Diet and Brain

Humans require vitamins and minerals because they are crucial components of several essential metabolic pathways that maintain critical cellular processes. They are vital for brain and muscle function due to their role in energy-yielding metabolism, DNA synthesis, oxygen transport, and neural activities. These, in turn, have an impact on cognitive and psychological functions, including fatigue, both mentally and physically. The B vitamins (B1, 2, 3, 5, 6, 8, 9, and 12), vitamin C, iron, magnesium, and zinc, key players in these processes, are the main subjects of this review by Tardy et al. (2020). This review outlines the molecular and cellular biochemical mechanisms underlying these micronutrients' actions. It connects them to cognitive and psychological symptoms and possible manifestations of fatigue that may develop when the status or supplies of these micronutrients are insufficient. [NPID: B vitamins, vitamin C, iron, magnesium, zinc, energy production, mental and physical fatigue, anemia, cognition, mood]

Over the last decades, a substantial increase was seen in the prevalence of mental health disorders, including depression, anxiety, cognitive, and sleep disorders. Diet and its bioactive components have been recognized as modifiable risk factors, possibly influencing their pathogenesis. This review aimed to summarize molecular mechanisms underlying the putative beneficial effects toward brain health of different dietary factors, such as micro- and macronutrient intake, and habits, such as feeding time and circadian rhythm. The role of hormonal homeostasis in the context of glucose metabolism and adiponectin regulation and its impact on systemic and neuro-inflammation has also been considered and deepened. Additionally, a summary of the effects of specific bioactive molecules with antioxidant and anti-inflammatory properties, such as polyphenols and omega-3 fatty acids, which are thought to be good for the central nervous system by influencing microglia activation, adult neurogenesis, synaptic and neuronal plasticity, has been provided. The steps regulating the gut-brain axis and its impact on controlling systemic inflammation and oxidative stress have been examined. Finally, a summary of how bioactive chemicals affect oxidative stress, inflammation, and brain function has been provided. [NPID: Brain, depression, diet, inflammation, mental health, neuronal plasticity, neurons, oxidative stress, polyphenols, sleep]

One of the leading health issues in the United States is obesity. Studies using human and rodent models have shown that overeating and subsequent obesity is caused by functional abnormalities in cerebral motivation centers, such as the nucleus accumbens (NAc). Vollbrecht et al. (2023) discuss that, in obese vs. obese-resistant rats, there are basal increases in the excitability of NAc GABAergic medium spiny neurons (MSN) and decreases in the basal expression of AMPA-type glutamate receptors. The mechanism behind the control of extracellular glutamate and GABA in the NAc of these animals, however, is poorly understood. In this study, the authors used liquid chromatography-mass spectrometry (LC-MS) analysis of NAc dialysate to look at the real-time incorporation of 13 C6 -glucose into glutamate, glutamine, and GABA in rats that were prone to obesity as well as rats who were resistant to it. This unique method allowed examining changes in how these carefully grown lines used glucose to produce neurotransmitters. The authors discovered that 13 C6 -glucose, whether consumed voluntarily or infused into the stomach, penetrates the NAc quickly and is converted into 13 C2 -glutamine, 13 C2 -glutamate, and 13 C2 -GABA in both rat groups within minutes. Although basal levels of glutamate were higher in obesity-prone rats than obesity-resistant rats, the degree of increases in NAc 13 C2 -glutamine and 13 C2 -GABA were less pronounced. This suggested that these analytes' astrocytic regulation differs in some way. Thereafter, the authors looked at the expression of the GAD67, GLT-1, and NAc glutamine synthetase proteins. NAc glutamine synthetase and GLT-1 protein expression were decreased in the obesity-prone vs. obesity-resistant groups, consistent with lower 13 C2 -glutamine and 13 C2 -GABA levels. The authors conclude that their findings demonstrate how the usage of NAc glucose differs significantly between obese and non-obese rats, preferring glutamate generation over GABA production in obese rats, and that deficits in NAc astrocytic glutamate recycling contribute to these variations. These results were examined in light of known variations in NAc function across these models and the NAc's involvement in eating behavior. [NPID: Animal model, glucose, Glutamate Ammonia Ligase, glutamic acid, glutamine, Nucleus Accumbens, obesity, rats, Gamma Aminobutyric acid]

