Manipulations of Central Amygdala Neurotensin Neurons Alter the Consumption of Ethanol and Sweet Fluids in Mice.

The central nucleus of the amygdala plays a significant role in alcohol use and other affective disorders; however, the genetically-defined neuronal subtypes and projections that govern these behaviors are not well known. Here we show that neurotensin neurons in the central nucleus of the amygdala of male mice are activated by in vivo ethanol consumption and that genetic ablation of these neurons decreases ethanol consumption and preference in non-ethanol-dependent animals. This ablation did not impact preference for sucrose, saccharin, or quinine. We found that the most robust projection of the central amygdala neurotensin neurons was to the parabrachial nucleus, a brain region known to be important in feeding behaviors, conditioned taste aversion, and alarm. Optogenetic stimulation of projections from these neurons to the parabrachial nucleus is reinforcing, and increases ethanol drinking as well as consumption of sucrose and saccharin solutions. These data suggest that this central amygdala to parabrachial nucleus projection influences the expression of reward-related phenotypes and is a novel circuit promoting consumption of ethanol and palatable fluids.SIGNIFICANCE STATEMENT Alcohol use disorder (AUD) is a major health burden worldwide. Although ethanol consumption is required for the development of AUD, much remains unknown regarding the underlying neural circuits that govern initial ethanol intake. Here we show that ablation of a population of neurotensin-expressing neurons in the central amygdala decreases intake of and preference for ethanol in non-dependent animals, whereas the projection of these neurons to the parabrachial nucleus promotes consumption of ethanol as well as other palatable fluids.

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala.

Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HTDRN) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRFBNST) in mice. Specifically, 5-HTDRN projections to the BNST, via actions at 5-HT2C receptors (5-HT2CRs), engage a CRFBNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRFBNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF1R, also known as CRHR1), given that CRF1R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HTDRN→CRFBNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.