Optogenetic modulation of glutamatergic afferents from the ventral subiculum to the nucleus accumbens: Effects on dopamine function, response vigor and locomotor activity

Abstract

Dopamine (DA) signalling in the nucleus accumbens (NAc) motivates behavior in part by adjusting the exerted effort according to the anticipated value of the outcome. Here we examined the effects of optogenetic activation or inhibition of the glutamatergic ventral subiculum (vSub) to NAc pathway on motivation to work for food rewards and locomotor behavior. Using a novel probe that combines optical stimulation with microdialysis, we show that channelrhodopsin2 (ChR2)-mediated activation of these glutamatergic afferents increased DA efflux in the NAc. This protocol also selectively influenced motivation to seek food in a progressive-ratio (PR) task by re-invigorating lever-pressing, but only during a period of reduced motivation following failure to achieve food reward (i.e., after the breakpoint, BP). Importantly, identical ChR2-mediated photostimulation parameters failed to affect the rate of operant responding in the PR segment prior to reaching the BP. In contrast, during the segment of vigorous lever-pressing prior to the BP, halorhodopsin-mediated optogenetic inhibition of glutamatergic vSub-NAc activity caused an immediate and sustained suppression of food-seeking behavior. Based on these results, we conclude that glutamatergic vSub-NAc afferents can modulate food-seeking behavior, including ‘response vigor’, as a function of present motivational state. In a ‘low-motivational state’ following failure to achieve an anticipated reward, optogenetic stimulation of this pathway can reinvigorate lever-pressing behavior. In turn, inhibition of this glutamatergic pathway appears to decrease motivated responding. These data may be relevant to dysregulated motivational states common to psychiatric conditions, including depression, schizophrenia, and substance use disorders.