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CCK stimulation of GLP-1 neurons involves α1-adrenoceptor-mediated increase in glutamatergic synaptic inputs.

Hisadome K, Reimann F, Gribble FM, Trapp S - Diabetes (2011)

Bottom Line: Inhibition of adrenergic signaling abolished the excitatory action of CCK.CCK activates NTS-PPG cells by a circuit involving adrenergic and glutamatergic neurons.NTS-PPG neurons integrate a variety of peripheral signals that indicate both long-term energy balance and short-term nutritional and digestional status to produce an output signal to feeding and autonomic circuits.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.

ABSTRACT

Objective: Glucagon-like peptide 1 (GLP-1) is involved in the central regulation of food intake. It is produced within the brain by preproglucagon (PPG) neurons, which are located primarily within the brain stem. These neurons project widely throughout the brain, including to the appetite centers in the hypothalamus, and are believed to convey signals related to satiety. Previous work demonstrated that they are directly activated by leptin and electrical activity of the afferent vagus. Another satiety hormone, cholecystokinin (CCK), has also been linked to activation of brain stem neurons, suggesting that it might act partially via centrally projecting neurons from the nucleus tractus solitarius (NTS). The aim of this study was to investigate the neuronal circuitry linking CCK to the population of NTS-PPG neurons.

Research design and methods: Transgenic mice expressing yellow fluorescent protein (Venus) under the control of the PPG promoter were used to identify PPG neurons in vitro and to record their electrical and pharmacological profile.

Results: PPG neurons in the NTS were excited by CCK and epinephrine, but not by the melanocortin receptor agonist melanotan II. Both CCK and epinephrine acted to increase glutamatergic transmission to the PPG neurons, and this involved activation of α(1)-adrenergic receptors. Inhibition of adrenergic signaling abolished the excitatory action of CCK.

Conclusions: CCK activates NTS-PPG cells by a circuit involving adrenergic and glutamatergic neurons. NTS-PPG neurons integrate a variety of peripheral signals that indicate both long-term energy balance and short-term nutritional and digestional status to produce an output signal to feeding and autonomic circuits.

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Related in: MedlinePlus

CCK stimulation of sEPSCs is sensitive to TTX but not picrotoxin. A: The vast majority of sEPSCs in PPG neurons are glutamatergic, as demonstrated by their inhibition by 10 μmol/L DNQX in this voltage-clamp recording at a holding potential of −70 mV. Bottom traces: Overlay of 15 consecutive 500 ms traces from the recording above under control conditions (top) and in the presence of DNQX (bottom). B: CCK-8s, bath-applied at 100 nmol/L, led to an increase in sEPSC frequency. C: Mean normalized effects of CCK on sEPSC frequency in the presence or absence of various drugs. The mean sEPSC frequency in presence of the drug (freqD) as a fraction of the frequency in the absence of any drug (freqC) is plotted. The excitatory CCK effect is not reduced by the GABA and glycine receptor antagonist picrotoxin (30 μmol/L) but is prevented by TTX (0.5 μM). *P < 0.05 compared with control; **P < 0.01 compared with control; #P < 0.05 compared with CCK. Numbers of cells tested are given above the bars.
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Figure 2: CCK stimulation of sEPSCs is sensitive to TTX but not picrotoxin. A: The vast majority of sEPSCs in PPG neurons are glutamatergic, as demonstrated by their inhibition by 10 μmol/L DNQX in this voltage-clamp recording at a holding potential of −70 mV. Bottom traces: Overlay of 15 consecutive 500 ms traces from the recording above under control conditions (top) and in the presence of DNQX (bottom). B: CCK-8s, bath-applied at 100 nmol/L, led to an increase in sEPSC frequency. C: Mean normalized effects of CCK on sEPSC frequency in the presence or absence of various drugs. The mean sEPSC frequency in presence of the drug (freqD) as a fraction of the frequency in the absence of any drug (freqC) is plotted. The excitatory CCK effect is not reduced by the GABA and glycine receptor antagonist picrotoxin (30 μmol/L) but is prevented by TTX (0.5 μM). *P < 0.05 compared with control; **P < 0.01 compared with control; #P < 0.05 compared with CCK. Numbers of cells tested are given above the bars.

Mentions: The previous results suggested that CCK might exert its effects via enhancement of glutamatergic synaptic inputs. To explore this possibility further, voltage-clamp recordings were performed to isolate EPSCs. EPSCs had a frequency of 2.3 ± 0.3 Hz (n = 53) and a mean amplitude of 25 ± 2 pA. These were predominantly glutamatergic, since DNQX (10 μmol/L) inhibited spontaneous synaptic activity by 91 ± 5% (Fig. 2; n = 6). Application of 100 nmol/L CCK-8s caused a reversible increase in sEPSC frequency in ∼60% PPG neurons tested (18 of 29; Fig. 2). The remaining cells showed no response.


