Summary Fear is a graded central motive state ranging from mild to intense. As threat intensity increases, fear transitions from discriminative to generalized. The circuit mechanisms that process threats of different intensity are not well resolved. Here, we isolate a unique population of locally projecting neurons in the central nucleus of the amygdala (CeA) that produce the neuropeptide corticotropin-releasing factor (CRF). CRF-producing neurons and CRF in the CeA are required for discriminative fear, but both are dispensable for generalized fear at high US intensities. Consistent with a role in discriminative fear, CRF neurons undergo plasticity following threat conditioning and selectively respond to threat-predictive cues. We further show that excitability of genetically isolated CRF-receptive (CRFR1) neurons in the CeA is potently enhanced by CRF and that CRFR1 signaling in the CeA is critical for discriminative fear. These findings demonstrate a novel CRF gain-control circuit and show separable pathways for graded fear processing.

Dopamine is highly implicated both as a teaching signal in reinforcement learning and in motivating actions to obtain rewards. However, theoretical disconnects remain between the temporal encoding properties of dopamine neurons and the behavioral consequences of its release. Here, we demonstrate in rats that dopamine evoked by Pavlovian cues increases during acquisition, but dissociates from stable conditioned appetitive behavior as this signal returns to pre-conditioning levels with extended training. Experimental manipulation of the statistical parameters of the behavioral paradigm revealed that this attenuation of cue-evoked dopamine release during the post-asymptotic period was attributable to acquired knowledge of the temporal structure of the task. In parallel, conditioned behavior became less dopamine dependent after extended training. Thus, the current work demonstrates that as the presentation of reward-predictive stimuli becomes anticipated through the acquisition of task information, there is a shift in the neurobiological substrates that mediate the motivational properties of these incentive stimuli.

Summary The calcium-activated small conductance potassium channel, SK3, plays an essential role in the regulation of dopamine neuron activity patterns. Here we demonstrate that expression of a human disease-related SK3 mutation (hSK3Δ) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3Δ suppressed endogenous SK currents, reducing coupling between SK channels and NMDA receptors (NMDARs) and increasing permissiveness for burst firing. Consistent with enhanced excitability of dopamine neurons, hSK3Δ increased evoked calcium signals in dopamine neurons in vivo and potentiated evoked dopamine release. Specific expression of hSK3Δ led to deficits in attention and sensory gating and heightened sensitivity to a psychomimetic drug. Sensory-motor alterations and psychomimetic sensitivity were recapitulated in a mouse model of transient, reversible dopamine neuron activation. These results demonstrate the cell-autonomous effects of a human ion channel mutation on dopamine neuron physiology and the impact of activity pattern disruption on behavior.

Protein Kinase A (PKA) mediates synaptic plasticity and is widely implicated in learning and memory. The hippocampal dentate gyrus (DG) is thought to be responsible for processing and encoding distinct contextual associations in response to highly similar inputs. The mossy fiber (MF) axons of the dentate granule cells convey strong excitatory drive to CA3 pyramidal neurons and express presynaptic, PKA-dependent forms of plasticity. Here, we demonstrate an essential role for the PKA anchoring protein, AKAP7, in mouse MF axons and terminals. Genetic ablation of AKAP7 specifically from dentate granule cells results in disruption of MF-CA3 LTP directly initiated by cAMP, and the AKAP7 mutant mice are selectively deficient in pattern separation behaviors. Our results suggest that the AKAP7/PKA complex in the MF projections plays an essential role in synaptic plasticity and contextual memory formation.DOI: http://dx.doi.org/10.7554/eLife.20695.001