Optimization of activity-dependent plasticity of cortical circuits: role of neuromodulators, sensory experience, and "arousal"

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Brain development is, in part, guided by external, environmental influences. Further, the mature brain also changes in response to external stimuli, a characteristic that allows neurons to encode long-lasting memories. Long-term potentiation (LTP), a relatively stable increase in synaptic strength, is thought to be involved in developmental brain maturation and information encoding in the adult brain. The experiments described here examine mechanisms that mediate the influence of external stimuli and internal (brain) states on brain plasticity (LTP). Three lines of investigation are proposed: 1. How do neuromodulators regulate synaptic plasticity? Levels of many neuromodulators vary with different brain and associated behavioral states (e.g., alertness/attention, active locomotion, stress, sleep). We will identify those neuromodulators (and their mechanisms of action) that play critical roles in the state-dependent regulation of LTP in brain areas known to play an important role in information encoding (hippocampus, neocortex). 2. How does early postnatal sensory (auditory) experience influence the development and plasticity properties of the auditory-receptive area (auditory cortex) of the brain? Lack of "normal" auditory stimulation during postnatal life inhibits the development of the auditory cortex. We will examine the synaptic mechanisms underlying this developmental impairment and will test if it is reversible by appropriate auditory stimulation in adult life. 3. How does emotional "arousal" influence memory encoding and synaptic plasticity (LTP)? It is known that optimal "arousal" levels can facilitate memory encoding. We have observed that rats have an enhanced memory for spatial locations if they encountered a predator stimulus (cat hair) in that location. We will identify brain areas and neurochemicals responsible for mediating this memory-enhancing effect. Together, these studies characterize critical mechanisms that mediate interactions between external stimuli (sensory, predatory), brain and associated behavioral states (brain activation, "arousal"), and the ability of neurons to modify connectivity, an essential process underlying the development and life-long refinement of the central nervous system.