The goal of this proposal is to better understand the molecular mechanisms by which the retrieval of declarative/episodic memory occurs. The proposal focuses on the time-limited role that norepinephrine (NE) and ?1-adrenergic signaling play in the hippocampus during memory retrieval.
The first aim will determine in which hippocampal cell(s) ?1 signaling acts to promote memory retrieval. Contextual fear, which depends to NE and ?1 signaling, will be used to assess hippocampus-dependent memory. Cued (tone) fear, which does not depend on NE or ?1 signaling, will be used to test whether manipulations affect performance or memory. Imaging of immediate-early gene induction in mice will be employed as a marker of neuronal activity following exposure to salient and neutral contexts, ?1 signaling in the mice will be manipulated pharmacologically and genetically so that it is blocked or activated either, systemically, only in the dorsal hippocampus, or in specific subfields of the hippocampus. Because ?1 signaling activates the cAMP / protein kinase A pathway, the second aim will determine whether this pathway is required for memory retrieval. Dorsal hippocampal infusions of agents that block this pathway will be performed in control mice, and infusions of agents that stimulate this pathway will be performed in mutant mice that lack ?1 signaling. The relationship between NE and activation of extracellular signal-regulated kinase and phosphatidylinositol 3- kinase, which are also required for retrieval, will be determined. Further, one of the most prominent physiological effects of ?1 signaling in the hippocampus is reduction of the slow afterhyperpolarization (sAHP) that mediates accommodation of firing.
The third aim will determine whether calcium influx through voltage-dependent calcium channels influences retrieval, and whether pharmacologic block of the sAHP rescues retrieval in mutant mice lacking ?1 signaling.
This aim will also determine whether there is a transient reduction in the sAHP that can be observed in brain slices of mice after fear conditioning but not pseudoconditioning and, if so, whether the reduction depends on ?1 signaling. Finally, a key hypothesis explaining why NE is required for some but not all memory retrieval will be tested in the fourth aim. Relevance: Dysfunction of adrenergic signaling may contribute to symptoms of depression and post- traumatic stress disorder that include difficulties with memory retrieval in the former and unwanted, intrusive retrieval of traumatic memories in the latter. Results from this proposal may also be relevant to potential cognitive side effects that might arise when treating heart failure, hypertension and performance anxiety with drugs that block ? receptors. Finally, results should also be relevant to understanding how dysregulation of neuronal Ca++ homeostasis in the elderly may lead to memory deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063352-09
Application #
8100379
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
2001-04-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$350,831
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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