The ability to remember potential dangers in an environment is necessary to the survival of animals and humans. The cyclic AMP responsive element binding protein (CREB) is a key transcription factor in synaptic plasticity and memory consolidation. We have found that in CaMKIV(-/-) mice--which are deficient in a component of the calcium calmodulin-dependent protein kinase (CaMK) pathway, a major pathway of CREB activation--fear memory, but not persistent pain, was significantly reduced. CREB activation by fear conditioning and synaptic potentiation in the amygdala and cortical areas was reduced or blocked. We propose that cognitive memory related to a noxious shock can be disassociated from behavioral responses to tissue injury and inflammation.

Identifying higher brain central region(s) that are responsible for the unpleasantness of pain is the focus of many recent studies. Here we show that direct stimulation of the anterior cingulate cortex (ACC) in mice produced fear-like freezing responses and induced long-term fear memory, including contextual and auditory fear memory. Auditory fear memory required the activation of N-methyl-D-aspartate (NMDA) receptors in the amygdala. To test the hypothesis that neuronal activity in the ACC contributes to unpleasantness, we injected a GABA A receptor agonist, muscimol bilaterally into the ACC. Both contextual and auditory memories induced by foot shock were blocked. Furthermore, activation of metabotropic glutamate receptors in the ACC enhanced behavioral escape responses in a noxious hot-plate as well as spinal nociceptive tail-flick reflex. Our results provide strong evidence that the excitatory activity in the ACC contribute to pain-related fear memory as well as descending facilitatory modulation of spinal nociception.

Different kainate receptor (KAR) subtypes contribute to the regulation of both excitatory and inhibitory transmission. However, no study has reported a role for KAR subtypes in behavioral responses to persistent pain and fear memory. Here we show that responses to capsaicin or inflammatory pain were significantly reduced in mice lacking glutamate receptor 5 (GluR5) but not GluR6 subunits. In classic fear-memory tests, mice lacking GluR6 but not GluR5 showed a significant reduction in fear memory when measured 3, 7, or 14 d after training. Additionally, synaptic potentiation was significantly reduced in the lateral amygdala of GluR6 but not GluR5 knock-out mice. Our findings provide evidence that distinct KAR subtypes contribute to chemical/inflammatory pain and fear memory. Selectively targeting different KAR subtypes may provide a useful strategy for treating persistent pain and fear-related mental disorders.

The ability to remember potential dangers in an environment is necessary to the survival of animals and humans. The cyclic AMP responsive element binding protein (CREB) is a key transcription factor in synaptic plasticity and memory consolidation. We have found that in CaMKIV(-/-) mice--which are deficient in a component of the calcium calmodulin-dependent protein kinase (CaMK) pathway, a major pathway of CREB activation--fear memory, but not persistent pain, was significantly reduced. CREB activation by fear conditioning and synaptic potentiation in the amygdala and cortical areas was reduced or blocked. We propose that cognitive memory related to a noxious shock can be disassociated from behavioral responses to tissue injury and inflammation.