The vagus nerve is the primary means of neural communication between the gastrointestinal (GI) tract and the brain. Vagally mediated GI signals activate the hippocampus (HPC), a brain region classically linked with memory function. However, the endogenous relevance of GI-derived vagal HPC communication is unknown. Here we utilize a saporin (SAP)-based lesioning procedure to reveal that selective GI vagal sensory/afferent ablation in rats impairs HPC-dependent episodic and spatial memory, effects associated with reduced HPC neurotrophic and neurogenesis markers. To determine the neural pathways connecting the gut to the HPC, we utilize monosynaptic and multisynaptic virus-based tracing methods to identify the medial septum as a relay connecting the medial nucleus tractus solitarius (where GI vagal afferents synapse) to dorsal HPC glutamatergic neurons. We conclude that endogenous GI-derived vagal sensory signaling promotes HPC-dependent memory function via a multi-order brainstem–septal pathway, thereby identifying a previously unknown role for the gut–brain axis in memory control.

Classical mechanisms through which brain-derived molecules influence behavior include neuronal synaptic communication and neuroendocrine signaling. Here we provide evidence for an alternative neural communication mechanism that is relevant for food intake control involving cerebroventricular volume transmission of the neuropeptide melanin-concentrating hormone (MCH). Results reveal that the cerebral ventricles receive input from approximately one-third of MCH-producing neurons. Moreover, MCH cerebrospinal fluid (CSF) levels increase prior to nocturnal feeding and following chemogenetic activation of MCH-producing neurons. Utilizing a dual viral vector approach, additional results reveal that selective activation of putative CSF-projecting MCH neurons increases food intake. In contrast, food intake was reduced following immunosequestration of MCH endogenously present in CSF, indicating that neuropeptide transmission through the cerebral ventricles is a physiologically relevant signaling pathway for energy balance control. Collectively these results suggest that neural-CSF volume transmission signaling may be a common neurobiological mechanism for the control of fundamental behaviors.

Understanding the neurobiological controls of feeding behavior is critical in light of the growing obesity pandemic, a phenomenon largely based on excessive caloric consumption. Feeding behavior and its underlying biological substrates are frequently divided in the literature into two separate categories: [1] homeostatic processes involving energy intake based on caloric and other metabolic deficits, and [2] non-homeostatic processes that involve feeding driven by environmental and cognitive factors. The present review summarizes both historic and recent research examining the homeostatic regulation of feeding with specific emphasis on hypothalamic and hindbrain circuitry that monitor and regulate various metabolic signals. Regarding non-homeostatic controls, we highlight higher-order brain structures that integrate feeding-relevant external, interoceptive, and cognitive factors, including sensory cortical processing, learned associations in the hippocampus, and reward-based processing in the nucleus accumbens and interconnected mesolimbic circuitry. Finally, the current review focuses on recent evidence that challenges the traditional view that distinct neural systems regulate homeostatic vs. non-homeostatic controls of feeding behavior. Specifically, we highlight several feeding-related endocrine systems that act on both lower- and higher-order substrates, present evidence for the modulation of learned and cognitive feeding-relevant behaviors by lower-order brain regions, and highlight data showing that apparent homeostatic-based feeding behavior is modulated by higher-order brain regions. Our concluding perspective is that the classic dissociation between homeostatic and non-homeostatic constructs in relation to feeding behavior is limited with regards to understanding the complex integrated neurobiological systems that control energy balance.

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.

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