Synaptic and Behavioral Profile of Multiple Glutamatergic Inputs to the Nucleus Accumbens

Abstract

SUMMARY Excitatory afferents to the nucleus accumbens (NAc) are thought to facilitate reward seeking by encoding reward-associated cues. Selective activation of different glutamatergic inputs to the NAc can produce divergent physiological and behavioral responses, but mechanistic explanations for these pathway-specific effects are lacking. Here, we compared the innervation patterns and synaptic properties of ventral hippocampus, basolateral amygdala, and prefrontal cortex input to the NAc. Ventral hippocampal input was found to be uniquely localized to the medial NAc shell, where it was predominant and selectively potentiated following cocaine exposure. In vivo, bidirectional optogenetic manipulations of this pathway attenuated and enhanced cocaine-induced locomotion. Challenging the idea that any of these inputs encode motivationally-neutral information, activation of each discrete pathway reinforced instrumental behaviors. Finally, direct optical activation of medium spiny neurons proved to be capable of supporting self-stimulation, demonstrating that behavioral reinforcement is an explicit consequence of strong excitatory drive to the NAc.

Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

“…Extracellular glutamate levels are tightly regulated by numerous neuronal and glial release and uptake functions. One possibility is that repeated cycles of CIE exposure produce a persistent hyperexcitable state in the NAc driven by increased activity in glutamatergic afferents arising from the prefrontal cortex and limbic (hippocampus and amygdala) nuclei (Britt et al, 2012). In the NAc, mGluR2 and mGluR3 receptors are predominantly located in the neurons, pre-and postsynaptically (Ohishi et al, 1998;Tamaru et al, 2001).…”

Resolving the neural circuits of anxiety

“…Moreover, the mPFC is ideally poised to orchestrate shifts between anxiety-like and reward-motivated behaviors, as it sends projections both to the amygdala and nucleus accumbens (NAc). mPFC efferents to the latter affect information processing within striatal projection neurons 119 , and stimulation of this pathway is reinforcing 120 .…”

The Other Face of the Nucleus Accumbens: Aversion

“…Cocaine selectively increases the presynaptic release probability of excitatory synapses within the PFCNAc pathway but not the BLA-NAc pathway, and amygdala fibers have a relatively low probability of transmitter release [7,9]. Chronic non-contingent or contingent cocaine exposure and withdrawal evoke input-and cell type-specific plasticity in the NAc, which may underlie behavioral adaptations in addiction, such as craving and relapse [7,10]. Optogenetic-mediated, pathway-specific stimulation reveals that the activation of inputs from the PFC, vHipp, and BLA to the NAc is rewarding and can reinforce instrumental behavior [6,7].…”

“…Both positive reinforcement (rewarding effects of drugs) and negative reinforcement (aversive emotional state associated with withdrawal) have been considered to play critical roles in the etiology and maintenance of drug addiction, and NAc neurons are capable of processing both reward and aversion [4,5]. Optogenetic activation of inputs from the PFC, ventral hippocampus (vHipp), and basolateral amygdala (BLA) to the NAc drives positive reinforcement and facilitates rewardseeking behavior [6,7], but a recent paper in Nature [8] has identified another face of the NAc. The pathway from the paraventricular nucleus of the thalamus (PVT) to the NAc is key to the aversive emotional state of drug withdrawal.…”

“…Chronic non-contingent or contingent cocaine exposure and withdrawal evoke input-and cell type-specific plasticity in the NAc, which may underlie behavioral adaptations in addiction, such as craving and relapse [7,10]. Optogenetic-mediated, pathway-specific stimulation reveals that the activation of inputs from the PFC, vHipp, and BLA to the NAc is rewarding and can reinforce instrumental behavior [6,7]. However, still unknown is the specific NAc circuitry that underlies negative emotional and motivational states after withdrawal.…”