Grant: Discovery Grants Program - Individual

Arousing and emotional circumstances can affect memory directionally, either by strengthening, or conversely, by weakening memory of events or stimuli. In mammalian systems, the brainstem nucleus the locus coeruleus (LC) provides the signal for arousal by firing in phasic, transient bursts of activity, releasing the neurotransmitter norepinephrine (NE) throughout the brain. One of the largest targets of LC-NE is the memory structure the hippocampus. It was first reported that phasic release of NE leads to a long-term increases in cellular activity in the hippocampal region the dentate gyrus (DG) (a physiological phenomenon called NE-induced long-term potentiation, or NE-LTP). However, a recent study has also reported that phasic NE release is also capable of producing long-term depression (NE-LTD) of neuronal activity at the same synapses. ******It may first appear that these results are contradictory, however, a new theory “glutamate amplification of norepinephrine effects” or GANE, provides possible explanation of how NE could produce these divergent responses. GANE predicts that the relationship of NE with the most prevalent excitatory neurotransmitter, glutamate, could yield either NE-LTP or NE-LTD dependent upon the levels of initial activation, and by recurrent activity initiated by feedback communication. We will directly assess elements contributing to the facilitated NE signal, or glutamate initiated NE Hotspot' proposed by GANE to better understand the mechanisms leading to the bidirectional responses initiated by the LC-NE signal. Second, we will use optogenetic technology, a method of activating neurons using light activation, to ask if LC firing patterns themselves set bidirectional plasticity and, consequently, we will attempt to examine the effects of patterned LC activation on hippocampus-dependent behavior. ******We predict that release of NE can indeed produce both NE-LTP and NE-LTD in the DG of rats, and predict that experimental conditions that manipulate activity of glutamate, will bias the direction of the response after phasic LC activation. Additionally, it is predicted that phasic activation of LC neurons will produce more robust NE-LTP, while tonic activation, a pattern most associated with anxiety and stress, would be expected to produce depression of activity. We also predict that manipulating LC-NE in a manner that produces NE-LTP will enhance memory of hippocampus-dependent tasks, while those that produce NE-LTD will be more likely to inhibit memory for the same task. ******Harnessing our understanding of how the LC-NE system modulates memory and brain plasticity will provide a deeper explanation of a system that has the potential to increase or decrease our ability to learn and remember. Ultimately, as the LC system has been identified as a region that can be compromised during the aging process, this will have farther reaching implications for the cognitive changes that occur throughout the lifespan.**