Ted M. Hsu

Blood-brain barrier disruption: mechanistic links between Western diet consumption and dementia.

Both obesity and Alzheimer’s disease (AD) are major health burdens in Western societies. While commonly viewed as having separate etiologies, this review highlights data suggesting that intake of “Western diets”, diets high in saturated fatty acids (SFA) and simple carbohydrates, may pose a common environmental risk factor contributing to the development of both of these adverse pathologies. We discuss the effects of Western Diet intake on learning and memory processes that are dependent on the hippocampus, as well as the importance of this brain region in both obesity development and the onset of Alzheimer’s and other dementias. A putative mechanism is discussed that mechanistically links Western diet consumption, blood brain barrier (BBB) degradation, and subsequent hippocampal damage and dementia pathology.

Effects of sucrose and high fructose corn syrup consumption on spatial memory function and hippocampal neuroinflammation in adolescent rats.

Excessive consumption of added sugars negatively impacts metabolic systems; however, effects on cognitive function are poorly understood. Also unknown is whether negative outcomes associated with consumption of different sugars are exacerbated during critical periods of development (e.g., adolescence). Here we examined the effects of sucrose and high fructose corn syrup‐55 (HFCS‐55) intake during adolescence or adulthood on cognitive and metabolic outcomes. Adolescent or adult male rats were given 30‐day access to chow, water, and either (1) 11% sucrose solution, (2) 11% HFCS‐55 solution, or (3) an extra bottle of water (control). In adolescent rats, HFCS‐55 intake impaired hippocampal‐dependent spatial learning and memory in a Barnes maze, with moderate learning impairment also observed for the sucrose group. The learning and memory impairment is unlikely based on nonspecific behavioral effects as adolescent HFCS‐55 consumption did not impact anxiety in the zero maze or performance in a non‐spatial response learning task using the same mildly aversive stimuli as the Barnes maze. Protein expression of pro‐inflammatory cytokines (interleukin 6, interleukin 1β) was increased in the dorsal hippocampus for the adolescent HFCS‐55 group relative to controls with no significant effect in the sucrose group, whereas liver interleukin 1β and plasma insulin levels were elevated for both adolescent‐exposed sugar groups. In contrast, intake of HFCS‐55 or sucrose in adults did not impact spatial learning, glucose tolerance, anxiety, or neuroinflammatory markers. These data show that consumption of added sugars, particularly HFCS‐55, negatively impacts hippocampal function, metabolic outcomes, and neuroinflammation when consumed in excess during the adolescent period of development.

Hippocampal GLP-1 Receptors Influence Food Intake, Meal Size, and Effort-Based Responding for Food through Volume Transmission

Glucagon-like peptide-1 (GLP-1) is produced in the small intestines and in nucleus tractus solitarius (NTS) neurons. Activation of central GLP-1 receptors (GLP-1Rs) reduces feeding and body weight. The neural circuits mediating these effects are only partially understood. Here we investigate the inhibition of food intake and motivated responding for food in rats following GLP-1R activation in the ventral hippocampal formation (HPFv), a region only recently highlighted in food intake control. Increased HPFv GLP-1R activity following exendin-4 administration potently reduced food intake (both chow and Western diet) and body weight, whereas HPFv GLP-1R blockade increased food intake. These hypophagic effects were based on reduced meal size, and likely do not involve nausea as HPFv exendin-4 did not induce a conditioned flavor avoidance. HPFv GLP-1R activation also reduced effort-based responding for food under an operant progressive ratio reinforcement schedule, but did not affect food conditioned place preference expression. To investigate possible routes of HPFv GLP-1 signaling, immunohistochemical analysis revealed the absence of GLP-1 axon terminals in the HPFv, suggesting volume transmission as a mechanism of action. Consistent with this, the presence of active GLP-1 was detected in both the cerebrospinal fluid (CSF) and the HPFv. The source of CSF GLP-1 may be NTS GLP-1-producing neurons, as, (1) ∼30% of NTS GLP-1 neurons colocalized with the retrograde tracer fluorogold (FG) following lateral ventricle FG injection, and (2) GLP-1-immunoreactive axon terminals were observed adjacent to the ventricular ependymal layer. Collectively these findings illuminate novel neuronal and behavioral mechanisms mediating food intake reduction by GLP-1.

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.

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.