Consumption of a Western Diet (WD) that is high in saturated fat and added sugars negatively impacts cognitive function, particularly mnemonic processes that rely on the integrity of the hippocampus. Emerging evidence suggests that the gut microbiome influences cognitive function via the gut-brain axis, and that WD factors significantly alter the proportions of commensal bacteria in the gastrointestinal tract. Here we review mechanisms through which consuming a WD negatively impacts neurocognitive function, with a particular focus on recent evidence linking the gut microbiome with dietary- and metabolic-associated hippocampal impairment. We highlight evidence linking gut bacteria to altered intestinal permeability and blood brain barrier integrity, thus making the brain more vulnerable to the influx of deleterious substances from the circulation. WD consumption also increases production of endotoxin by commensal bacteria, which may promote neuroinflammation and cognitive dysfunction. Recent findings also show that diet-induced alterations in gut microbiota impair peripheral insulin sensitivity, which is associated with hippocampal neuronal derrangements and associated mnemonic deficits. In some cases treatment with specific probiotics or prebiotics can prevent or reverse some of the deleterious impact of WD consumption on neuropsychological outcomes, indicating that targeting the microbiome may be a successful strategy for combating dietary- and metabolic-associated cognitive impairment.

Brain-derived neurotrophic factor (BDNF) mediates energy metabolism and feeding behavior. As a neurotrophin, BDNF promotes neuronal differentiation, survival during early development, adult neurogenesis, and neural plasticity; thus, there is the potential that BDNF could modify circuits important to eating behavior and energy expenditure. The possibility that "faulty" circuits could be remodeled by BDNF is an exciting concept for new therapies for obesity and eating disorders. In the hypothalamus, BDNF and its receptor, tropomyosin-related kinase B (TrkB), are extensively expressed in areas associated with feeding and metabolism. Hypothalamic BDNF and TrkB appear to inhibit food intake and increase energy expenditure, leading to negative energy balance. In the hippocampus, the involvement of BDNF in neural plasticity and neurogenesis is important to learning and memory, but less is known about how BDNF participates in energy homeostasis. We review current research about BDNF in specific brain locations related to energy balance, environmental, and behavioral influences on BDNF expression and the possibility that BDNF may influence energy homeostasis via its role in neurogenesis and neural plasticity. food intake; body weight; ventromedial hypothalamus; paraventricular nucleus; brain-derived neurotrophic factor BRAIN-DERIVED NEUROTROPHIC factor (BDNF) is a member of the neurotrophin family of growth factors (151), along with nerve growth factor (152), and neurotrophin (NT) 3 (67, 163), NT 4/5 (28), and NT 6 (88). Neurotrophins are synthesized as 32-35-kDa pro-isoforms, which are later cleaved to mature forms that dimerize after translation and then act as receptor ligands (136). Whereas the precursor forms of other neurotrophins are constitutively secreted, the 32-kDa pro-BDNF is packaged into vesicles of a regulated pathway and is secreted in an activitydependent manner (87). Pro-BDNF may be secreted as is (48), cleaved by the extracellular protease plasmin (202), or interact with the pan-neurotrophin receptor p75 NTR and other receptors that cause an independent biological effect (244). Alternatively, pro-BDNF is processed to the mature form intracellularly by furin or proconvertases, where it forms C-terminal dimers (212, 226).Mature BDNF is considered the biologically active form, which has a high affinity for the tropomyosin-related kinase B (TrkB) receptor (130). Both BDNF and TrkB are present in presynaptic axon terminals and postsynaptic dendritic compartments of neurons, and they are capable of bidirectional release and activity [for review, see Tyler et al. (259)]. Typical of the neurotrophic factors, BDNF stimulates the development and differentiation of new neurons (3, 131) and promotes long-term potentiation (LTP) (139,140,205), and neuron survival (97,105,116). BDNF is abundantly expressed throughout the developing and mature CNS and in many peripheral tissues, including muscle, liver, and adipose (42,159,182,261). Regional differences between BDNF mRNA levels and protein concentrations in the CNS a...

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.

Feeding behavior rarely occurs in direct response to metabolic deficit, yet the overwhelming majority of research on the biology of food intake control has focused on basic metabolic and homeostatic neurobiological substrates. Most animals, including humans, have habitual feeding patterns in which meals are consumed based on learned and/or environmental factors. Here we illuminate a novel neural system regulating higher-order aspects of feeding through which the gut-derived hormone ghrelin communicates with ventral hippocampus (vHP) neurons to stimulate meal-entrained conditioned appetite. Additional results show that the lateral hypothalamus (LHA) is a critical downstream substrate for vHP ghrelin-mediated hyperphagia and that vHP ghrelin activated neurons communicate directly with neurons in the LHA that express the neuropeptide, orexin. Furthermore, activation of downstream orexin-1 receptors is required for vHP ghrelin-mediated hyperphagia. These findings reveal novel neurobiological circuitry regulating appetite through which ghrelin signaling in hippocampal neurons engages LHA orexin signaling.DOI: http://dx.doi.org/10.7554/eLife.11190.001