Locus Coeruleus-Dependent Dopamine Release in the Dorsal Hippocampus: Mechanisms and Modulation of Synaptic Plasticity

Locus coeruleus (LC) neurons coordinate the overwhelming majority of norepinephrine (NE) signaling throughout the mammalian neocortex and hippocampus. Recent discoveries indicate that dopamine (DA), the biosynthetic precursor of NE, is also released from LC axons. These axons innervate most brain regions, and are especially prevalent in the rodent dorsal hippocampus, including area CA1. It was previously thought that the only supply of CA1 dopamine was the ventral tegmental area, but several recent studies have identified LC fibers as the main source of DA in this region. However, both the mechanism by which LC-DA is released, and whether or not it is released in sufficient quantities to influence DA-dependent processes in the hippocampus, remain unclear. These questions have major implications for theories concerning the molecular basis of learning, since the consolidation of episodic memories in CA1 requires activation of dopamine D1-like receptors. Therefore, the focus of this dissertation is to determine if LC-originating DA can modulate synaptic plasticity, and therefore learning and memory, in CA1 of the mouse hippocampus. We also sought to uncover the molecular mechanism of this LC-DA release. The following experiments study the effects of LC-dopamine on CA1 function using optogenetic, electrophysiological, pharmacological, and behavioral approaches. We show that optogenetically evoked LC-DA release is sufficient to activate D1/D5 receptors (D1/5R) on CA1 pyramidal neurons and modulate synaptic potentiation at Schaffer collateral synapses, a necessary step for the consolidation of learning. In accordance with this, we find that LC-specific knockdown of DA synthesis can block learning at the behavioral level (Chapter 2). We also demonstrate that one possible LC-DA release mechanism is reverse transport through the norepinephrine transporter (NET), and advance the idea that presynaptic NMDA receptors on LC terminals may play a role in this release. Furthermore, as DA and NE should be co-released in dorsal CA1, we show that they act together to enhance synaptic strength (Chapter 3). Since LC activity is known to be involved in attention and memory, our results contribute new insight into how the LC can link attentional processes to memory formation at the molecular, circuit, and behavioral levels (Chapter 4).