br Conclusions In sum enhanced

Conclusions In sum, enhanced incentive motivation in obesity-prone rats is mediated by NAc CP-AMPARs. These neurobehavioral differences may render obesity-susceptible populations more sensitive to the motivational influence of food cues, producing more intense, focused, “wanting” that may limit the ability to divert behavior towards healthier alternatives. These data also demonstrate that in addition to mediating the intensification of cocaine-seeking (Huang et al., 2015, Wolf, 2016), NAc CP-AMPARs also mediate the BS-181 HCl of PIT for a food cue. This raises important questions about whether CP-AMPAR up-regulation represents aberrant vs. normal neural processes that underlie cue-triggered reward seeking behaviors, and the degree to which susceptibility to obesity shares features of addiction.
Financial disclosure Dr. Ferrario received funding for this research from the NIDDK, grant number R01-DK106188. Ms. Derman received funding for this research from the NIDA, grant number T32-DA007281 and from the NIDDK, grant number 1F31-DK111194-01. Both authors of this paper declare having no financial conflicts of interest.
Acknowledgements This work was supported by NIDDKR01-DK106188 to CRF. RCD was supported by NIDAT32-DA007281 and NIDDK1F31-DK111194-01. We thank Drs. Travis Brown and Terry Robinson for helpful comments.
Introduction Postnatal refinement of existing neural circuits through experience occurs during a period of heightened glutamatergic synaptic plasticity (Fagiolini et al., 1994; Kirkwood et al., 1995), commonly described as the critical period. Experience-dependent establishment and strengthening of functional connections during the critical period are thought to play an essential role in the formation of fully functional neural circuits during postnatal development (Ashby and Isaac, 2011; Ishikawa et al., 2014; Wu et al., 1996). On the other hand, anatomical studies have revealed that pruning of existing connections during the critical period also contributes to the refinement of neural circuits (Antonini and Stryker, 1993; Holtmaat et al., 2005; Zuo et al., 2005a). These two seemingly antagonistic processes for modifying connectivity allow experience to sculpt excitatory neural circuits during development. How these processes are coordinated to produce functional optimization is poorly understood. Fast, excitatory synaptic transmission in the mammalian central nervous system is primarily mediated by two types of ionotropic glutamatergic receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs). Although all glutamatergic synapses contain NMDARs, they are sub-categorized into two major types: AMPAR-positive and AMPAR-silent synapses, also defined as active and silent synapses (Liao et al., 1995). The recruitment of AMPARs to AMPAR-silent synapses (unsilencing) and the stabilization of the unsilenced synapses, the process that converts AMPAR-silent synapses to AMPAR-positive synapses, is thought to be important for glutamatergic synapse maturation (Huang et al., 2015) and the strengthening of neural connectivity during postnatal development (Ashby and Isaac, 2011; Wu et al., 1996). Functional analyses point toward an NMDAR-dependent mechanism akin to long-term potentiation (LTP) that unsilences AMPAR-silent synapses (Isaac et al., 1995; Liao et al., 1995; Rumpel et al., 1998). Were it to act alone or even predominate, this mechanism would enhance glutamatergic synaptic transmission, consistent with observed increases in the number of AMPAR-positive synapses at certain developmental stages (Ashby and Isaac, 2011; Phillips et al., 2011). It has also been shown that axon arbors, the presynaptic structural correlate, and dendritic spines, the postsynaptic structural correlate of excitatory synapses, are eliminated during postnatal development as neural circuits are refined (Antonini and Stryker, 1993; Holtmaat et al., 2005; Zuo et al., 2005a), suggesting a loss of connectivity at the anatomical level. Sensory deprivation prevents spine elimination, and recovery from sensory deprivation and heightened sensory experience leads to accelerated spine elimination, suggesting that synapse elimination during development requires experience (Bian et al., 2015; Zuo et al., 2005b). Although it has been proposed that spine elimination and stabilization are coordinated events during development (Bian et al., 2015), the functional impact of experience-dependent refinement on glutamatergic synaptic transmission is unknown.