Hypothalamic Proopiomelanocortin Neurons Are Glucose Responsive and Express KATP Channels

Hypothalamic proopiomelanocortin (POMC) neurons are critical for controlling homeostatic functions in the mammal. We used a transgenic mouse model in which the POMC neurons were labeled with enhanced green fluorescent protein to perform visualized, whole-cell patch recordings from prepubertal female hypothalamic slices. The mouse POMC-enhanced green fluorescent protein neurons expressed the same endogenous conductances (a transient outward K current and a hyperpolarization-activated, cation current) that have been described for guinea pig POMC neurons. In addition, the selective -opioid receptor agonist DAMGO induced an outward current (maximum of 12.8 1.2 pA), which reversed at K equilibrium potential (EK), in the majority (85%) of POMC neurons with an EC50 of 102 nM. This response was blocked by the opioid receptor antagonist naloxone with an inhibition constant of 3.1 nM. In addition, the -aminobutyric acidB receptor agonist baclofen (40 M) caused an outward current (21.6 4.0 pA) that reversed at EK in these same neurons. The ATP-sensitive potassium channel opener diazoxide also induced an outward K current (maximum of 18.7 2.2 pA) in the majority (92%) of POMC neurons with an EC50 of 61 M. The response to diazoxide was blocked by the sulfonylurea tolbutamide, indicating that the POMC neurons express both Kir6.2 and sulfonylurea receptor 1 channel subunits, which was verified using single cell RT-PCR. This pharmacological and molecular profile suggested that POMC neurons might be sensitive to metabolic inhibition, and indeed, we found that their firing rate varied with changes in glucose concentrations. Therefore, it appears that POMC neurons may function as an integrator of metabolic cues and synaptic input for controlling homeostasis in the mammal

Serotonin 5hydroxytryptamine2C receptor signaling in hypothalamic proopiomelanocortin neurons: role in energy homeostasis in females

ABSTRACT Hypothalamic proopiomelanocortin (POMC) neurons play a critical role in the regulation of energy balance, and there is a convergence of critical synaptic input including GABA and serotonin on POMC neurons to regulate their output. We found previously that 17␤-estradiol (E 2 ) reduced the potency of the GABA B receptor agonist baclofen to activate G protein-coupled inwardly rectifying potassium (GIRK) channels in hypothalamic POMC neurons through a membrane estrogen receptor (mER) via a G␣ q phospholipase C (PLC)-protein kinase C␦-protein kinase A pathway. We hypothesized that the mER and neurotransmitter receptor signaling pathways converge to control energy homeostasis. Because 5-HT 2C receptors mediate many of the effects of serotonin in POMC neurons, we elucidated the common signaling pathways of E 2 and 5-HT in guinea pigs using single-cell reverse transcription-polymerase chain reaction (RT-PCR), real time RT-PCR, and whole-cell patch recording. The 5-HT 2C receptor was G␣ q -coupled to PLC activation and hydrolysis of plasma membrane phosphatidylinositol bisphosphate to directly inhibit GIRK channel activity. Coapplication of the two agonists at their EC 50 concentrations (DOI, 20 M, and E 2 , 50 nM) produced additive effects. Although there was a significant gender difference in the effects of E 2 on baclofen responses, there was no gender difference in 5-HT 2C receptor-mediated effects. Finally, both DOI and estrogen (intracerebroventricular) inhibited feeding in ovariectomized female mice. Therefore, the G␣ q signaling pathways of the mER and 5-HT 2C receptors may converge to enhance synaptic efficacy in brain circuits that are critical for maintaining homeostatic functions. The hypothalamus is a key central nervous system center for controlling many homeostatic processes, and hypothalamic POMC neurons are critical neurons in these hypothalamic circuit

Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state

In the face of starvation, animals will engage in high-risk behaviors that would normally be considered maladaptive. Starving rodents, for example, will forage in areas that are more susceptible to predators and will also modulate aggressive behavior within a territory of limited or depleted nutrients. The neural basis of these adaptive behaviors likely involves circuits that link innate feeding, aggression and fear. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are critically important for driving feeding and project axons to brain regions implicated in aggression and fear. Using circuit-mapping techniques in mice, we define a disynaptic network originating from a subset of AgRP neurons that project to the medial nucleus of the amygdala and then to the principal bed nucleus of the stria terminalis, which suppresses territorial aggression and reduces contextual fear. We propose that AgRP neurons serve as a master switch capable of coordinating behavioral decisions relative to internal state and environmental cues