Hypocretin/orexin neurons encode social discrimination and exhibit a sex-dependent necessity for social interaction

Summary: The hypothalamus plays a crucial role in the modulation of social behavior by encoding internal states. The hypothalamic hypocretin/orexin neurons, initially identified as regulators of sleep and appetite, are important for emotional and motivated behaviors. However, their role in social behavior remains unclear. Using fiber photometry and behavioral analysis, we show here that hypocretin neurons differentially encode social discrimination based on the nature of social encounters. The optogenetic inhibition of hypocretin neuron activity or blocking of hcrt-1 receptors reduces the amount of time mice are engaged in social interaction in males but not in females. Reduced hcrt-1 receptor signaling during social interaction is associated with altered activity in the insular cortex and ventral tegmental area in males. Our data implicating hypocretin neurons as sexually dimorphic regulators within social networks have significant implications for the treatment of neuropsychiatric diseases with social dysfunction, particularly considering varying prevalence among sexes

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

The central mechanism by which neurotensin (Nts) potentiates weight loss has remained elusive. We leveraged chemogenetics to reveal that Nts-expressing neurons of the lateral hypothalamic area (LHA) promote weight loss in mice by increasing volitional activity and restraining food intake. Intriguingly, these dual weight loss behaviors are mediated by distinct signaling pathways: Nts action via NtsR1 is essential for the anorectic effect of the LHA Nts circuit, but not for regulation of locomotor or drinking behavior. Furthermore, although LHA Nts neurons cannot reduce intake of freely available obesogenic foods, they effectively restrain motivated feeding in hungry, weight-restricted animals. LHA Nts neurons are thus vital mediators of central Nts action, particularly in the face of negative energy balance. Enhanced action via LHA Nts neurons may, therefore, be useful to suppress the increased appetitive drive that occurs after lifestyle-mediated weight loss and, hence, to prevent weight regain

Neurotensin Receptor-1 Identifies a Subset of Ventral Tegmental Dopamine Neurons that Coordinates Energy Balance.

Dopamine (DA) neurons in the ventral tegmental area (VTA) are heterogeneous and differentially regulate ingestive and locomotor behaviors that affect 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

Depleting hypothalamic somatostatinergic neurons recapitulates diabetic phenotypes in mouse brain, bone marrow, adipose and retina.

Aims/hypothesisHypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation.MethodsThe present data show that leptin receptor-deficient (db/db) mice exhibit reduced hypothalamic SST neurons, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus delivery of diphtheria toxin subunit A (DTA) driven by an SST-cre system to deplete these neurons in Sstcre/gfp mice (SST-DTA).ResultsSST-DTA mice exhibit enhanced hypothalamic c-Fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed haematopoiesis, generating excess granulocyte-monocyte progenitors and increased proinflammatory (C-C chemokine receptor type 2; CCR2hi) monocytes. SST-DTA mice exhibited a 'diabetic retinopathy-like' phenotype: reduced visual function by optokinetic response (0.4 vs 0.25 cycles/degree; SST-DTA vs control mice); delayed electroretinogram oscillatory potentials; and increased percentages of retinal monocytes. Finally, mesenteric visceral adipose tissue from SST-DTA mice was resistant to catecholamine-induced lipolysis, displaying 50% reduction in isoprenaline (isoproterenol)-induced lipolysis compared with control littermates. Importantly, hyperglycaemia was not observed in SST-DTA mice.Conclusions/interpretationThe isolated reduction in hypothalamic SST neurons was able to recapitulate several hallmark features of type 2 diabetes in disease-relevant tissues

Data_Sheet_1_Developmental or adult-onset deletion of neurotensin receptor-1 from dopamine neurons differentially reduces body weight.docx

Central neurotensin signaling via neurotensin receptor-1 (NtsR1) modulates various aspects of physiology, including suppressing feeding and promoting locomotor activity that can support weight loss. However, it remains unclear when and where NtsR1 expression contributes to control of body weight vs. other effects. We previously showed that activating ventral tegmental area (VTA) dopamine (DA) neurons that express NtsR1 promotes weight loss. We therefore hypothesized that deleting NtsR1 from DA neurons would promote weight gain by increasing food intake and decreasing physical activity. In contrast, developmental deletion of NtsR1 from DA neurons (by crossing DATCre mice with NtsR1flox/flox mice) had no impact on the feeding or body weight of mice fed a chow diet, though it augmented locomotor activity. Developmental deletion of NtsR1 from DA neurons protected mice from diet-induced obesity, but not via altering feeding, physical activity, or energy expenditure. Given that NtsR1 may exert distinct roles within development vs. adulthood, we then examined the impact of adult-onset deletion of NtsR1 from VTA DA neurons. We injected adult NtsR1flox/flox mice in the VTA with adeno associated virus to Cre-dependently delete NtsR1 in the VTA (VTAR1Null mice) and compared them to mice with intact NtsR1 (Controls). Again, in contrast to our hypothesis, VTAR1Null mice gained less weight than Controls while on normal chow or high fat diets. Moreover, VTAR1Null mice exhibited blunted feeding after fasting, suggesting a role for NtsR1 in adult VTA DA neurons in coordinating energy need and intake. Altogether, these data suggest that intact expression of NtsR1 in DA neurons is necessary for appropriate regulation of body weight, but a lack of NtsR1 in the developing vs. adult DA system protects from weight gain via different mechanisms. These findings emphasize the need for temporal and site-specific resolution to fully understand the role of NtsR1 within the brain.</p