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.

Activation of the mesolimbic dopamine system reinforces goal-directed behavior. With repetitive stimulation, for example by chronic drug abuse, the reinforcement may become compulsive and intake continues even when facing major negative consequences. Here we gave mice the opportunity for optogenetic dopamine neuron self-stimulation (oDASS) and observed that only a fraction of mice persevered if they had to endure an electric shock. Compulsive lever pressing was associated with an activity peak in orbitofrontal cortex (OFC) to striatum (DS) projection terminals. While

Here, we show neuronal inactivation-induced presynaptic remodeling and involvement of the mammalian homolog of Diaphanous (mDia) and Rho-associated coiled-coil-containing kinase (ROCK), Rho-regulated modulators of actin and myosin, in this process. We find that social isolation induces inactivation of nucleus accumbens (NAc) neurons associated with elevated anxiety-like behavior, and that mDia in NAc neurons is essential in this process. Upon inactivation of cultured neurons, mDia induces circumferential actin filaments around the edge of the synaptic cleft, which contract the presynaptic terminals in a ROCK-dependent manner. Social isolation induces similar mDia-dependent presynaptic contraction at GABAergic synapses from NAc neurons in the ventral tegmental area (VTA) associated with reduced synaptic efficacy. Optogenetic stimulation of NAc neurons rescues the anxiety phenotype, and injection of a specific ROCK inhibitor, Y-27632, into the VTA reverses both presynaptic contraction and the behavioral phenotype. mDia-ROCK signaling thus mediates actin-dependent presynaptic remodeling in inactivated NAc neurons, which underlies synaptic plasticity in emotional behavioral responses.

Addicts compulsively seek drug rewards. In mice, top down cortico-striatal projections have been implicated in persevering consumption of rewards even when punished. The temporo-spatial determinants of the activity underlying the emergence of compulsive reward seeking however remains elusive. Here we take advantage of a defining 2.7.3 DREADD validation. 2.7.4 eArchT3.0 validation. 2.8 Fibre photometry recordings. 2.9 Acute inhibition of the DS 2.10 Tissue preparation for imaging. 2.11 Statistics 2.12 Clustering method

Loss of control over drug intake and persistent drug-seeking despite negative consequences define addiction. Increase dopamine levels in the mesolimbic system may constitute the initial trigger. Optogenetic self-stimulation of VTA DA neurons (oDASS) has thus been proposed as an addiction model. Indeed, lever pressing to turn on a laser aimed at ChR2 expressing DA neurons is strongly reinforcing. Clinical observations indicate that drug-seeking even with the risk of harmful consequences occurs only in a fraction of users, with chronic drug consumption. Here, mice carried out a seek-take chain in order to selectively study compulsive seeking behavior. Once fully established, a probabilistic punishment of the seeking lever led to the emergence of two classes of mice; those that persevered and those that renounced oDASS. Ex vivo characterization of three distinct cortico-striatal streams demonstrated a selective potentiation of excitatory synapses of the orbito-frontal cortex (OFC) to dorsal striatum projection in persevering mice. Taken together, our data indicate a gain-of-function of OFC striatal control in compulsive oDASS. Harada et al. Compulsive oDASS seeking