108:491-500
Ouyang, Ming; Young, Matthew B; Lestini, Melissa M et al. (2012) Redundant catecholamine signaling consolidates fear memory via phospholipase C. J Neurosci 32:1932-41
Schutsky, Keith; Ouyang, Ming; Castelino, Christina B et al. (2011) Stress and glucocorticoids impair memory retrieval via ?2-adrenergic, Gi/o-coupled suppression of cAMP signaling. J Neurosci 31:14172-81
Murchison, C F; Schutsky, K; Jin, S-H et al. (2011) Norepinephrine and ýýýýý-adrenergic signaling facilitate activation of hippocampal CA1 pyramidal neurons during contextual memory retrieval. Neuroscience 181:109-16
Schutsky, Keith; Ouyang, Ming; Thomas, Steven A (2011) Xamoterol impairs hippocampus-dependent emotional memory retrieval via Gi/o-coupled ?2-adrenergic signaling. Learn Mem 18:598-604
Panjala, Surekha Rani; Jiang, Youde; Kern, Timothy S et al. (2011) Increased tumor necrosis factor-ýý, cleaved caspase 3 levels and insulin receptor substrate-1 phosphorylation in the ýýýýý-adrenergic receptor knockout mouse. Mol Vis 17:1822-8
Maison, Stéphane F; Le, Mina; Larsen, Erik et al. (2010) Mice lacking adrenergic signaling have normal cochlear responses and normal resistance to acoustic injury but enhanced susceptibility to middle-ear infection. J Assoc Res Otolaryngol 11:449-61

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