Brain mechanisms controlling Pavlovian fear conditioning.

A key insight of associative learning theory is that learning depends on the actions of prediction error: a discrepancy between the actual and expected outcomes of a conditioning trial. This view of learning has inspired, and in turn been supported by, work in the neurosciences ranging from single unit recording and neuroimaging studies to pharmacological, chemogenetic, and optogenetic interventions. Here we review evidence describing how error-correcting learning rules are instantiated in the activity of distributed neural circuits controlling the effectiveness of unconditioned stimuli during Pavlovian fear conditioning. We show that these prediction error signals, controlling variations in event processing, are fundamental to Pavlovian fear association formation. We also argue that variations in event processing are embedded within multiplexed learning signals and that a coherent understanding of the nature and relationships between these multiple signals at specific times during the conditioning trial is needed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Distinct Accumbens Shell Output Pathways Promote versus Prevent Relapse to Alcohol Seeking.

Contexts exert bi-directional control over relapse to drug seeking. Contexts associated with drug self-administration promote relapse, whereas contexts associated with the absence of self-administration protect against relapse. The nucleus accumbens shell (AcbSh) is a key brain region determining these roles of context. However, the specific cell types, and projections, by which AcbSh serves these dual roles are unknown. Here, we show that contextual control over relapse and abstinence is embedded within distinct output circuits of dopamine 1 receptor (Drd1) expressing AcbSh neurons. We report anatomical and functional segregation of Drd1 AcbSh output pathways during context-induced reinstatement and extinction of alcohol seeking. The AcbSh→ventral tegmental area (VTA) pathway promotes relapse via projections to VTA Gad1 neurons. The AcbSh→lateral hypothalamus (LH) pathway promotes extinction via projections to LH Gad1 neurons. Targeting these opposing AcbSh circuit contributions may reduce propensity to relapse to, and promote abstinence from, drug use.

Basolateral Amygdala Neurons Maintain Aversive Emotional Salience.

BLA neurons serve a well-accepted role in fear conditioning and fear extinction. However, the specific learning processes related to their activity at different times during learning remain poorly understood. We addressed this using behavioral tasks isolating distinct aspects of fear learning in male rats. We show that brief optogenetic inhibition of BLA neurons around moments of aversive reinforcement or nonreinforcement causes reductions in the salience of conditioned stimuli, rendering these stimuli less able to be learned about and less able to control fear or safety behaviors. This salience reduction was stimulus-specific, long-lasting, and specific to learning about, or responding to, the same aversive outcome, precisely the goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition. They show that a primary function of the unconditioned stimulus-evoked activity of BLA neurons is to maintain the salience of conditioned stimuli that precede it. This maintenance of salience is a necessary precursor for these stimuli to gain and maintain control over fear and safety behavior.SIGNIFICANCE STATEMENT The amygdala is essential for learning to fear and learning to reduce fear. However, the specific roles served by activity of different amygdala neurons at different times during learning is poorly understood. We used behavioral tasks isolating distinct aspects of learning in rats to show that brief optogenetic inhibition of BLA neurons around moments of reinforcement or nonreinforcement disrupts maintenance of conditioned stimulus salience. This causes a stimulus-specific and long-lasting deficit in the ability of the conditioned stimulus to be learned about or control fear responses. These consequences are the precisely goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition.