A typical “Western diet” contains higher than recommended levels of added sugar, saturated fatty acids, and processed foods. Our research revealed that habitual consumption of these dietary factors leads to deficits in hippocampal-dependent memory processes via altered neurotrophic signaling, neuroinflammation, and disrupted acetylcholine signaling. We’ve shown that the juvenile and adolescent phase of development is a particularly vulnerable period through which Western diet consumption disrupts hippocampal-dependent memory function in rats. These memory deficits are long-lasting and not reversible when switched to a healthy during adulthood. Our additional results reveal that early life Western diet consumption produces robust changes in the gut microbiome in rats, and that these bacteria alterations are functionally related to the long-lasting neurocognitive deficits.

Recent publications on this theme (* indicates corresponding author)

Hayes AMR, Tierno Lauer L, Kao AE, Sun S, Klug ME, Tsan L, Rea JJ, Subramanian KS, Gu C, Tanios N, Ahuja A, Donohue KN, Décarie-Spain L, Fodor AA, *Kanoski SE (2024). Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling. Brain, Behavior, and Immunity, 118: 408-22.

Hayes AMR, Kao AE, Ahuja A, Subramanian KS, Klug ME, Rea JJ, Nourbash AC, Tsan L, *Kanoski SE (2024). Early- but not late-adolescent Western diet consumption programs for long-lasting memory impairments in male but not female rats. Appetite, 194: 107150

Chometton S., Tsan L., Hayes A.M.R., Kanoski S.E., *Schier L.A. (2023). Early life influences of low-calorie sweetener consumption on sugar taste. Physiology and Behavior, 264: 114133.

^Hayes A.M.R., ^Tsan L., Kao A.E., Schwartz G., Décarie-Spain L., Tierno Lauer L., Klug M.E., Schier L.A., *Kanoski S.E. (2022). Early life low-calorie sweetener consumption impacts energy balance during adulthood. Nutrients, 14(22): 4709 (^ denotes equal author contributions).

Tsan L., Chometton S., Hayes A.M.R., Klug M.E., Zho Y., Sun S., Bridi L. Lan R., Fodor A.A., Noble E.E., Yang X., *Kanoski S.E., *Schier L.A. (2022). Early life low-calorie sweetener consumption disrupts glucose regulation, sugar-motivated behavior, and memory function in rats. JCI Insight, 7(20): e157714.

^Tsan L., ^Sun S., Hayes A.M.R., Bridi L., Chirala L.S., Noble E.E., Fodor A.A., *Kanoski S.E. (2022). Early life Western diet-induced memory impairments and gut microbiome changes in female rats are long-lasting despite healthy dietary intervention. Nutritional Neuroscience, 25(12): 2490-2506 (^ denotes equal author contributions)

Noble E.E., Olson CA, Davis EA, Tsan L, Chen Y.W., Schade R., Liu C.M., Suarez A.N., Jones R.B., de la Serre C., Yang X., *Hsiao E.Y., *Kanoski S.E. (2021). Gut microbial taxa elevated by dietary sugar disrupt memory function. Translational Psychiatry, 11: 194.

Tsan L., Décarie-Spain L., *Noble E.E., *Kanoski S.E. (2021). Western diet consumption during development: setting the stage for neurocognitive dysfunction. Frontiers in Neuroscience, 10.

Noble E.E., Hsu T.M., Liang J., *Kanoski S.E. (2019). Early life sugar consumption has long-term negative effects on memory function in male rats. Nutritional Neuroscience, 22(4): 273-282.

Noble E.E., Hsu T.M., Jones R., Fodor A., Goran M.I., *Kanoski S.E. (2017). Early life sugar consumption affects the microbiome in rodents independent of obesity. Journal of Nutrition, 147(1): 20-28.

Noble E.E., Hsu T.M., *Kanoski S.E (2017). Gut to brain dysbiosis: mechanisms linking Western Diet consumption, the microbiota, and cognitive impairment. Frontiers in Behavioral Neuroscience, 11(9): 1-10.

Noble E.E., *Kanoski S.E. (2016). Early life exposure to obesogenic diets and learning and memory dysfunction. Curr Opin in Behav Sciences, 9: 7-14.

Hsu T.M., Konunar V.K., Taing L., Usui R., Kaiser B.D., Goran M.I., *Kanoski S.E. (2015). Effects of sucrose and high fructose corn syrup on spatial memory function and hippocampal neuroinflammation in adolescent rats. Hippocampus, 25(2): 227-39.

Food intake is a complex behavior that can occur or cease to occur for a multitude of reasons. Decisions about where, when, what, and how much to eat are not merely reflexive responses to food-relevant stimuli or to changes in energy status. Rather, eating behavior is powerfully modulated by various contextual factors and by previous experiences. Thus, in addition to classic hindbrain and hypothalamic feeding centers, brain regions involved in complex cognitive processes must also play a critical role in energy balance control. Our research focuses on the hippocampus, a brain region historically linked with control of visuospatial and relational memory processes. Our perspective is that the hippocampus constitutes an important neural substrate converging the external context (including visuospatial and social factors), interoceptive signals, and previous learned experiences to control both appetitive and ingestive behavior. Consistent with this framework, our recent findings reveal that interoceptive energy balance signals are communicated to the hippocampus (particularly the ventral subregion, illustrated in this photomicrograph) via endocrine and neuropeptide signals that function to reduce (leptin, glucagon-like peptide-1) or increase (ghrelin, melanin-concentrating hormone, oxytocin) food intake and food motivated responses. Collectively our recent results and ongoing projects highlight endocrine and neuropeptidergic signaling in hippocampal neurons as a novel substrate of importance in the higher-order regulation of feeding behavior via downstream connections to cortical, septal, striatal, and hypothalamic targets.

Recent publications on this theme (* indicates corresponding author)

Rea J.J., Liu C.M., Hayes A.M.R., Bashaw A.G., Schwartz G., Ohan R., Décarie-Spain L., Kao A.E., Klug M.E., Phung K.J., Waldow A.I., Wood R.I., *Kanoski S.E. (2024). Hippocampus oxytocin signaling promotes prosocial eating in rats. Biological Psychiatry, 97(5): 540-549.

Décarie-Spain L., Liu C.M., Tierno Lauer L., Subramanian K., Bashaw A.G., Klug M.E., Gianatiempo I.H., Suarez A.N., Noble E.E., Donohue K.N., Cortella A.M., Hahn J.D., Davis E.A., *Kanoski S.E. (2022). Ventral hippocampus-lateral septum circuitry promotes foraging-related memory. Cell Reports 40(13): 111402.

*Parent M.B., Higgs S., Cheke L.G., Kanoski S.E. (2022). Memory and eating: a bidirectional relationship implicated in obesity. Neuroscience & Biobehavioral Reviews, 132: 110-129.

Suarez A.N., Liu C.M., Cortella A.M., Noble E.E., *Kanoski S.E. (2020). Ghrelin and orexin interact to increase meal size through a descending hippocampus to hindbrain signaling pathway. Biological Psychiatry, 87(11): 1001-1011.

Hsu T.M., Noble E.E., Liu C.M., Cortella A.M., Konanur V.R., Suarez A.N., Reiner D.J., Hahn J.D., Hayes M.R., *Kanoski S.E. (2018). A hippocampus to prefrontal cortex neural pathway inhibits food motivation through glucagon-like peptide-1 signaling. Molecular Psychiatry, 23(7): 1555-1565.

Liu C.M., *Kanoski S.E. (2018). Homeostatic and non-homeostatic controls of feeding behavior: distinct vs. common neural systems. Physiology and Behavior, 193(Pt B): 223- 231.

Hsu T.M., Noble E.E., Reiner D.J., Liu C.M., Suarez A.N., Konanur V.R., Hayes M.R., *Kanoski S.E. (2018). Hippocampal ghrelin receptor signaling promotes socially- mediated learned food preference. Neuropharmacology, 131: 487-496.

*Kanoski S.E., Grill H.J. (2017). Hippocampus contributions to food intake control: mnemonic, neuroanatomical, and endocrine mechanisms. Biological Psychiatry, 81(9): 748-756. (paper recommended by the Faculty of 1000 as being of special significance in its field).

Hsu T.M., Suarez A.N., *Kanoski S.E. (2016). Ghrelin: A link between memory and ingestive behavior. Physiology and Behavior, 162: 10-17.

Hsu T.M., Hahn J.D., Konanur V.R., Noble E.E., Suarez A.N., Thai J., Nakamoto E.M., *Kanoski S.E. (2015). Hippocampus ghrelin signaling mediates appetite through lateral hypothalamic orexin pathways. eLife, 2015;4: e11190.

Hsu T.M., Hahn J.D., Konanur V.K., Lam A., *Kanoski S.E. (2015). Hippocampal GLP- 1 receptors influence food intake, meal size, and effort-based responding for food through volume transmission. Neuropsychopharmacology, 40(2): 327-37.

During the preprandial (before eating), prandial, and postprandial stages of consuming a meal, various endocrine, neuropeptidergic, and neural signals are released to regulate appetite, meal size (satiation), and the inter-meal interval (satiety). Emerging evidence reveals that in addition to regulating food intake control, these energy status-related biological systems also play a critical role in learning and memory function, particularly with regards to remembering when, how, and where food was obtained and consumed (e.g., foraging behavior, as depicted in the illustration). From an evolutionary perspective, eating is a profoundly important behavior, and having biological systems designed to encode and remember critical details of an eating episode will more efficiently guide future foraging and eating behaviors. Our research highlights the vagus nerve as a critical link between gut-originating meal-related signals and hippocampal-dependent memory function. In the absence of gut-to-brain vagal signaling, rats are impaired in visuospatial and episodic memory processes, and these effects appear to be based on reduced neurotrophic and neurogenic signaling in the hippocampus. Our ongoing research is mapping out the precise neuroanatomical pathways connecting the gut and the hippocampus, as well as the molecular signaling pathways through which meal-related signals promote memory function.

Recent publications on this theme (* indicates corresponding author)

Décarie-Spain L., Hayes A.M.R., Tierno Lauer L., *Kanoski S.E. (2024). The gut-brain axis and cognitive control: a role for the vagus nerve. Seminars in Cell and Developmental Biology, 156: 201-209.

Décarie-Spain L., *Kanoski S.E. (2021). Ghrelin and glucagon-like peptide-1: a gut-brain axis battle for food reward. Nutrients, 13, 977.

Davis E.A., Wald H.S., Suarez A.N., Zubcevic J., Liu C.M., Cortella A.M., Kamitakahara A.K., Polson J.W., Arnold M., Grill H.J., *de Lartigue G., *Kanoski S.E. (2020). Ghrelin signaling affects feeding behavior, metabolism, and memory through the vagus nerve. Current Biology, 30(22): P4510-4518.

Suarez A.N., Noble E.E., *Kanoski S.E. (2019). Regulation of memory function by feeding-relevant biological systems: following the breadcrumbs to the hippocampus. Frontiers in Molecular Neuroscience, 12:101.

Suarez A.N., Hsu T.M., Liu C.M., Noble E.E., Cortella A.M., Nakamoto E.M., Hahn J.D., *De Lartigue, G., *Kanoski S.E. (2018). Gut vagal sensory signaling regulates hippocampus function through multi-order pathways. Nature Communications, 9(1): 2181.

 NEUROPEPTIDERGIC CONTROL OF eating BEHAVIOR

Food intake is potently regulated by neuropeptides that are synthesized in the hypothalamus. Our research is focusing on a population of neurons located in the lateral hypothalamus and zona incerta that produce the orexigenic neuropeptide, melanin-concentrating hormone (MCH; depicted in blue in the photomicrograph). Classical signaling mechanisms through which MCH and other neuropeptides influence behavior include neuronal synaptic communication and neuroendocrine signaling. Our findings provide evidence for an alternative neural communication mechanism that is relevant for food intake control involving ‘volume transmission’ of MCH within the brain. More specifically, we discovered that MCH increases food intake, in part, via release into the cerebrospinal fluid.

Impulsive behavior can lead to unintended negative consequences. Surprisingly little is known about the neurobiological substrates regulating impulsivity. We identified a novel neural circuit that selectively regulates impulsive responding for palatable food through which MCH signals to the pyramidal layer of the ventral hippocampus field CA1 (vCA1). Elevated impulsivity was observed when this system was perturbed in either direction (gain or loss of function), suggesting that impulsive behavior is kept in check by endogenous MCH neuropeptidergic tone to the vCA1. Ongoing research is investigating the nucleus accumbens shell as a downstream target of this impulse control system.

Unlike MCH, oxytocin potently reduces food intake. However, the behavioral mechanisms and specific brain regions mediating these effects are poorly understood. Our ongoing work is investigating the interaction between oxytocin’s effects on social behavior and food intake, as well as exploring novel sites of action and signaling mechanisms through which oxytocin reduces food intake. Our recent published and ongoing work reveals that oxytocin may actually have bidirectional influences on food intake that are dependent on the social context and the activation of oxytocin neurons in distinct hypothalamic nuclei.

Recent publications on this theme (* indicates corresponding author)

Rea J.J., Liu C.M., Hayes A.M.R., Bashaw A.G., Schwartz G., Ohan R., Décarie-Spain L., Kao A.E., Klug M.E., Phung K.J., Waldow A.I., Wood R.I., *Kanoski S.E. (2024). Hippocampus oxytocin signaling promotes prosocial eating in rats. Biological Psychiatry, 97(5): 540-549.

Subramanian KS, Tierno Lauer L, Hayes AMR, Décarie-Spain L, McBurnett K, Nourbash AC, Donohue KN, Kao AE, Bashaw AG, Burdakov D, Noble EE, Schier LA, *Kanoski SE (2023). Hypothalamic melanin-concentrating hormone neurons integrate food-motivated appetitive and consummatory processes in rats. Nature Communications, 14(1): 1755.

Fujita A, Zhong L, Antony M, Chamiec-Case E, Mickelsen LE, Kanoski SE, Flynn W, *Jackson AC (2021). Neurokinin B-expressing neurons of the central extended amygdala mediate inhibitory synaptic input onto melanin-concentrating hormone neuron subpopulations. Journal of Neuroscience, 41(46): 9539-60.

Liu CM, Spaulding MO, Rea JJ, *Noble EE, *Kanoski SE (2021). Oxytocin and food intake control: neural, behavioral, and signaling mechanisms. International Journal of Molecular Sciences, 22 10859.

Lord MN, Subramanian KS, *Kanoski SE, *Noble EE (2021). Melanin-concentrating hormone and food intake control. Peptides, 137: 170476.

Liu CM, Hsu TM, Suarez AN, Subramanian KS, Fatemi RA, Cortella AM, Noble EE, Roitman MF, *Kanoski SE (2020). Central oxytocin signaling inhibits food reward-motivated behaviors and VTA dopamine responses to food-predictive cues in male rats. Hormones and Behavior, 126: 104855.

Terrill SJ, Subramanian KS, Lan R, Liu CM, Cortella AM, *Noble EE, *Kanoski SE (2020). Nucleus accumbens melanin-concentrating hormone signaling promotes feeding in a sex-dependent manner. Neuropharmacology, 178(1): 108270.

Liu CM, Davis EA, Suarez AN, Wood RI, *Noble EE. *Kanoski SE (2020). Sex differences and estrous influences on oxytocin control of food intake. Neuroscience, 447: 63-73.

Noble EE, Wang Z, Liu CM, Davis EA, Suarez AN, Stein LM, Tsan L, Terrill SJ, Hsu TM, Jung A, Raycraft LM, Hahn JD, Darvas M, Cortella AM, Schier LA, Johnson AW, Hayes MR, Holschneider DP, *Kanoski SE (2019). Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone. Nature Communications, 10: 4123.

Noble E.E., Hahn J.D., Konanur V.R., Hsu T.M., Page S.J., Cortella A.M., Liu C.M., Song M.Y., Suarez A.N., Szujewski C.C., Rider D.R., Clarke J.E., Darvas M., Appleyard S.M.,*Kanoski S.E. (2018). Control of feeding behavior by cerebral ventricular volume transmission of melanin-concentrating hormone. Cell Metabolism, 28(1): 55-68. (article featured on July 2018 Cell Metabolism cover page and highlighted in Nature Reviews Endocrinology; article recommended by the Faculty of 1000 as being of special significance in its field).