Mechanisms Underlying Associative Learning: Classical Conditioning Paradigms and the Functional Neuronal Changes that Support Acquisition


Classical conditioning is a form of associative learning and can be used as a behavioral paradigm to model and investigate the neural mechanisms underlying associative learning. In this work, classical conditioning paradigms are used to test the effectiveness of a disease model on the impact of learning and emotional regulation as well as to examine the functional neural changes in various brain regions as a result of declarative or non-declarative associative learning. Using fear conditioning, we determined that a single exposure to a blast overpressure to induce mild traumatic brain injury (mTBI) in mice resulted in enhanced fear during fear conditioning but impairments in the memory for the associative fear conditioning task. The results indicate that a single exposure to a blast overpressure can induce symptoms of posttraumatic stress disorder (PTSD) as well as memory impairments. Eyeblink conditioning is another classical conditioning paradigm, and one that can be modified to suit the neurological changes that one wishes to examine. We modified the conditioned stimulus (CS) during a trace eyeblink conditioning paradigm to be a whisker vibration rather than a flash of light or a tone and determined that mice were able to successfully learn trace eyeblink conditioning. The advantage of using a whisker vibration as a CS during trace eyeblink conditioning is that neural changes can be easily mapped in the highly organized barrel cortex of murine animals. Delay eyeblink conditioning, on the other hand, offers its own advantages, including the fact that it is cerebellar-dependent, which allows for learning-related changes in cerebellar Purkinje cells to be examined. We determined an increase in intrinsic excitability in Purkinje cells following training on delay eyeblink conditioning, marked by a smaller postburst AHP and increased spikelets in complex waveforms. Intrinsic excitability has also been shown to increase with learning in CA1 neurons of the hippocampus (Moyer et al, 1996; Matthews et al, 2009). In the CA1 region, intrinsic excitability is not only an important marker, but also a major determinant of learning. The lateral entorhinal cortex (LEC) is a cortical region that is extremely important in the acquisition of hippocampus-dependent tasks such as trace conditioning, with layer III of the LEC (LEC III) projecting directly to the CA1 region. The LEC is also highly susceptible to aging-related changes, which may contribute to aging-related learning impairments (Yassa et al, 2010; Khan et al, 2013). We measured intrinsic excitability as well as persistent firing ability in LEC III neurons from young and aged rats that were behaviorally naïve or trained on trace eyeblink conditioning. Behaviorally naïve aged animals exhibited decreased persistent firing ability and intrinsic excitability (as measured by the postburst AHP) in LEC III neurons compared to behaviorally naïve young animals, while successful acquisition of trace eyeblink conditioning increased persistent firing ability and intrinsic excitability in both young and aged animals. However, intrinsic excitability and persistent firing ability were decreased in learning-impaired aged animals that failed to successfully acquire trace eyeblink conditioning. Intrinsic excitability in LEC III may also be a major determinant of learning in hippocampus-dependent associative learning, driving changes in persistent firing ability.

Alternate Identifier
Date created
Resource type
Rights statement