CCK stimulation of GLP-1 neurons involves α1-adrenoceptor-mediated increase in glutamatergic synaptic inputs.

Hisadome K, Reimann F, Gribble FM, Trapp S - Diabetes (2011)

CCK stimulation of sEPSCs is sensitive to TTX but not picrotoxin. A: The vast majority of sEPSCs in PPG neurons are glutamatergic, as demonstrated by their inhibition by 10 μmol/L DNQX in this voltage-clamp recording at a holding potential of −70 mV. Bottom traces: Overlay of 15 consecutive 500 ms traces from the recording above under control conditions (top) and in the presence of DNQX (bottom). B: CCK-8s, bath-applied at 100 nmol/L, led to an increase in sEPSC frequency. C: Mean normalized effects of CCK on sEPSC frequency in the presence or absence of various drugs. The mean sEPSC frequency in presence of the drug (freqD) as a fraction of the frequency in the absence of any drug (freqC) is plotted. The excitatory CCK effect is not reduced by the GABA and glycine receptor antagonist picrotoxin (30 μmol/L) but is prevented by TTX (0.5 μM). *P < 0.05 compared with control; **P < 0.01 compared with control; #P < 0.05 compared with CCK. Numbers of cells tested are given above the bars.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3198097&req=5

Figure 2: CCK stimulation of sEPSCs is sensitive to TTX but not picrotoxin. A: The vast majority of sEPSCs in PPG neurons are glutamatergic, as demonstrated by their inhibition by 10 μmol/L DNQX in this voltage-clamp recording at a holding potential of −70 mV. Bottom traces: Overlay of 15 consecutive 500 ms traces from the recording above under control conditions (top) and in the presence of DNQX (bottom). B: CCK-8s, bath-applied at 100 nmol/L, led to an increase in sEPSC frequency. C: Mean normalized effects of CCK on sEPSC frequency in the presence or absence of various drugs. The mean sEPSC frequency in presence of the drug (freqD) as a fraction of the frequency in the absence of any drug (freqC) is plotted. The excitatory CCK effect is not reduced by the GABA and glycine receptor antagonist picrotoxin (30 μmol/L) but is prevented by TTX (0.5 μM). *P < 0.05 compared with control; **P < 0.01 compared with control; #P < 0.05 compared with CCK. Numbers of cells tested are given above the bars.
Mentions: The previous results suggested that CCK might exert its effects via enhancement of glutamatergic synaptic inputs. To explore this possibility further, voltage-clamp recordings were performed to isolate EPSCs. EPSCs had a frequency of 2.3 ± 0.3 Hz (n = 53) and a mean amplitude of 25 ± 2 pA. These were predominantly glutamatergic, since DNQX (10 μmol/L) inhibited spontaneous synaptic activity by 91 ± 5% (Fig. 2; n = 6). Application of 100 nmol/L CCK-8s caused a reversible increase in sEPSC frequency in ∼60% PPG neurons tested (18 of 29; Fig. 2). The remaining cells showed no response.

Bottom Line: Inhibition of adrenergic signaling abolished the excitatory action of CCK.CCK activates NTS-PPG cells by a circuit involving adrenergic and glutamatergic neurons.NTS-PPG neurons integrate a variety of peripheral signals that indicate both long-term energy balance and short-term nutritional and digestional status to produce an output signal to feeding and autonomic circuits.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.

ABSTRACT

Objective: Glucagon-like peptide 1 (GLP-1) is involved in the central regulation of food intake. It is produced within the brain by preproglucagon (PPG) neurons, which are located primarily within the brain stem. These neurons project widely throughout the brain, including to the appetite centers in the hypothalamus, and are believed to convey signals related to satiety. Previous work demonstrated that they are directly activated by leptin and electrical activity of the afferent vagus. Another satiety hormone, cholecystokinin (CCK), has also been linked to activation of brain stem neurons, suggesting that it might act partially via centrally projecting neurons from the nucleus tractus solitarius (NTS). The aim of this study was to investigate the neuronal circuitry linking CCK to the population of NTS-PPG neurons.

Research design and methods: Transgenic mice expressing yellow fluorescent protein (Venus) under the control of the PPG promoter were used to identify PPG neurons in vitro and to record their electrical and pharmacological profile.

Results: PPG neurons in the NTS were excited by CCK and epinephrine, but not by the melanocortin receptor agonist melanotan II. Both CCK and epinephrine acted to increase glutamatergic transmission to the PPG neurons, and this involved activation of α(1)-adrenergic receptors. Inhibition of adrenergic signaling abolished the excitatory action of CCK.

Conclusions: CCK activates NTS-PPG cells by a circuit involving adrenergic and glutamatergic neurons. NTS-PPG neurons integrate a variety of peripheral signals that indicate both long-term energy balance and short-term nutritional and digestional status to produce an output signal to feeding and autonomic circuits.

Show MeSH
Related in: MedlinePlus