Neurotensin neurons in the extended amygdala control dietary choice and energy homeostasis.

Obesity is a global pandemic that is causally linked to many life-threatening diseases. Apart from some rare genetic conditions, the biological drivers of overeating and reduced activity are unclear. Here, we show that neurotensin-expressing neurons in the mouse interstitial nucleus of the posterior limb of the anterior commissure (IPAC), a nucleus of the central extended amygdala, encode dietary preference for unhealthy energy-dense foods. Optogenetic activation of IPACNts neurons promotes obesogenic behaviors, such as hedonic eating, and modulates food preference. Conversely, acute inhibition of IPACNts neurons reduces feeding and decreases hedonic eating. Chronic inactivation of IPACNts neurons recapitulates these effects, reduces preference for sweet, non-caloric tastants and, furthermore, enhances locomotion and energy expenditure; as a result, mice display long-term weight loss and improved metabolic health and are protected from obesity. Thus, the activity of a single neuronal population bidirectionally regulates energy homeostasis. Our findings could lead to new therapeutic strategies to prevent and treat obesity.

A Central Amygdala-Globus Pallidus Circuit Conveys Unconditioned Stimulus-Related Information and Controls Fear Learning.

The central amygdala (CeA) is critically involved in a range of adaptive behaviors, including defensive behaviors. Neurons in the CeA send long-range projections to a number of extra-amygdala targets, but the functions of these projections remain elusive. Here, we report that a previously neglected CeA-to-globus pallidus external segment (GPe) circuit plays an essential role in classical fear conditioning. By anatomic tracing, in situ hybridization and channelrhodopsin (ChR2)-assisted circuit mapping in both male and female mice, we found that a subset of CeA neurons send projections to the GPe, and the majority of these GPe-projecting CeA neurons express the neuropeptide somatostatin. Notably, chronic inhibition of GPe-projecting CeA neurons with the tetanus toxin light chain (TeLC) completely blocks auditory fear conditioning. In vivo fiber photometry revealed that these neurons are selectively excited by the unconditioned stimulus (US) during fear conditioning. Furthermore, transient optogenetic inactivation or activation of these neurons selectively during US presentation impairs or promotes, respectively, fear learning. Our results suggest that a major function of GPe-projecting CeA neurons is to represent and convey US-related information through the CeA-GPe circuit, thereby regulating learning in fear conditioning.SIGNIFICANCE STATEMENT The central amygdala (CeA) has been implicated in the establishment of defensive behaviors toward threats, but the underlying circuit mechanisms remain unclear. Here, we found that a subpopulation of neurons in the CeA, which are mainly those that express the neuropeptide somatostatin, send projections to the globus pallidus external segment (GPe), and this CeA-GPe circuit conveys unconditioned stimulus (US)-related information during classical fear conditioning, thereby having an indispensable role in learning. Our results reveal a previously unknown circuit mechanism for fear learning.