The basolateral amygdala (BLA) plays a crucial role in emotional learning irrespective of valence1–5. While the BLA projection to the nucleus accumbens (NAc) is hypothesized to modulate cue-triggered motivated behaviors4, 6, 7,, our understanding of the interaction between these two brain regions has been limited by the inability to manipulate neural circuit elements of this pathway selectively during behavior. To circumvent this limitation, we used in vivo optogenetic stimulation or inhibition of glutamatergic fibers from the BLA to the NAc, coupled with intracranial pharmacology and ex vivo electrophysiology. We show that optical stimulation of the BLA-to-NAc pathway in mice reinforces behavioral responding to earn additional optical stimulations of these synaptic inputs. Optical stimulation of BLA-to-NAc glutamatergic fibers required intra-NAc dopamine D1-type, but not D2-type, receptor signaling. Brief optical inhibition of BLA-to-NAc fibers reduced cue-evoked intake of sucrose, demonstrating an important role of this specific pathway in controlling naturally occurring reward-related behavior. Moreover, while optical stimulation of medial prefrontal cortex (mPFC) to NAc glutamatergic fibers also elicited reliable excitatory synaptic responses, optical self-stimulation behavior was not observed by activation of this pathway. These data suggest that while the BLA is important for processing both positive and negative affect, the BLA-to-NAc glutamatergic pathway in conjunction with dopamine signaling in the NAc promotes motivated behavioral responding.

SummaryThe comorbidity of anxiety and dysfunctional reward processing in illnesses such as addiction1 and depression2 suggests that common neural circuitry contributes to these disparate neuropsychiatric symptoms. The extended amygdala, including the bed nucleus of the stria terminalis (BNST), modulates fear and anxiety3,4, but also projects to the ventral tegmental area (VTA) 5,6, a region implicated in reward and aversion7–13, thus providing a candidate neural substrate for integrating diverse emotional states. However, the precise functional connectivity between distinct BNST projection neurons and their postsynaptic targets in the VTA, as well as the role of this circuit in controlling motivational states have not been described. Here, we recorded and manipulated the activity of genetically and neurochemically identified VTA-projecting BNST neurons in freely behaving mice. Collectively, aversive stimuli exposure produced heterogeneous firing patterns in VTA-projecting BNST neurons. In contrast, in vivo optically-identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli, whereas the firing rate of identified GABAergic projection neurons was suppressed. Channelrhodopsin-2 (ChR2) assisted circuit mapping revealed that both BNST glutamatergic and GABAergic projections preferentially innervate postsynaptic non-dopaminergic VTA neurons, thus providing a mechanistic framework for in vivo circuit perturbations. In vivo photostimulation of BNST glutamatergic projections resulted in aversive and anxiogenic behavioral phenotypes. In contrast, activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes, which were also recapitulated by direct inhibition of VTA GABAergic neurons. These data demonstrate that functionally opposing BNST to VTA circuits regulate rewarding and aversive motivational states and may serve as a critical circuit node for bidirectionally normalizing maladaptive behaviors.

SUMMARY Optimally orchestrating complex behavioral states such as the pursuit and consumption of food is critical for an organism’s survival. The lateral hypothalamus (LH) is a neuroanatomical region essential for appetitive and consummatory behaviors, but whether individual neurons within the LH differentially contribute to these interconnected processes is unknown. Here we show that selective optogenetic stimulation of a molecularly defined subset of LH GABAergic (Vgat-expressing) neurons enhances both appetitive and consummatory behaviors, while genetic ablation of these neurons reduced these phenotypes. Furthermore, this targeted LH subpopulation is distinct from cells containing the feeding-related neuropeptides, melanin-concentrating hormone (MCH) and orexin (Orx). Employing in vivo calcium imaging in freely behaving mice, to record activity dynamics from hundreds of cells, we identified individual LH GABAergic neurons that preferentially encode aspects of either appetitive or consummatory behaviors, but rarely both. These tightly regulated, yet highly intertwined, behavioral processes are thus dissociable at the cellular level.

The growing prevalence of overeating disorders is a key contributor to the worldwide obesity epidemic. Dysfunction of particular neural circuits may trigger deviations from adaptive feeding behaviors. The lateral hypothalamus (LH) is a crucial neural substrate for motivated behavior including feeding, but the precise functional neurocircuitry that controls LH neuronal activity to engage feeding has not been defined. We observed that inhibitory synaptic inputs from the extended amygdala preferentially innervate and suppress the activity of LH glutamatergic neurons to control food intake. These findings help explain how dysregulated activity at a number of unique nodes can result in a cascading failure within a defined brain network to produce maladaptive feeding.

Lateral habenula (LHb) projections to the ventral midbrain, including the rostromedial tegmental nucleus (RMTg) conveys negative reward-related information, but the behavioral ramifications of selective activation of this pathway remain unexplored. We found that exposure to aversive stimuli in mice increased LHb excitatory drive onto RMTg neurons. Further, optogenetic activation of this pathway promoted active, passive, and conditioned behavioral avoidance. These data demonstrate that activity of LHb efferents to the midbrain is aversive, but can also serve to negatively reinforce behavioral responding.