The Pavlovian Conditioning

The Pavlovian conditioning is an implicit learning which does not require consciousness of the subject. Hippocampus-impaired patients can still learn new motor skills through this mechanism. Even invertebrate animals with simple neural circuits may be trained by the Pavlovian conditional reflex, which is essentially the association between conditioned and unconditioned stimuli. In the original Pavlov's experiments on the dog, food is the unconditioned stimulus which elicits the secretion of saliva by native response. The unconditioned stimulus was preceded by a conditioned stimulus (the bell-ringing) which initially did not produce salivation. After a few paired stimulations, the bell-ringing itself could produce salivation.

The molecular mechanism of the Pavlovian conditioning has been well understood for the Aplysia system which contains a simple neural circuit. In this system, the unconditioned stimulus is a strong shock to the tail, eliciting gill movement by native reaction. The conditioned stimulus is a weak tactile stimulus to either siphon or mantle shelf, which initially does not cause the gill movement (Figure 14A). After a few paired stimulations (weak stimulus to siphon followed by tail shock), the weak stimulus to siphon alone can cause the gill movement. To explain its molecular mechanism, let us first explain the mechanism of sensitization, which refers to the potentiation of synaptic transmission by the unconditioned stimulus alone.

Figure 15. Molecular mechanism of the Pavlovian conditioning for the Aplysia system.

In Fig. 15A, the unconditioned stimulus (tail shock) not only elicits gill movement directly, but also activates a modulatory neuron which releases 5-HT (serotonin) to bind on its G-protein-coupled receptor (5-HTR) in the nerve terminal of the conditioned pathway. This nerve terminal may release neurotransmitters to excite a postsynaptic neuron which is directly responsible for the gill movement. Binding of 5-HT to its receptor can activate adenylyl cyclase (AC), producing cAMP. The cAMP triggers phosphorylation of potassium channels by activating the protein kinase A (PKA). Phosphorylation of potassium channels in this system reduces channel opening probability. The reduction of K⁺ currents slows the repolarization of action potentials, thereby increasing Ca²⁺ influx to release more excitatory neurotransmitters. Hence, the synaptic transmission in the conditioned pathway is potentiated.

The sensitization by the unconditioned stimulus alone may or may not be significant, depending on the system. As explained below, the efficacy of synaptic transmission in the conditioned pathway will be greatly enhanced if the unconditioned stimulus is paired with the conditioned stimulus.

In the conditioned pathway, Ca²⁺ ions may move into the nerve terminal upon the arrival of the action potential. Initially, the duration of the action potential is short so that the Ca²⁺ influx cannot release sufficient neurotransmitters to elicit the gill movement. However, after Ca²⁺ ions move into the nerve terminal, they may bind with calmodulin (CAM). The Ca²⁺/calmodulin complex could also activate adenylyl cyclase to produce more cAMP for the phosphorylation of potassium channels. Therefore, the conditioned stimulus, if paired with the unconditioned stimulus, can amplify the activation of adenylyl cyclase. After a few paired stimulations, the reduction of K⁺ outflux may increase the duration of action potentials to the extent that the conditioned stimulus (i.e., the weak stimulus to siphon) alone can induce sufficient Ca²⁺ influx to elicit the gill movement.

In the Pavlovian conditioning, the unconditioned stimulus has to be applied shortly after the conditioned stimulus. The optimal interval between the two stimuli was found to be 0.5 second for the case of Aplysia. The 0.5 second interval may correspond to the time required for the binding of Ca²⁺ with calmodulin. Thus, the adenylyl cyclase can be activated almost simultaneously by the Ca²⁺/calmodulin complex from the conditioned pathway and the G protein from the unconditioned pathway.

Review Article:

Pavlovian Conditioning of Hermissenda: Current Cellular, Molecular, and Circuit Perspectives - Learning and Memory, 2004.