In this study by Alateeq et al. (2023), the authors sought to research the relationship between dietary magnesium intake (Mg) and middle-to-early-old age brain sizes and white matter lesions (WMLs). Using data on individuals from the UK Biobank (n = 6001) categorized by sex, ranging in age from 40 to 73, an online computerized 24-hour recall questionnaire was used to quantify dietary Mg to estimate daily Mg consumption. To determine if baseline blood pressure (BP) contributes to the association between Mg consumption and brain health, associations between baseline Mg, BP measurements, and between baseline Mg, Mg trajectories, and BP changes (between baseline and wave 2) were also looked at. Health and socio-demographic factors were considered in all analyses, in addition to whether menopausal status and Mg trajectories may combine to predict brain volumes and WMLs. Analysis of the results identified three groups of magnesium intake using latent class analysis: "high-decreasing" (men = 3.2%, women = 1.9%), "low-increasing" (men = 1.09%, women = 1.62%), and "stable-normal" (men = 95.71%, women = 96.51%). In both men and women, larger gray matter (GM), left hippocampus (LHC), and right hippocampal (RHC) sizes were generally related to higher baseline dietary Mg consumption. Compared to the "stable-normal" trajectory, only the "high-decreasing" trajectory was substantially linked with bigger brain volumes (GM, RHC). The "low-increasing" trajectory was associated with lower brain volumes (GM; white matter [WM], LHC, RHC) and larger WMLs. Mg and BP measurements revealed generally non-significant relationships. Moreover, post-menopausal women appeared to benefit more from the "high-decreasing" trajectory's demonstrated neuroprotective impact than pre-menopausal women. The authors conclude that better brain health is associated with higher dietary Mg consumption in the overall population, especially in women. [NPID: Magnesium, neuroimaging, blood pressure, sex, UK biobank]

The underlying processes for promoting excessive calorie consumption and weight increase by Western diets high in fat and sugar are unknown. Although there is a well-established link between obesity and altered brain dopamine function, it is unclear whether these changes are (1) pre-existing - and therefore - increase a person's susceptibility to weight gain, (2) a result of obesity, or (3) are directly related to repeated exposure to the Western diet. In this randomized, controlled trial by Thanarajah et al. (2023), subjects of average weight were given the option of an 8-week high-fat/high-sugar refreshment or a low-fat/low-sugar snack in addition to their usual diet. The authors observed that, in the high-fat/high-sugar intervention group, a resulting reduction in the desire for low-fat food and enhancement of associative learning and neural responses to food independent of food signals or rewards. The authors conclude that high-fat, high-sugar meals directly impact neurobehavioral adaptations that may raise the risk for overeating and weight gain while also noting that these modifications were irrespective of changes in body weight and metabolic metrics. [NPID: Dopamine, fMRI, high fat diet, neural plasticity, obesity, prediction error, preference, reinforcement learning, reward, taste, value]

The lateral hypothalamic region (LHA) is crucial for eating and drinking behavior, where the activation of LHA neurons concurrently encourages eating and drinking for the most part, yet the LHA has received very little research on its specific role in regulating drinking. LHA neurons that produce neurotensin (LHANts neurons) are a remarkable exception. When activated, they increase water intake but only slightly reduce eating. In this study by Kurt et al. (2022), the authors demonstrate how LHANts neurons are connected, their role in the processes of eating and drinking, and how the availability of resources and timing affect how they modulate these behaviors. Brain areas associated with energy and water sensing provide information to LHANts neurons. Additionally, the lateral preoptic area (LPO), a part of the brain associated with modifying drinking behavior, is one of the several areas of the brain to which LHANts neurons transmit. Activation of LHANts neurons selectively encourages drinking during the light cycle, when ingestive desire is low, even though it is not necessary to sustain homeostatic water or food intake. No matter how many calories are in the fluids, activating LHANts neurons at this time also boosts the desire to seek water or other pleasant fluids. Furthermore, the authors demonstrate that stimulating the LHANts LPO projection alone is enough to regulate drinking behavior, but does not inhibit eating as was seen after activating all LHANts neurons in general. In contrast, LHANts neuronal activity during the dark cycle was found to decrease eating during this period rather than promote drinking. The authors conclude that their findings reveal how and when LHANts neurons may control ingestive behaviors in an opposing manner. [NPID: Arcuate nucleus, central amygdala, lateral hypothalamic area, neurotensin, lateral preoptic area, body weight, feeding, homeostasis, reward]

