Body weight is determined by feeding and volitional physical activity behaviors that are regulated, in part, by dopamine (DA) neurons of the ventral tegmental area (VTA). Here, we sought to ...understand how the neuropeptide, neurotensin (Nts) engages VTA DA neurons to modify body weight. The rationale for this work is that pharmacologic application of Nts into the VTA suppresses food intake and promotes locomotor activity, yet the endogenous circuits by which Nts acts on the VTA to modify these behaviors and body weight remain unclear. First, we identified the endogenous sources of Nts input to the VTA; using retrograde tracing we found that the lateral hypothalamic area (LHA), a critical neural hub for coordinating energy balance, provides substantial Nts projections to the VTA. We next examined how Nts directly engages VTA DA neurons by identifying Nts receptor-expressing cells in the VTA. To do this, we generated mice expressing Cre-recombinase in Nts receptor 1 (NtsR1) or Nts receptor 2 (NtsR2) cells, which revealed that NtsR1 is expressed on many VTA DA neurons, whereas NtsR2 is predominantly restricted to glial cells. Furthermore, only the VTA NtsR1 neurons project to the nucleus accumbens (NA), where DA release is known to modify feeding and locomotor behavior. We therefore tested the physiologic necessity for Nts action via the VTA by genetically ablating VTA NtsR1 neurons. Mice lacking VTA NtsR1-DA neurons were hyperactive, failed to gain weight, and could not appropriately coordinate feeding behavior with peripheral energy cues, demonstrating that VTA NtsR1 neurons are essential for energy balance. Finally, we tested the hypothesis that endogenous Nts input from the LHA to the mesolimbic DA system would be sufficient to regulate body weight. Indeed, chemogenetic activation of LHA Nts neurons increased physical activity, restrained food intake, and promoted weight loss in lean mice. Interestingly, the anorectic effects of LHA Nts activation were mediated via NtsR1 and DA signaling, while the physical activity was NtsR1-independent. Furthermore, in hungry mice (a state in which increased appetitive drive can promote overeating and weight gain), activation of LHA Nts neurons suppressed intake of chow and palatable sucrose rewards. Collectively, this work defines an endogenous LHA Nts circuit that engages the mesolimbic DA system via NtsR1 to suppress food intake in both energy replete and energy depleted states. Enhancing action via this circuit may thus be useful to support dual weight loss behaviors in an obesogenic environment.
Dopamine (DA) neurons in the ventral tegmental area (VTA) are heterogeneous and differentially regulate ingestive and locomotor behaviors that impact energy balance. Identification of which VTA DA ...neurons mediate behaviors that limit weight gain has been hindered, however, by the lack of molecular markers to distinguish VTA DA populations. Here, we identified a specific subset of VTA DA neurons that express neurotensin receptor-1 (NtsR1) and preferentially comprise mesolimbic, but not mesocortical, DA neurons. Genetically targeted ablation of VTA NtsR1 neurons uncouples motivated feeding and physical activity, biasing behavior toward energy expenditure and protecting mice from age-related and diet-induced weight gain. VTA NtsR1 neurons thus represent a molecularly-defined subset of DA neurons that are essential for the coordination of energy balance. Modulation of VTA NtsR1 neurons may therefore be useful to promote behaviors that prevent the development of obesity.
Woodworth et al. identify a subset of VTA dopamine neurons that express neurotensin receptor-1. Ablation of these neurons leads to enhanced physical activity and energy expenditure that protects mice from diet-induced obesity, revealing an important role for VTA NtR1 neurons in the regulation of body weight.
Inflammatory bowel disease (IBD) increases the risk of developing colorectal cancer. It is hypothesized that dietary interventions can reduce inflammation and associated cancer risk. The long chain ...omega‐3 fatty acid, docosahexaenoic acid (DHA) has potent anti‐inflammatory properties. The objective of this study was to determine whether dietary DHA could reduce experimentally induced colitis and subsequent colon cancer risk. We utilized a mouse model of colitis and colon adenocarcinoma formation (SMAD3−/−). When SMAD3−/− mice are exposed to H. hepaticus, colitis is observed 4 wks post infection. Mice (10 per group) were fed AIN‐93G powdered diets supplemented with corn oil, safflower oil, or DHA‐rich fish oil (doses ranging from 0.75–6%) for 8 wks. Mice were then gavaged with H. hepaticus, continued on their diets and sacrificed 4 weeks post‐infection. Colon and cecal tissue were collected for histopathology and scored for inflammation and dysplasia. Spleen, peyers patch and mesenteric lymph nodes were collected for CD3+ cell populations. Contrary to expectations, DHA (2.25–6%) induced severe colitis and adenocarcinoma formation. Increased severity of colitis in DHA fed mice was associated with a CD8+ driven response to bacterial infection. These results suggest that DHA supplementation in immune‐associated diseases like IBD should be approached with caution.
Neural proliferation in the dentate gyrus (DG) is closely linked with learning and memory, but the transcriptional programming that drives adult proliferation remains incompletely understood. Our lab ...previously elucidated the critical role of the transcription factor ΔFosB in the dorsal hippocampus (dHPC) in learning and memory, and the FosB gene has been suggested to play a role in neuronal proliferation. However, the subregion-specific and potentially cell-autonomous role of dHPC ΔFosB in neurogenesis-dependent learning has not been studied. Here, we crossed neurotensin receptor-2 (NtsR2) Cre mice, which express Cre within the subgranular zone (SGZ) of dHPC DG, with floxed FosB mice to show that knockout of ΔFosB in hippocampal SGZ neurons reduces antidepressant-induced neurogenesis and impedes hippocampus-dependent learning in the novel object recognition task. Taken together, these data indicate that FosB gene expression in SGZ is necessary for both hippocampal neurogenesis and memory formation.
•The NtsR2 Cre mouse is a useful tool for manipulating cells of the hippocampal SGZ.•The transcription factor ΔFosB is robustly expressed in NtsR2-positive SGZ cells.•SGZ knockout of the FosB gene reduces hippocampal cell proliferation.•SGZ knockout of the FosB gene impedes hippocampus-dependent learning.
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