Abstract
The mammalian biological clock, located in the hypothalamic suprachiasmatic nuclei (SCN), imposes its temporal structure on the organism via neural and endocrine outputs. To further investigate SCN control of the autonomic nervous system we focused in the present study on the daily rhythm in plasma glucose concentrations. The hypothalamic paraventricular nucleus (PVN) is an important target area of biological clock output and harbors the pre-autonomic neurons that control peripheral sympathetic and parasympathetic activity. Using local administration of GABA and glutamate receptor (ant)agonists in the PVN at different times of the light/dark-cycle we investigated whether daily changes in the activity of autonomic nervous system contribute to the control of plasma glucose and plasma insulin concentrations. Activation of neuronal activity in the PVN of non-feeding animals, either by administering a glutamatergic agonist or a GABAergic antagonist, induced hyperglycemia. The effect of the GABA-antagonist was time dependent, causing increased plasma glucose concentrations only when administered during the light period. The absence of a hyperglycemic effect of the GABA-antagonist in SCN-ablated animals provided further evidence for a daily change in GABAergic input from the SCN to the PVN. On the other hand, feeding-induced plasma glucose and insulin responses were suppressed by inhibition of PVN neuronal activity only during the dark period. These results indicate that the pre-autonomic neurons in the PVN are controlled by an interplay of inhibitory and excitatory inputs. Liver-dedicated sympathetic pre-autonomic neurons (responsible for hepatic glucose production) and pancreas-dedicated pre-autonomic parasympathetic neurons (responsible for insulin release) are controlled by inhibitory GABAergic contacts that are mainly active during the light period. Both sympathetic and parasympathetic pre-autonomic PVN neurons also receive excitatory inputs, either from the biological clock (sympathetic pre-autonomic neurons) or from non-clock areas (para-sympathetic pre-autonomic neurons), but the timing information is mainly provided by the GABAergic outputs of the biological clock.
Highlights
The role of the CNS in glucoregulation has been recognized since the classical experiments of Bernard in 1849 [1]
We proposed that the biological clock generates the daily rhythm in plasma melatonin concentrations via the combination of a continuous stimulation of the pre-autonomic neurons in the paraventricular nucleus of the hypothalamus (PVN) that are at the origin of the sympathetic innervation of the pineal, and a nocturnal withdrawal of the inhibitory (GABA-ergic) suprachiasmatic nuclei (SCN) inputs to these neurons [10,11]
To further investigate SCN control of autonomic nervous activity we focused in the present study on the daily rhythm in plasma glucose concentrations, especially in view of the recently demonstrated rhythmic control of glucose metabolism in the liver [12,13,14,15] and the clear involvement of the sympathetic and parasympathetic input to the liver in glucose metabolism
Summary
The role of the CNS in glucoregulation has been recognized since the classical experiments of Bernard in 1849 [1]. We proposed that the biological clock generates the daily rhythm in plasma melatonin concentrations via the combination of a continuous (glutamatergic) stimulation of the pre-autonomic neurons in the paraventricular nucleus of the hypothalamus (PVN) that are at the origin of the sympathetic innervation of the pineal, and a nocturnal withdrawal of the inhibitory (GABA-ergic) SCN inputs to these neurons [10,11]. We recently found that local administration of the GABA-A receptor antagonist bicucilline (BIC) or the glutamate receptor agonist NMDA in the PVN caused pronounced hyperglycemia In both conditions this hyperglycemic effect of PVN stimulation could be prevented by a selective denervation of the sympathetic autonomic input to the liver [21]. By combining the ICV administration of BIC with a euglycemic clamp Lang et al [22] clearly showed that the BIC induced hyperglycemia is due to an increased HGP
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