Altered heterosynaptic plasticity impairs visual discrimination learning in adenosine A1 receptor knockout mice

ABSTRACTTheoretical and modeling studies demonstrate that heterosynaptic plasticity - changes at synapses inactive during induction - facilitates fine-grained discriminative learning in Hebbian-type systems, and helps to achieve a robust ability for repetitive learning. A dearth of tools for selective manipulation has hindered experimental analysis of the proposed role of heterosynaptic plasticity in behavior. Here we circumvent this obstacle by testing specific predictions about changes in heterosynaptic plasticity, and associated behavioral consequences, following experimental manipulation of adenosine A1 receptors (A1R). We show that, compared to wild-type controls, A1R-knockout mice have impaired synaptic plasticity in visual cortex neurons, coupled with significant deficits in visual discrimination learning. Deficits in A1R-knockouts were seen specifically during re-learning, becoming progressively more apparent with learning on sequential visual discrimination tasks of increasing complexity. These behavioral results confirm our model predictions, and provide the first experimental evidence for a proposed role of heterosynaptic plasticity in learning.HighlightsSynaptic plasticity is impaired in visual cortex neurons in adenosine A1R knockout miceHomosynaptic and heterosynaptic plasticity in A1R KO mice is dominated by depressionLearning on sequential, increasingly complex visual tasks is impaired in A1R KO miceLearning deficits match predicted effects of impaired heterosynaptic plasticity

Dissociable and Paradoxical Roles of Rat Medial and Lateral Orbitofrontal Cortex in Visual Serial Reversal Learning

ABSTRACT Much evidence suggests that reversal learning is mediated by cortico-striatal circuitries with the orbitofrontal cortex (OFC) playing a prominent role. The OFC is a functionally heterogeneous region, but potential differential roles of lateral (lOFC) and medial (mOFC) portions in visual reversal learning have yet to be determined. We investigated the effects of pharmacological inactivation of mOFC and lOFC on a deterministic serial visual reversal learning task for rats. For reference, we also targeted other areas previously implicated in reversal learning: prelimbic (PrL) and infralimbic (IL) prefrontal cortex, and basolateral amygdala (BLA). Inactivating mOFC and lOFC produced opposite effects; lOFC impairing, and mOFC improving, performance in the early, perseverative phase specifically. Additionally, mOFC inactivation enhanced negative feedback sensitivity, while lOFC inactivation diminished feedback sensitivity in general. mOFC and lOFC inactivation also affected novel visual discrimination learning differently; lOFC inactivation paradoxically improved learning, and mOFC inactivation had no effect. We also observed dissociable roles of the OFC and the IL/PrL. Whereas the OFC inactivation affected only perseveration, IL/PrL inactivation improved learning overall. BLA inactivation did not affect perseveration, but improved the late phase of reversal learning. These results support opponent roles of the rodent mOFC and lOFC in deterministic visual reversal learning.