Emily E. Noble

Hippocampus ghrelin signaling mediates appetite through lateral hypothalamic orexin pathways

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

Gut to Brain Dysbiosis: Mechanisms Linking Western Diet Consumption, the Microbiome, and Cognitive Impairment.

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.

Early-Life Sugar Consumption Affects the Rat Microbiome Independently of Obesity

BACKGROUND The gut microbiome has been implicated in various metabolic and neurocognitive disorders and is heavily influenced by dietary factors, but there is a paucity of research on the effects of added sugars on the gut microbiome. OBJECTIVE With the use of a rodent model, our goal was to determine how added-sugar consumption during the juvenile and adolescent phase of development affects the gut microbiome. METHODS Forty-two juvenile male Sprague-Dawley rats [postnatal day (PND) 26; 50-70 g] were given access to 1 of 3 different 11%-carbohydrate solutions designed to model a range of monosaccharide ratios commonly consumed in sugar-sweetened beverages: 1) 35% fructose:65% glucose, 2) 50% fructose:50% glucose, 3) 65% fructose:35% glucose, and 4) control (no sugar). After ad libitum access to the respective solutions for the juvenile and adolescent period (PND 26-80), fecal samples were collected for next-generation 16S ribosomal RNA sequencing and multivariate microbial composition analyses. Energy intake, weight change, and adiposity index were analyzed in relation to sugar consumption and the microbiota. RESULTS Body weight, adiposity index, and total caloric intake did not differ as a result of sugar consumption. However, sugar consumption altered the gut microbiome independently of anthropometric measures and caloric intake. At the genus level, Prevotella [linear discriminant analysis (LDA) score = -4.62; P < 0.001] and Lachnospiraceae incertae sedis (LDA score = -3.01; P = 0.03) were reduced, whereas Bacteroides (LDA score = 4.19; P < 0.001), Alistipes (LDA score = 3.88; P < 0.001), Lactobacillus (LDA score = 3.78; P < 0.001), Clostridium sensu stricto (LDA score = 3.77; P < 0.001), Bifidobacteriaceae (LDA score = 3.59; P = 0.001), and Parasutterella (LDA score = 3.79; P = 0.004) were elevated by sugar consumption. No overall pattern could be attributable to monosaccharide ratio. CONCLUSIONS Early-life sugar consumption affects the gut microbiome in rats independently of caloric intake, body weight, or adiposity index; these effects are robust across a range of fructose-to-glucose ratios.

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

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.

Amylin Acts in the Lateral Dorsal Tegmental Nucleus to Regulate Energy Balance Through Gamma-Aminobutyric Acid Signaling

BACKGROUND The pancreatic- and brain-derived hormone amylin promotes negative energy balance and is receiving increasing attention as a promising obesity therapeutic. However, the neurobiological substrates mediating amylins effects are not fully characterized. We postulated that amylin acts in the lateral dorsal tegmental nucleus (LDTg), an understudied neural processing hub for reward and homeostatic feeding signals. METHODS We used immunohistochemical and quantitative polymerase chain reaction analyses to examine expression of the amylin receptor complex in rat LDTg tissue. Behavioral experiments were performed to examine the mechanisms underlying the hypophagic effects of amylin receptor activation in the LDTg. RESULTS Immunohistochemical and quantitative polymerase chain reaction analyses show expression of the amylin receptor complex in the LDTg. Activation of LDTg amylin receptors by the agonist salmon calcitonin dose-dependently reduces body weight, food intake, and motivated feeding behaviors. Acute pharmacological studies and longer-term adeno-associated viral knockdown experiments indicate that LDTg amylin receptor signaling is physiologically and potentially preclinically relevant for energy balance control. Finally, immunohistochemical data indicate that LDTg amylin receptors are expressed on gamma-aminobutyric acidergic neurons, and behavioral results suggest that local gamma-aminobutyric acid receptor signaling mediates the hypophagia after LDTg amylin receptor activation. CONCLUSIONS These findings identify the LDTg as a novel nucleus with therapeutic potential in mediating amylins effects on energy balance through gamma-aminobutyric acid receptor signaling.

