Cracking the brain’s code for an associative memory

A fundamental goal of neuroscience is to understand how changes in cellular properties contribute to learning, memory and disease-related dysfunction.  However, there are few examples in the literature in which a form of associative learning or memory can be studied at both the systems-behavioral and cellular-molecular levels simultaneously in the mammalian brain.  A key impediment to such analyses has been the inability to identify and study the specific cells that participate in a form of learning and/or memory. Our joint project constitutes a first step in identifying the complete circuitry and cellular/synaptic elements involved in a working memorya component of memory that involves the short-term storage of information to make decisions or guide behavior. Sometimes called “scratchpad memory”, examples include remembering a phone number while dialing or remembering previously searched locations while looking for your keys.-like behavior in the rat – trace eyelid conditioningEyelid conditioning, one of the best-characterized forms of associate learning in the mammalian brain, involves the repeated pairing of a neutral, conditioned stimulus (CS; often a tone) with a reinforcing, blink-evoking unconditioned stimulus (US; often an airpuff to the eye). With repeated presentations, the experimental subject learns to close its eye to the CS. The two most common forms of eyelid conditioning – delay and trace – differ procedurally only in the timing of the delivery of the US. For delay conditioning the US is delivered during the CS, whereas for trace conditioning the US is delivered after the offset of the CS (after a stimulus free “trace interval”). Whereas delay eyelid conditioning requires the cerebellum and occurs largely independent of the forebrain, for trace eyelid conditioning the presence of the trace interval necessitates several forebrain structures (e.g. hippocampus, prefrontal cortex, striatum and sensory cortex), in addition to the cerebellum..

Trace eyelid conditioning

Several recent findings from our labs have advanced our knowledge of trace conditioning circuitry:

Trace eyelid conditioning requires the medial prefrontal cortex (mPFC), regions of the pons that receive input from mPFC and the cerebellum.

– To learn and express trace eyelid conditioned responses, the cerebellum requires an input from the pons that persists through the stimulus-free trace interval (Kalmbach Et al. 2009; 2010B).

-Neurons in mPFC and a specific region of the pons respond persistently to presentations of the CS in well-trained animals.

Together, these findings suggest that the mPFC provides the cerebellum, via the pons, with an input that persists through the stimulus-free trace interval to enable learning and its ongoing expression.

Our goal is to understand the cellular changes that contribute to the ability of mPFC neurons to fire persistently during working-memory related tasks like trace eyelid conditioning.