Inhibiting ventral hippocampal NMDA receptors and Arc increases energy intake in male rats

Research into the neural mechanisms that underlie higher-order cognitive control of eating behavior suggests that ventral hippocampal (vHC) neurons, which are critical for emotional memory, also inhibit energy intake. We showed previously that optogenetically inhibiting vHC glutamatergic neurons during the early postprandial period, when the memory of the meal would be undergoing consolidation, caused rats to eat their next meal sooner and to eat more during that next meal when the neurons were no longer inhibited. The present research determined whether manipulations known to interfere with synaptic plasticity and memory when given pretraining would increase energy intake when given prior to ingestion. Specifically, we tested the effects of blocking vHC glutamatergic N-methyl-D-aspartate receptors (NMDARs) and activity-regulated cytoskeleton-associated protein (Arc) on sucrose ingestion. The results showed that male rats consumed a larger sucrose meal on days when they were given vHC infusions of the NMDAR antagonist APV or Arc antisense oligodeoxynucleotides than on days when they were given control infusions. The rats did not accommodate for that increase by delaying the onset of their next sucrose meal (i.e., decreased satiety ratio) or by eating less during the next meal. These data suggest that vHC NMDARs and Arc limit meal size and inhibit meal initiation.

Research into the higher-order cognitive controls of eating behavior has demonstrated that hippocampal neurons, which are critical for learning and memory, also regulate energy intake (Benoit et al. 2010; Parent 2016; Kanoski and Grill 2017). The hippocampus is functionally divided along its longitudinal axis into dorsal (posterior in primates) and ventral (anterior in primates) poles (Moser and Moser 1998; Fanselow and Dong 2010; Strange et al. 2014). Generally, dorsal hippocampal (dHC) neurons are necessary for episodic and spatial memory, whereas ventral hippocampal (vHC) neurons are essential for affective and motivational processes and emotional memory (Fanselow and Dong 2010; Strange et al. 2014). dHC and vHC have different anatomical connections, cellular and circuit properties and patterns of gene expression that likely contribute to the different functions that they serve (Moser and Moser 1998; Thompson et al. 2008; Dong et al. 2009; Barkus et al. 2010; Fanselow and Dong 2010; Bienkowski et al. 2018).vHC neurons, in particular, are poised to integrate energy-related signals with mnemonic processes because they contain receptors for numerous food-related signals (Kanoski and Grill 2017) and project to several brain regions critical for food intake (Namura et al. 1994; Cenquizca and Swanson 2006; Radley and Sawchenko 2011; Hsu et al. 2015b). vHC lesions increase food consumption and body mass (Davidson et al. 2009, 2012, 2013), and activation of vHC receptors for gut hormones affects food intake and food-related memory (Kanoski et al. 2011, 2013; Hsu et al. 2015a, 2017, 2018). Additionally, vHC glutamatergic projections to the bed nucleus of the stria terminalis, lateral septum, and prefrontal cortex inhibit energy intake (Sweeney and Yang 2015; Hsu et al. 2017).It is possible that vHC neurons contribute to the representation of the memory of a meal and inhibit subsequent intake. In support, we have shown that vHC neurons inhibit energy intake during the postprandial period. Specifically, optogenetic inhibition of vHC principle glutamatergic neurons given after the end of a sucrose or chow meal, timed to occur when the memory of the meal would be undergoing consolidation, accelerates the onset of the next meal and increases the amount eaten during the next meal when the neurons are no longer inhibited (Hannapel et al. 2019). Inactivation of these neurons given after a saccharin meal also hastens the initiation of the next saccharin meal and increases the size of that next meal, suggesting that vHC inhibition does not increase intake by disrupting the processing of interoceptive visceral signals (Hannapel et al. 2019).If vHC neurons inhibit intake through a process that involves memory, then well-defined molecular events necessary for vHC synaptic plasticity should play a role in controlling meal timing and meal size because synaptic plasticity at hippocampal excitatory synapses is a critical mechanism underlying memory formation (Bailey et al. 2015; Bartsch and Wulff 2015). Activation of glutamatergic N-methyl-D-aspartate receptors (NMDARs) is required for most forms of hippocampal synaptic plasticity (Malenka and Nicoll 1993; Volianskis et al. 2015). NMDAR-dependent increases in intracellular calcium activate proteins and stimulate mRNA synthesis and protein translation that collectively act to increase glutamate AMPA receptor function in the postsynaptic cell, thereby increasing glutamate signaling and synaptic strength (Shanley et al. 2001; Bevilaqua et al. 2005; Herring and Nicoll 2016). Synaptic plasticity in vHC is NMDAR-dependent and vHC NMDARs are often necessary for vHC-dependent memory (Zhang et al. 2001; Xu et al. 2005; Kent et al. 2007; Czerniawski et al. 2012; Portero-Tresserra et al. 2014; Zhu et al. 2014; Clark et al. 2015; Maggio et al. 2015). Of note, feeding-related hormones such as insulin and leptin enhance NMDAR functionality in hippocampal cultured neurons and slices (Liu et al. 1995; Shanley et al. 2001).Hippocampal synaptic plasticity is also dependent on the activation of the immediate early gene (IEG) activity-regulated cytoskeleton-associated protein (Arc). Arc is considered a master regulator of synaptic plasticity (Bramham et al. 2010; Korb and Finkbeiner 2011; Shepherd and Bear 2011). It is downstream from many molecular signaling pathways and is necessary for virtually every type of synaptic plasticity (Bramham et al. 2008; Korb and Finkbeiner 2011; Shepherd and Bear 2011). Learning experiences produce small but significant increases in Arc that are typically maximal within 15 min of the experience, and unlike other IEGs, Arc expression reflects synaptic plasticity rather than neuronal activity (Fletcher et al. 2006; Guzowski et al. 2006; Carpenter-Hyland et al. 2010). vHC Arc is necessary for memory consolidation because disrupting vHC Arc expression with Arc antisense (anti-Arc) oligodeoxynucleotides (ODN) disrupts vHC-dependent memory (Czerniawski et al. 2011, 2012; Chia and Otto 2013). We have shown that sucrose consumption increases vHC Arc expression during the early postprandial period (Hannapel et al. 2017), suggesting that ingestion activates molecular processes required for synaptic plasticity in vHC.Although it is well established that vHC neurons influence energy regulation, it is unknown whether vHC neurons regulate energy intake through a process that requires NMDARs and Arc. In the present experiments, we tested the prediction that disrupting vHC NMDAR activation and Arc expression would increase meal size and decrease the interval between meals. Specifically, NMDAR antagonists or anti-Arc ODNs were infused into the vHC and subsequent intake of sucrose was assessed.     

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