A Novel Excitatory Paraventricular Nucleus to AgRP Neuron Circuit that Drives Hunger

Summary Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to its control. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake1-5. Consistent with their obligatory role in regulating appetite, genetic ablation or pharmacogenetic inhibition of AgRP neurons decreases feeding3,6,7. Excitatory input to AgRP neurons is key in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric state-dependent synaptic plasticity8-10. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing Thyrotropin-releasing hormone (TRH) and Pituitary adenylate cyclase-activating polypeptide (PACAP). Pharmaco-genetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.

Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D

Dynamic GABAergic afferent modulation of AgRP neurons

Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues prior to ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the pre-consummatory modulation of ARCAgRP neurons. In a manner reciprocal to ARCAgRP neurons, ARC-projecting leptin receptor (LepR)-expressing GABAergic DMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, DMHLepR neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARCAgRP neuron activity and feeding behavior

Lateral hypothalamic neurotensin neurons promote arousal and hyperthermia.

Sleep and wakefulness are greatly influenced by various physiological and psychological factors, but the neuronal elements responsible for organizing sleep-wake behavior in response to these factors are largely unknown. In this study, we report that a subset of neurons in the lateral hypothalamic area (LH) expressing the neuropeptide neurotensin (Nts) is critical for orchestrating sleep-wake responses to acute psychological and physiological challenges or stressors. We show that selective activation of NtsLH neurons with chemogenetic or optogenetic methods elicits rapid transitions from non-rapid eye movement (NREM) sleep to wakefulness and produces sustained arousal, higher locomotor activity (LMA), and hyperthermia, which are commonly observed after acute stress exposure. On the other hand, selective chemogenetic inhibition of NtsLH neurons attenuates the arousal, LMA, and body temperature (Tb) responses to a psychological stress (a novel environment) and augments the responses to a physiological stress (fasting)

Synaptotagmin-11 mediates a vesicle trafficking pathway that is essential for development and synaptic plasticity.

Synaptotagmin-11 (Syt11) is a Synaptotagmin isoform that lacks an apparent ability to bind calcium, phospholipids, or SNARE proteins. While human genetic studies have linked mutations in the gene to schizophrenia and Parkinson\u27s disease, the localization or physiological role of Syt11 remain unclear. We found that in neurons, Syt11 resides on abundant vesicles that differ from synaptic vesicles and resemble trafficking endosomes. These vesicles recycle via the plasma membrane in an activity-dependent manner, but their exocytosis is slow and desynchronized. Constitutive knockout mice lacking Syt11 died shortly after birth, suggesting Syt11-mediated membrane transport is required for survival. In contrast, selective ablation of Syt11 in excitatory forebrain neurons using a conditional knockout did not affect life span but impaired synaptic plasticity and memory. Syt11-deficient neurons displayed normal secretion of fast neurotransmitters and peptides but exhibited a reduction of long-term synaptic potentiation. Hence, Syt11 is an essential component of a neuronal vesicular trafficking pathway that differs from the well-characterized synaptic vesicle trafficking pathway but is also essential for life

Synaptotagmin-11 is essential for long-term synaptic plasticity and spatial memory

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Estimation of Current and Future Physiological States in Insular Cortex

Livneh et al. find that slow changes in ongoing population activity patterns in insular cortex reflect physiological need states independent of behavior and hypothalamic hunger/thirst neurons. Food/water cues and consumption drive population activity to transiently “simulate” a future satiety state