Neurokinin B in emotional and metabolic processing

Emotional-affective and metabolic disorders affect an increasing number of patients. If untreated, these disorders may increase the risk for the development of a metabolic syndrome, including diabetes mellitus type 2, cardiovascular disease and result in premature death. In particular, post-traumatic stress disorder, an emotional-affective disease that develops in response to severe, life-threatening trauma, constitutes an important risk factor for abnormal eating habits, obesity and cardiovascular disease. Therefore, a better understanding of the underlying mechanisms of fear, anxiety and eating regulation and how these phenomena mutually interact, may eventually lead to improved therapeutic strategies. Neuropeptides are small proteins that severe as modulatory neurotransmitters in the central and peripheral nervous systems. Exceptionally high amounts of these neuropeptides are expressed in limbic brain areas and are fundamentally shaping emotional behaviors. Ample evidence supports their role also in the modification of metabolic control. The tachykinin neurokinin B (NKB) is one of these neuropeptides, which is strongly expressed in the amygdala, a brain area central for emotional processing. However, very little is known on the function of NKB in amygdala circuitries. Our main aim is thus to investigate the role of NKB-expressing amygdala neurons, and especially the neuropeptide transmitter NKB, in fear- and eating-related processes. More precisely, we want to find out how hunger and fear interact with each other, and define the role of NKB in this interaction. We will combine genetic and pharmacological modification of NKB neurons in defined brain areas with metabolic and emotional-affective behavioral testing. Implementation of CRISPR/cas9 technologies will allow us to address dedicated neurotransmitters of specific neuronal populations in metabolic and fear / anxiety-dependent testing. This project will add new insights into the function of a specific neuropeptide (NKB) as well as its neuronal pathways. It will add completely novel findings about the metabolic relevance of NKB and integrate these data into different aspects of emotional-affective processing. It will also demonstrate how NKB modifies the integration of hunger and fear and produce an adaptive behavior.

Anxiety and eating disorders are frequently associated and affect worldwide an increasing number of individuals. Untreated, they may not only decrease the quality of life but also increase the risk for associated conditions, such as metabolic and cardiovascular disease, as well as premature death. Therefore, a better understanding of the underlying mechanisms of anxiety and eating regulation, and how these phenomena mutually interact, may eventually lead to improved therapeutic strategies. Neuropeptides are small proteins that serve as modulatory neurotransmitters in the central and peripheral nervous systems. The tachykinin neurokinin B (NKB) is one of these neuropeptides, which is strongly expressed in the amygdala, a brain area central for emotional processing. We investigated the role of NKB-expressing amygdala neurons, and especially the release of the neuropeptide modulator NKB, in anxiety- and eating-related processes. We combined genetic and pharmacological modifications in defined brain areas with metabolic and emotional-affective behavioral testing. Our main findings are that NKB-expressing neurons in the bed nucleus of the stria terminalis (BNST), an emotional and metabolically active forebrain region and part of the extended amygdala, are inhibitory neurons, using GABA as their main neurotransmitter. In addition, they co-release a specific cocktail of bioactive neuropeptides that significantly modulates neuronal signaling and associated functions. It is interesting to note that NKB expressing neurons are activated by dedicated internal and external stimuli, such as nausea and anxiety-inducing challenges. Accordingly, experimental activation of these neurons inhibits food intake, while drinking and activity remains unaffected. These neurons reduce food intake over longer periods of time and even when the drive to feed is high, such as during fasting-refeeding. Various reasons may account for reduced food intake, such as aversion, pain, nausea or malaise. Specifically, we found that NKB-expressing neurons in the basal forebrain reduce food intake by induction of anxiety-like behavior. Since NKB-expressing BNST neurons may release several neuromodulators, we focused on the contribution of NKB to the observed behavior. While these neurons function also in the absence of NKB, our results indicate that co-release of NKB predominantly maintains a sustained emotional-affective and metabolic state, which seems to be essential for the induction of anxiety-related behavior. Interestingly, only chronic ablation but not acute inhibition of these neurons modified metabolic behavior, emphasizing the sustained responses generated by NKB release. Furthermore, it is important to note that these effects were seen in male but not in female mice, highlighting the potential sex-specific integration of NKB neurons into BNST related brain circuitries. In summary, our findings demonstrate how NKB and NKB neurons modify the integration of hunger and anxiety to produce an adaptive behavioral response in a sex-specific manner. These data unravel several interaction points for tailored therapies of emotional-affective disorders with associated somatic symptoms.