Accumbal D1R Neurons Projecting to Lateral Hypothalamus Authorize Feeding

Abstract

Feeding satisfies metabolic need but is also controlled by external stimuli, like palatability or predator threat. Nucleus accumbens shell (NAcSh) projections to the lateral hypothalamus (LH) are implicated in mediating such feeding control, but the neurons involved and their mechanism of action remain elusive. We show that dopamine D1R-expressing NAcSh neurons (D1R-MSNs) provide the dominant source of accumbal inhibition to LH and provide rapid control over feeding via LH GABA neurons. In freely feeding mice, D1R-MSN activity reduced during consumption, while their optogenetic inhibition prolonged feeding, even in the face of distracting stimuli. Conversely, activation of D1R-MSN terminals in LH was sufficient to abruptly stop ongoing consumption, even during hunger. Direct inhibition of LH GABA neurons, which received input from D1R-MSNs, fully recapitulated these findings. Together, our study resolves a feeding circuit that overrides immediate metabolic need to allow rapid consumption control in response to changing external stimuli. VIDEO ABSTRACT.

Homeostasis Meets Motivation in the Battle to Control Food Intake

“…These data, together with findings from in vivo DA measurements and cell-ablation studies, suggest that DA levels in DS and NAc, acting via D1R-MSNs, signal the nutritive and gustatory quality of sugar, respectively, and that DS output may serve to prioritize energy seeking over taste quality (Tellez et al, 2016;de Araujo, 2016). Surprisingly, in vivo recordings of NAc D1R-MSNs found that the activity of these neurons reduced during palatable food consumption and, consistent with this observation, noncontingent optogenetic inhibition of NAc D1R-MSNs prolonged food intake (O'Connor et al, 2015). Moreover, lick-contingent and noncontingent optogenetic stimulation of D1R-MSN projections to LH inhibited palatable food intake, even in food deprived mice, suggesting that the NAc D1R-MSN to LH pathway may serve to override immediate metabolic need and allow rapid consumption control in response to changing external stimuli (O'Connor et al, 2015).…”

“…Surprisingly, in vivo recordings of NAc D1R-MSNs found that the activity of these neurons reduced during palatable food consumption and, consistent with this observation, noncontingent optogenetic inhibition of NAc D1R-MSNs prolonged food intake (O'Connor et al, 2015). Moreover, lick-contingent and noncontingent optogenetic stimulation of D1R-MSN projections to LH inhibited palatable food intake, even in food deprived mice, suggesting that the NAc D1R-MSN to LH pathway may serve to override immediate metabolic need and allow rapid consumption control in response to changing external stimuli (O'Connor et al, 2015). The contradictory findings between these two studies may reflect further segregation of NAc D1R-MSN function according to projection targeting of the ventral pallidum (Tellez et al, 2016) or LH (O'Connor et al, 2015).…”

“…It is not known whether such heterogeneity is segregated among the different projections of these neurons, including those innervating VTA. Finally, LH also contains a distinct, non-Hcrt/Ox-expressing population of GABA neurons (Karnani et al, 2013;Jennings et al, 2015;O'Connor et al, 2015), some of which are glucose inhibited (Karnani et al, 2013). Other LH neuropeptide populations have also been described, including neuropeptide Y, thyrotropin-releasing hormone, encephalin, and urocortin-3 expressing neuron populations (Marston et al, 2011;Bonnavion et al, 2016) and glucose activated melanin-concentrating hormone neurons (Qu et al, 1996;de Lecea et al, 1998;.…”

“…Unlike DS, the projection pattern of NAc MSNs is not clearly segregated according to DA receptor expression. Both D1R-and D2R-MSNs innervate the ventral pallidum (Kupchik et al, 2015), whereas D1R-MSNs form the major projection from accumbens to LH (O'Connor et al, 2015) and VTA (Bocklisch et al, 2013). The function of accumbens is perhaps best described as a "limbicmotor interface" (Mogenson et al, 1980), playing a critical role in conditioned motivation, hedonic evaluation, and acting as a "sensory sentinel" to allow flexible control of consumption via its descending projections to premotor effector areas (Taha and Fields, 2005;Baldo and Kelley, 2007;Berridge et al, 2010;O'Connor et al, 2015).…”

“…Moreover, lick-contingent and noncontingent optogenetic stimulation of D1R-MSN projections to LH inhibited palatable food intake, even in food deprived mice, suggesting that the NAc D1R-MSN to LH pathway may serve to override immediate metabolic need and allow rapid consumption control in response to changing external stimuli (O'Connor et al, 2015). The contradictory findings between these two studies may reflect further segregation of NAc D1R-MSN function according to projection targeting of the ventral pallidum (Tellez et al, 2016) or LH (O'Connor et al, 2015). Indeed, stimulation of dynophinergic cells (i.e., predominantly D1R-MSNs) in the dorsal or ventral NAc shell induces reinforcement or aversion, respectively (AlHasani et al, 2015), although the projection targets of these functionally opposing populations are not known.…”