Lateral hypothalamic GLP-1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight

Increased motivation for highly rewarding food is a major contributing factor to obesity. Most of the literature focuses on the mesolimbic nuclei as the core of reward behavior regulation. However, the lateral hypothalamus (LH) is also a key reward-control locus in the brain. Here we hypothesize that manipulating glucagon-like peptide-1 receptor (GLP-1R) activity selectively in the LH can profoundly affect food reward behavior, ultimately leading to obesity. Progressive ratio operant responding for sucrose was examined in male and female rats, following GLP-1R activation and pharmacological or genetic GLP-1R blockade in the LH. Ingestive behavior and metabolic parameters, as well as molecular and efferent targets, of the LH GLP-1R activation were also evaluated. Food motivation was reduced by activation of LH GLP-1R. Conversely, acute pharmacological blockade of LH GLP-1R increased food motivation but only in male rats. GLP-1R activation also induced a robust reduction in food intake and body weight. Chronic knockdown of LH GLP-1R induced by intraparenchymal delivery of an adeno-associated virus-short hairpin RNA construct was sufficient to markedly and persistently elevate ingestive behavior and body weight and ultimately resulted in a doubling of fat mass in males and females. Interestingly, increased food reinforcement was again found only in males. Our data identify the LH GLP-1R as an indispensable element of normal food reinforcement, food intake and body weight regulation. These findings also show, for we believe the first time, that brain GLP-1R manipulation can result in a robust and chronic body weight gain. The broader implications of these findings are that the LH differs between females and males in its ability to control motivated and ingestive behaviors.

Control of Feeding Behavior by Cerebral Ventricular Volume Transmission of Melanin-Concentrating Hormone

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.

Early-life sugar consumption has long-term negative effects on memory function in male rats

Objectives: Added dietary sugars contribute substantially to the diet of children and adolescents in the USA, and recent evidence suggests that consuming sugar-sweetened beverages (SSBs) during early life has deleterious effects on hippocampal-dependent memory function. Here, we test whether the effects of early-life sugar consumption on hippocampal function persist into adulthood when access to sugar is restricted to the juvenile/adolescent phase of development. Methods: Male rats were given ad libitum access to an 11% weight-by-volume sugar solution (made with high fructose corn syrup-55) throughout the adolescent phase of development (post-natal day (PN) 26–56). The control group received a second bottle of water instead, and both groups received ad libitum standard laboratory chow and water access throughout the study. At PN 56 sugar solutions were removed and at PN 175 rats were subjected to behavioral testing for hippocampal-dependent episodic contextual memory in the novel object in context (NOIC) task, for anxiety-like behavior in the Zero maze, and were given an intraperitoneal glucose tolerance test. Results: Early-life exposure to SSBs conferred long-lasting impairments in hippocampal-dependent memory function later in life- yet had no effect on body weight, anxiety-like behavior, or glucose tolerance. A second experiment demonstrated that NOIC performance was impaired at PN 175 even when SSB access was limited to 2 hours daily from PN 26–56. Discussion: Our data suggest that even modest SSB consumption throughout early life may have long-term negative consequences on memory function during adulthood. GRAPHICAL ABSTRACT

Gut vagal sensory signaling regulates hippocampus function through multi-order pathways

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-relevant vagal signaling occurs between the gastrointestinal tract and the brain, but it is unclear if this pathway influences cognitive processes. This study shows that endogenous gastrointestinal derived vagal sensory signaling promotes hippocampal-dependent memory function via a multi-order brainstem–septal pathway.

Glucagon-like peptide-1 receptor (GLP-1R) signaling in the ventral hippocampus reduces feeding via monosynaptic communication to the medial prefrontal cortex (mPFC)

Ventral hippocampus (field CA1; vCA1) pyramidal neurons monosynaptically project to the mPFC [a back-labeled vCA1 neurons (blue) following mPFC Fluoro-Gold injections] and these mPFC-projecting vCA1 neurons express glucagon-like peptide-1 receptors (GLP-1R) [b combined Fluoro-Gold immunofluorescence (blue) with GLP-1R mRNA fluorescent in situ hybridization (green)]. vCA1 glutamatergic projection neurons were infected with an adeno-associated virus (AAV) driving expression of inhibitory DREADDs [c AAV2-CaMKIIa hM4Di DREADDs, and d AAV2-CaMKIIa-GFP (Control)]. This allowed for chemogeneticmediated synaptic silencing of vCA1 to mPFC communication via direct mPFC administration of the DREADDs ligand, clozapine-N-oxide. Synaptic silencing of this pathway eliminated the food intake and body weight reducing effects of vCA1 GLP-1R activation.