Glucokinase neurons of the paraventricular nucleus of the thalamus sense glucose and decrease food consumption

Abstract

Summary The paraventricular nucleus of the thalamus (PVT) controls goal-oriented behavior through its connections to the nucleus accumbens (NAc). We previously characterized Glut2 aPVT neurons that are activated by hypoglycemia, and which increase sucrose seeking behavior through their glutamatergic projections to the NAc. Here, we identified glucokinase ( Gck )-expressing neurons of the PVT (Gck aPVT ) and generated a mouse line expressing the Cre recombinase from the glucokinase locus ( Gck Cre/+ mice). Ex vivo calcium imaging and whole-cell patch clamp recordings revealed that Gck aPVT neurons that project to the NAc were mostly activated by hyperglycemia. Their chemogenetic inhibition or optogenetic stimulation, respectively, enhanced food intake or decreased sucrose-seeking behavior. Collectively, our results describe a neuronal population of Gck-expressing neurons in the PVT, which has opposite glucose sensing properties and control over feeding behavior than the previously characterized Glut2 aPVT neurons. This study allows a better understanding of the complex regulation of feeding behavior by the PVT.

Structural and molecular characterization of paraventricular thalamic glucokinase‐expressing neuronal circuits in the mouse

“…Because this analysis was performed using overnight food-deprived mice, this may suggest that synaptic remodeling is activated in the fasted state. This would be compatible with these neurons being glucose responsive (Kessler et al, 2021) and with the observation that synaptic remodeling is activated by fasting in hypothalamic neurons involved in feeding control (Kong et al, 2016;Liu et al, 2012).…”

“…We have so far confirmed their contribution to sucrose seeking behavior through their projections to the NAc (Kessler et al, 2021). Further functional studies are required in order to untangle the complex involvement of PVT neuronal subpopulations in behavioral responses and the detailed characterization of Gck aPVT neurons provided with the current study is setting the basis for exploration of additional circuits involved.…”

“…The strongest innervation is in telencephalic structures such as the NAc, amygdala, and the BNST, and in hypothalamic nuclei such as the VMH. Weaker projections are observed in the (Kessler et al, 2021;Kirouac, 2015;Labouèbe et al, 2016;Otis et al, 2019;Ren et al, 2018;Vertes & Hoover, 2008;Zhu et al, 2016).…”

Neuronal regulation of glucagon secretion and gluconeogenesis

“…In mice, hypoglycemia‐sensing neurons, characterized by the expression of Glut2, have been identified in the PVT and found to play a role in the motivated feeding response to hypoglycemia: when activated by hypoglycemia or by optogenetics, these neurons, through their projections to the nucleus accumbens, increase sucrose‐seeking behavior 26 . GE neurons have also been identified in the PVT that are characterized by the expression of glucokinase 27 . When activated by optogenetics, they suppress glucose‐seeking behavior; in contrast, when inhibited by chemogenetics, they increase feeding.…”

Hindbrain catecholaminergic inputs to the paraventricular thalamus scale feeding and metabolic efficiency in stress-related contexts

“…Emerging evidence strongly suggests that the paraventricular nucleus of the thalamus (PVT), a dorsal midline thalamic relay, may represent a functional hot-spot where interoceptive and exteroceptive stimuli may converge to orchestrate the selection of adaptive and appropriate behavioral responses aimed at regulating homeostatic and cognitive processes (Penzo & Gao, 2021). Given their elaborated connectivity (Kirouac, 2015), PVT excitatory (glutamate) neurons are well positioned to serve as functional integrators of orexigenic and anorexigenic stimuli (Ong et al ., 2017; Meffre et al ., 2019), glucose fluctuations (Labouèbe et al ., 2016; Kessler et al ., 2021), learning and memory processes (Do-Monte et al ., 2015; Penzo et al ., 2015) as well as emotional states (Heydendael et al ., 2011; Barson et al ., 2020; Pliota et al ., 2020). This plethora of PVT-related brain functions highly relies on different afferent projections which, by carrying distinct neurochemical information, synergistically scale the activity of PVT-neurons and their downstream connected regions.…”