This thesis represents a culmination of work which seeks to examine the prelimbic and anterior cingulate cortex (ACC) during trace fear memory across sleep and wakefulness states. In order to accomplish this task, a technical platform needed to be developed. Accordingly, the first chapter demonstrates that fear behavior can recorded utilizing neck electromyography (EMG). The second chapter examines the role of the ACC in trace fear memory, discovering that many neurons have premotor activity related to freezing behavior. Additionally, auditory-evoked potentials in the ACC demonstrate learning curves which match learning curves of fear. We suggest that the ACC is involved in affective-motor integration. The third chapter examines how genetic enhancement of trace fear learning, with calcium/calmodulin-dependent protein kinase IV (CaMKIV) over-expressed mice, can influence electro-cortical potentials during wakefulness, learning and sleep. We found that CaMKIV potentiates electro-cortical brain waves during learning and sleep. In particular 4-7.5Hz rhythms were potentiated in CaMKIV over-expressed mice during learning, and are likely to be localized to regions of the prelimbic cortex. Taken together the results of this thesis demonstrate that the trace fear memory paradigm engages the ACC and prelimbic regions, as evidenced at the single cell and cortical field potential level, for sensory-affective and premotor functions related to anticipating painful stimulation. CaMKIV appears to be a protein which modulates learning and electro-cortical potentials and may be a potential target for sleep-dependent memory consolidation in the prefrontal cortex.

This thesis represents a culmination of work which seeks to examine the prelimbic and anterior cingulate cortex (ACC) during trace fear memory across sleep and wakefulness states. In order to accomplish this task, a technical platform needed to be developed. Accordingly, the first chapter demonstrates that fear behavior can recorded utilizing neck electromyography (EMG). The second chapter examines the role of the ACC in trace fear memory, discovering that many neurons have premotor activity related to freezing behavior. Additionally, auditory-evoked potentials in the ACC demonstrate learning curves which match learning curves of fear. We suggest that the ACC is involved in affective-motor integration. The third chapter examines how genetic enhancement of trace fear learning, with calcium/calmodulin-dependent protein kinase IV (CaMKIV) over-expressed mice, can influence electro-cortical potentials during wakefulness, learning and sleep. We found that CaMKIV potentiates electro-cortical brain waves during learning and sleep. In particular 4-7.5Hz rhythms were potentiated in CaMKIV over-expressed mice during learning, and are likely to be localized to regions of the prelimbic cortex. Taken together the results of this thesis demonstrate that the trace fear memory paradigm engages the ACC and prelimbic regions, as evidenced at the single cell and cortical field potential level, for sensory-affective and premotor functions related to anticipating painful stimulation. CaMKIV appears to be a protein which modulates learning and electro-cortical potentials and may be a potential target for sleep-dependent memory consolidation in the prefrontal cortex.

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Nicotine has been shown to enhance multiple forms of learning and memory. However the substrates through which these effects occur are not well understood. To examine the specific substrates of nicotine's acute effects on trace fear conditioning, I infused nicotine into areas thought to support trace fear conditioning, the dorsal hippocampus, ventral hippocampus and medial prefrontal cortex. Additionally, we investigated the contributions of nicotinic acetylcholinergic signaling to trace fear conditioning by infusing the nicotinic antagonists dihydro-beta-erythroidine (DHbE) and methyllycaconitine (MLA) into these areas. Nicotine had different effects on both trace and contextual fear conditioning depending on dose and brain region, as did the nicotinic antagonists. In the dorsal hippocampus nicotine infusion enhanced both trace and contextual conditioning, although these effects were dissociable by dose and training protocol. Additionally, the high-affinity nicotinic antagonist DHbE produced selective deficits in trace conditioning, suggesting that while enhancement of nicotinic signaling can affect both contextual and trace learning, nicotinic activity in the dorsal hippocampus is critically involved in trace but not contextual conditioning. In the ventral hippocampus nicotine infusion produced deficits in both trace and contextual fear conditioning, without affecting delay conditioning, while the antagonists had no effect. This finding suggests that altered nicotinic signaling in the ventral hippocampus can suppress hippocampus dependent learning. In the mPFC nicotine selectively enhanced trace conditioning though both antagonists also enhanced trace fear conditioning. Unlike in the mPFC or dorsal hippocampus, where nicotine and antagonist induced effects occurred during training, effects in the ventral hippocampus occurred at both training and testing, suggesting that the ventral hippocampus may be able to modulate acquisition as well as expression of hippocampus dependent learning. Additionally, antagonist infusion into the mPFC during testing produced deficits in expression, suggesting that this area can modulate fear expression. Thus, the substrates of nicotinic acetylcholinergic contributions to trace and contextual fear conditioning are diverse. I put forth a multi-component model of these contributions, where trace fear conditioning is supported by dorsal hippocampus dependent maintenance of the CS during the trace interval, long-term storage in the mPFC and ventral hippocampal mediated acquisition and expression. / Psychology