Drugs and bugs: The role of toll-like receptor 4 in nucleus accumbens synaptic physiology and reward behavior

Abstract

Substance use disorders and depression are significant societal burdens. Both pathologies are associated with alterations of the nucleus accumbens (NAc), a reward center of the brain. The NAc is composed of two types of medium spiny projection neurons (MSNs) that differentially modulate reward behavior. Neuron-mediated mechanisms of change at excitatory synapses within the NAc in response to drug experience and depression-like states are well-studied. However, growing evidence suggests the involvement of the brain’s innate immune system in modulating reward behavior and synaptic physiology. The innate immune system is implicated in regulating synaptic physiology and is recruited in multiple neurological actions, including reward processing. Toll-like receptor 4 (TLR4), a pattern-recognition molecule of the innate immune system, is involved in morphine- and cocaine-mediated reward learning. Despite these observations, there is a paucity of information delineating how the innate immune system alters NAc synaptic physiology in relation to reward behavior. To this end, electrophysiological, behavioral, and molecular experiments were performed comparing wild-type and toll-like receptor 4 knockout (TLR4.KO) mice. Expression of fluorescent reporter proteins allowed discrimination of MSN identity in an ex vivo brain slice preparation. Using electrophysiology, we found that TLR4.KO animals lack N-methyl-D-aspartate receptor (NMDAR) dependent plasticity of excitatory synaptic transmission. We also found differences in NMDAR stoichiometry between TLR4 KO and wild-type mice. This inability to induce plasticity, a common molecular mechanism of learning and memory, is associated with an attenuation in cocaine-reward behaviors. Assessments of synaptic physiology at different time-points following drug exposure also showed cell-type specific differences in NAc MSN synaptic physiology. Other experiments examined synaptic consequences of TLR4 activation, where high concentrations of agonist induce negative affect. This manifests as sickness, which is associated with depressive-like behaviors. In this setting we found cell-type specific differences in NAc MSN synaptic physiology. In total, these experiments add to the growing body of evidence demonstrating the importance of neuro-immune interactions and may help in the identification of therapeutic targets to mitigate neuronal pathologies.