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The ability to respond flexibly to changing environmental circumstances is a hallmark of goal-directed behavior, and compromised flexibility is associated with a wide range of psychiatric conditions in humans, such as addiction and stress-related disorders. To identify neural circuits and transmitter systems implicated in the provision of cognitive flexibility, suitable animal paradigms are needed. Ideally, such models should be easy to implement, allow for rapid task acquisition, provide multiple behavioral readouts, and permit combination with physiological and pharmacological testing and manipulation. Here, we describe a paradigm meeting these requirements and employ it to investigate the neural substrates and neurochemical modulation of adaptive behavior. Water-restricted rats learned to emit operant responses for positive reinforcement (water reward) within minutes in a free-operant conditioning environment. Without further training, animals were able to track changes in the reward schedule. Given prior evidence that the medial prefrontal cortex (mPFC) and the dopaminergic system are required for flexible behavior, we aimed to assess both in more detail. Silencing of mPFC compromised flexible behavior when avoidance of punishment was required. Systemic injections of the D2-receptor agonist quinpirole and the D2-receptor antagonist eticlopride had complex, differential impacts on reward seeking and adaptive behavior.

Neuronal activity has been shown to be essential for the proper formation of neuronal circuits, affecting developmental processes like neurogenesis, migration, programmed cell death, cellular differentiation, formation of local and long-range axonal connections, synaptic plasticity or myelination. Accordingly, neocortical areas reveal distinct spontaneous and sensory-driven neuronal activity patterns already at early phases of development. At embryonic stages, when immature neurons start to develop voltage-dependent channels, spontaneous activity is highly synchronized within small neuronal networks and governed by electrical synaptic transmission. Subsequently, spontaneous activity patterns become more complex, involve larger networks and propagate over several neocortical areas. The developmental shift from local to large-scale network activity is accompanied by a gradual shift from electrical to chemical synaptic transmission with an initial excitatory action of chloride-gated channels activated by GABA, glycine and taurine. Transient neuronal populations in the subplate (SP) support temporary circuits that play an important role in tuning early neocortical activity and the formation of mature neuronal networks. Thus, early spontaneous activity patterns control the formation of developing networks in sensory cortices, and disturbances of these activity patterns may lead to long-lasting neuronal deficits.

Neuronal activity has been shown to be essential for the proper formation of neuronal circuits, affecting developmental processes like neurogenesis, migration, programmed cell death, cellular differentiation, formation of local and long-range axonal connections, synaptic plasticity or myelination. Accordingly, neocortical areas reveal distinct spontaneous and sensory-driven neuronal activity patterns already at early phases of development. At embryonic stages, when immature neurons start to develop voltage-dependent channels, spontaneous activity is highly synchronized within small neuronal networks and governed by electrical synaptic transmission. Subsequently, spontaneous activity patterns become more complex, involve larger networks and propagate over several neocortical areas. The developmental shift from local to large-scale network activity is accompanied by a gradual shift from electrical to chemical synaptic transmission with an initial excitatory action of chloride-gated channels activated by GABA, glycine and taurine. Transient neuronal populations in the subplate support temporary circuits that play an important role in tuning early neocortical activity and the formation of mature neuronal networks. Thus, early spontaneous activity patterns control the formation of developing networks in sensory cortices, and disturbances of these activity patterns may lead to long-lasting neuronal deficits.