Title: Dopaminergic modulation of hippocampal neural circuitry
Description: Memory is a limited resource. Therefore, the circuitry that encodes memory must filter incoming information in accordance with its perceived value. The hippocampus, the hub of the declarative memory system, may achieve memory valuation using its rich variety of neuromodulatory afferent systems. The dopamine (DA) neurons in the ventral tegmental area (VTA) and susbtantia nigra pars compacta (SNpC) are in a particularly strategic position to aid the hippocampus in gating long-term memory. Their firing rates encode the salience of external cues in the environment and they send axons to the output node of the hippocampus, area CA1. In CA1, exogenous receptor stimulation with DA receptor agonists and antagonists suggests an important role for VTA/SNpC DA in learning and memory as the DA receptors powerfully modulate synaptic transmission, permit LTP induction, and enhance different forms of spatial memory. However, it remains unknown whether the VTA/SNpC DAergic axons are capable of activating those receptors and triggering the effects on hippocampal physiology.

The VTA/SNpC innervation density in the hippocampus is modest and, in many cases, the axons are distant from the neurons exhibiting the effects. Other sources of DA could couple to those receptors, such as the locus coeruleus, which also releases DA in the CA1 area. To investigate the VTA/SNpC's DAergic influence, I took a circuit-based approach and selectively evoked DA release from the VTA/SNpC DAergic afferents in CA1 in vitro with different patterns of optogenetically guided stimulation. I found that DA release directly modulates the CA3 Schaffer collateral (SC) synaptic excitation of CA1 in a bidirectional manner. A single light-burst (three 5-ms-long pulses at 66 Hz) suppresses the SC-evoked PSP in CA1 pyramidal neurons (PNs) through a D2-receptor dependent enhancement of parvalbumin-positive interneuron mediated feedforward inhibition. More prolonged DA release using 25 light-bursts (at 1 Hz) increases the SC PSP through a D1-type receptor dependent direct presynaptic effect on excitatory transmission.

Thus, I propose the following model for how VTA/SNpC DAergic afferents effect oppositional synaptic states to influence learning in the hippocampus in accordance with motivational demands. During tonic DA release, the D4 receptors become activated, globally weaken the SC synaptic input to CA1 PNs, and increase plasticity thresholds. In contrast, phasic DA release activates D1-type receptors, and transitions the SC synapse to a more efficacious state, during which weaker inputs can drive potentiation.