My project aims to investigate the neurobiological bases that underlie the balance between plasticity and stability in memory formation and maintenance. In mammals, hippocampus-dependent memory is mainly declarative, which is easy to form and forget (i.e. highly plastic). In contrast, striatum-dependent memory is mainly procedural or motor habits which form incrementally and hard to extinguish (i.e. highly stable). I hypothesize that adenylyl cyclases (AC) play an important role in this balance. AC1 is stimulated by Ca/CaM, and has high expression in the hippocampus, but is absent in the striatum, where ACS is the primary isoform. ACS is inhibited by Ca2+ and protein kinase A, two integral components of synaptic plasticity. I hypothesize that due to expression of ACS, there is a constraint on cAMP production in the striatum, causing reduced synaptic plasticity, and thus making striatum dependent memories more stable. I propose to test this using a transgenic approach: expressing AC1 in the striatum. I will test these mice biochemically for players in synaptic plasticity, and behaviorally in tasks that dissect striatum dependent memory. In terms of relevance of this research to public health, understanding the basis for corticostriatal plasticity is crucial for developing therapies for motorhabits related disorders that include Tourette Syndrome, obsessive compulsive disorder and addiction. ? ? ?
| Kheirbek, Mazen A; Beeler, Jeff A; Chi, Wanhao et al. (2010) A molecular dissociation between cued and contextual appetitive learning. Learn Mem 17:148-54 |
| Kheirbek, Mazen A; Britt, Jon P; Beeler, Jeff A et al. (2009) Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning. J Neurosci 29:12115-24 |
| Beeler, Jeff A; Cao, Zhen Fang Huang; Kheirbek, Mazen A et al. (2009) Loss of cocaine locomotor response in Pitx3-deficient mice lacking a nigrostriatal pathway. Neuropsychopharmacology 34:1149-61 |
| Kheirbek, Mazen A; Beeler, Jeff A; Ishikawa, Yoshihiro et al. (2008) A cAMP pathway underlying reward prediction in associative learning. J Neurosci 28:11401-8 |
