A Motivational and Neuropeptidergic Hub: Anatomical and Functional Diversity within the Nucleus Accumbens Shell

Abstract

The mesocorticolimbic pathway is canonically known as the "reward pathway." Embedded within the center of this circuit is the striatum, a massive and complex network hub that synthesizes motivation, affect, learning, cognition, stress, and sensorimotor information. Although striatal subregions collectively share many anatomical and functional similarities, it has become increasingly clear that it is an extraordinarily heterogeneous region. In particular, the nucleus accumbens (NAc) medial shell has repeatedly demonstrated that the rules dictated by more dorsal aspects of the striatum do not apply or are even reversed in functional logic. These discrepancies are perhaps most easily captured when isolating the functions of various neuromodulatory peptide systems within the striatum. Endogenous peptides are thought to play a critical role in modulating striatal signals to either amplify or dampen evoked behaviors. Here we describe the anatomical-functional backdrop upon which several neuropeptides act within the NAc to modulate behavior, with a specific emphasis on nucleus accumbens medial shell and stress responsivity. Additionally, we propose that, as the field continues to dissect fast neurotransmitter systems within the NAc, we must also provide considerable contextual weight to the roles local peptides play in modulating these circuits to more comprehensively understand how this important subregion gates motivated behaviors.

Keywords: affect; mesocorticolimbic; motivation; nucleus accumbens; opioid; peptides; stress; striatum.

Figure 1.. Basic structural anatomy of the striatum.

(A, left) Ring charts showing relative expression (%, gray text) of cell types (outer ring) or patch/matrix (inner ring). Cell types labeled with known and exclusive markers for each population. (B, right) Intra-striatal connectivity schematic showing preferential connections between cell types. Arrows signify projection target, circled arrows signify synapses onto other neurons of the same type. Cell populations: purple, direct pathway; green, indirect pathway; blue, fast-spiking interneuron; orange, low-threshold spiking interneurons; red, tonically active interneurons. Arrow thickness: thin, low connectivity; medium, moderate connectivity; thick, strong connectivity. (C, bottom, left) Schematic of rodent striatum, dividing dorsal, core, and shell into separable subregions(lateral and medial divided by dashed line). Matrix (brown) and patch (yellow) shaped and distributed to show relative expression in each subregion. (right) Table showing relative distribution of different cell types within each region of the striatum. Direct pathway neurons, purple; indirect pathway neurons, green; tonically active interneurons, red; fast-spiking interneurons, blue; low-threshold spiking interneurons, orange. +, low relative expression; ++, average relative expression; +++ high relative expression.

Figure 2.. Known projections and potential neuromodulatory afferents to NAc medial shell.

Schematic listing the known afferents to NAc medial shell. Afferents are roughly divided by rostrocaudal (top, rostral) and mediolateral coordinates (left, medial). Afferents are labeled by whether they send glutamatergic or GABAergic efferents: glutamate (green); GABA (red); or both (brown). Potential coreleased neuromodulators are denoted by individually colored dots within each afferent. Whether or not the listed peptide is actually coreleased in NAc is unknown, but the existence of the modulator in the afferent seed allows for the possibility. Abbreviations: AgRP, agouti-related peptide; CCK, cholecystokinin; CART, cocaine and amphetamine related transcript; DA, dopamine; Dyn, dynorphin; Enk, enkephalin, Gal, galanin; MCH, melanin-concentrating hormone; NPY, neuropeptide Y; NT, neurotensin; Noci, nociceptin; NE, norepinephrine; Orexin, orexin/hypocretin; POMC, proopiomelanocortin; 5HT, Serotonin; SP, Substance P.

Figure 3.. Peptidergic localization of function within NAc medial shell.

(A) Schematic showing site specific manipulations of various peptides in NAc medial shell, divided by dorsal versus ventral targets. Red text, enhancement of behavior; blue text, suppression of behavior; gray text, non-behavioral study. (b) Schematic showing site specific manipulations of various peptides in NAc medial shell, divided by rostral versus caudal targets. (c) Ring charts show proportion of peptide studies targeting all sites in NAc (pink) versus specific cites (black outline). Of the studies targeting specific sites, proportion of peptide studies in NAc medial shell targeting rostral (purple), caudal (orange), or both (gray) sites. Studies cited can be found in Table 2.