A hippocampus to prefrontal cortex neural pathway inhibits food motivation through glucagon-like peptide-1 signaling

Abstract

The hippocampus and the medial prefrontal cortex (mPFC) are traditionally associated with regulating memory and executive function, respectively. The contribution of these brain regions to food intake control, however, is poorly understood. The present study identifies a novel neural pathway through which monosynaptic glutamatergic ventral hippocampal field CA1 (vCA1) to mPFC connectivity inhibits food-motivated behaviors through vCA1 glucagon-like peptide-1 receptor (GLP-1R). Results demonstrate that vCA1-targeted RNA interference-mediated GLP-1R knockdown increases motivated operant responding for palatable food. Chemogenetic disconnection of monosynaptic glutamatergic vCA1 to mPFC projections using designer receptors exclusively activated by designer drugs (DREADDs)-mediated synaptic silencing ablates the food intake and body weight reduction following vCA1 GLP-1R activation. Neuropharmacological experiments further reveal that vCA1 GLP-1R activation reduces food intake and inhibits impulsive operant responding for palatable food via downstream communication to mPFC NMDA receptors. Overall these findings identify a novel neural pathway regulating higher-order cognitive aspects of feeding behavior.

Figures

Figure 1

vHP targeted A) AAV-GFP and B) AAV-GLP-1R shRNA delivery transfects vHP neurons. C) vHP AAV-GLP-1R shRNA significantly reduces GLP-1R mRNA expression. D) Meal pattern analyses in vHP GLP-1R KD vs. CTRL AAV rats. E) Operant responding on a FR1 reinforcement schedule in vHP GLP-1R KD vs. CTRL animals. F) Body weight gain and G) food intake in vHP GLP-1R KD vs. CTRL groups. CA1sp: CA1 pyramidal cells; alv = alveus. *p

Figure 2

vCA1 neurons provide monosynaptic and unilateral input to the mPFC. Unilateral iontophoretic vCA1 delivery of either PHAL (red) or AAV1-GFP (green) (representative injection sites in B and E respectively) reveals A, C) PHAL and D, F) AAV1-GFP fluorescent axon terminal fields in the mPFC ipsilateral to the vCA1 injection. A schematic representation of mPFC AAV1-GFP axon field terminals from the vHP is shown in G-J, where G) displays a representative vCA1 AAV1-GFP injection site and H-J) shows mPFC AAV1-GFP axon terminal field distribution (Swanson atlas levels 8–10). CA1sp: CA1 pyramidal layer; alv = alveus; PL = prelimbic area, ILA = infralimbic area; fa = corpus callosum, anterior forceps.

Figure 3

A) GLP-1R mRNA expression (green) in vCA1 cell bodies (DAPI, teal). B) Representative mPFC fluorogold injection site C) Distribution of backlabeled fluorogold vCA1 neurons that project to the mPFC. D) Representative vCA1 neurons that project to the mPFC (fluorogold, blue) co-express GLP-1R mRNA (green).

Figure 4

Reversible vHP to mPFC disconnection with inhibitory DREADDs. A) Shows the experimental design involving DREADDs mediated vHP-mPFC synaptic disconnection and pharmacological activation of vHP GLP-1Rs with exendin-4. B) AAV2-CaMKIIa hM4Di DREADDs and C) AAV2-CaMKIIa-GFP transfects vHP pyramidal neurons. D) Representative mPFC and E) vHP injection sites. F) 24 hr food intake and body weight following mPFC administration of CNO or vehicle (VEH) and vHP administration of exendin-4 (EX4) or VEH in vHP hM4Di DREADDs transfected animals. G) 24hr food intake and body weight following mPFC administration of CNO or VEH and vHP administration of EX4 or VEH in vHP CTRL AAV animals. *p

Figure 5

A) 24 hr food intake and body weight following mPFC administration of AP-5 or vehicle (VEH) and vHP administration of exendin-4 (EX-4) or VEH. B) 24 hr food intake and body weight following mPFC administration of CNQx or VEH and vHP administration of EX-4 or VEH. C) Phosphorylated NR2B expression in the mPFC following unilateral vHP delivery of exendin-4 or vehicle. *p

Figure 6

A) DRL 20 efficiency across a 10 day training period. B) DRL 20 test session after 24 hr food deprivation in animals receiving mPFC AP-5 or vehicle and vHP exendin-4 or vehicle. *p