The prevalence of obesity and the easy availability of attractive energy-dense meals highlight the urgent need for a deeper comprehension of the brain circuits that control hedonic eating (i,e., consuming food for the sole purpose of pleasure in the absence of dietary need or necessity). Both the body's homeostatic requirements and the food's hedonic values influence how we eat. In this study by Chen Z. et al. (2022), the authors demonstrate how neurons in the lateral septum that are positive for neurotensin (LSNts) are essential for controlling hedonistic eating. While LSNts that are activated reduce overall eating, those that are silenced particularly encourage the consumption of appetizing food. Neurotensin signals from LSNts to the supra mammillary nucleus (SUM) are sufficient to reduce total feeding, in contrast, LSNts neurons reach out to the tuberal nucleus (TU) via GABA signaling to control hedonic eating. Two LSNts populations that are involved in food-seeking and intake, respectively, are shown by in vivo calcium imaging and optogenetic manipulation to be activated and suppressed during eating. To minimize obesity brought on by high-fat diets, LSNts or LSNts→TU must be chronically activated. The authors conclude that a probable crucial route in controlling hedonic eating is the LSNts→TU pathway. [NPID: Feeding behavior, lateral hypothalamic area, mice, neurons, metabolism, neurotensin, obesity]

Several drivers of sedentary behavior and overeating are implicated in the pathology of obesity, a metabolic pandemic related to several chronic and serious diseases across the world. Save for our understanding of genetic conditions related to obesity, the evidence regarding these important drivers remains insufficient. In this study by Furlan et al. (2022), the authors demonstrate the role played by the central nervous system in guiding dietary preferences toward energy-dense food in mice. In particular, this role is performed by the interstitial nucleus of the posterior limb of the anterior commisurate’s (IPAC) neurotensin-expressing neurons. The authors demonstrated that the specific activation of the IPACNts enhanced preference for energy-dense food, hedonic eating, and obesity, while deactivation of the IPACNts promoted anti-obesity behaviors (reduction of hedonic eating and overall feeding). Furthermore, the continued suppression of IPACNts sustained these anti-obesity behaviors and enhanced energy expenditure and locomotion, leading to enhanced metabolic health, long-term weight loss, and a reduction in the odds of suffering from obesity. The authors highlight that their findings can present a new therapeutic target for combating obesity, as seen in the role played by IPAC neurons in stimulating and inhibiting obesogenic behavioral patterns and energy homeostasis. [NPID: Mice, energy metabolism, homeostasis, neurons, obesity]

Alzheimer’s disease (AD) is an uncommon condition that usually occurs late in life, a condition where several metabolic factors were found to contribute to its onset and course. Peripheral tissue insulin resistance and pathologies observed in tau proteins were demonstrated through studies of diabetes employing streptozotocin-injected and db/db mouse models. In their study, Xiong et al. (2022) fed pR5 mice (exhibiting P301L mutant human tau) a high-fat diet (HFD) in their attempt to create and characterize a new mouse model for the study of obesity, Type-II Diabetes Mellitus (T2DM) and AD, aimed to mirror AD patients whose clinical course is worsened by obesity and diabetes, two pervasive conditions in our modern society. Eight-week-old pR5 and C57BL/6 (wild type - WT) mice were given either a standard diet (STD) or HFD for a period of 30 weeks, during which their food consumption and weight were measured weekly, while their fasting glucose levels were recorded every fortnight. The mice were subjected to a series of behavioral tests to determine their depression, anxiety, and cognitive function statuses. Finally, insulin tolerance and glucose levels were investigated after 30 weeks of HFD, and tau protein pathology was investigated in both WT and P301L mice. Analysis of the results demonstrated that HFD led to enhancing obesity in pR5 mice compared to WTs and that this effect was more profound as the mice got older. Secondly, HFD increased glucose intolerance and insulin resistance, in addition to substantially worsening cognitive function and well-being (evident by increased depressive and anxiety-like behavior) in pR5 and WT mice. Finally, an increase in tau hyperphosphorylation in pR5 mice and overall total and hyperphosphorylated tau in WT mice was observed in long-term exposure to HFD, a known mechanism of AD pathology. The authors conclude that their results show the impact of obesity on pR5 transgenic mice expressing mutant human tau P301L in developing T2DM and enhancing tau phosphorylation, thus proving the model a viable platform to explore the links between AD, obesity, and T2DM, in addition to the biochemical and the mechanistic factors that govern AD tauopathies and metabolic diseases. [NPID: Alzheimer's disease, high fat diet, obesity, T2DM, tauopathy]

In an effort to reduce the calorie content of food, nonnutritive sweeteners (NNS) provide an alternative that helps sate sugar cravings. Despite their popular use in food and drink, several knowledge gaps remain, such as the potential impact of NNS on appetite, and the links between sex, obesity, and appetite responses to NNS versus other nutritive sweeteners. In this randomized, crossover clinical trial, Yunker et al. (2021) investigated the resultant neural activity from several high-caloric food cues (sweet and savory), metabolic reactions, and changes in feeding patterns following administration of sucralose (NNS), sucrose (nutritive sugar) or water (control) in a population of 74 healthy adults (43 women, 31 men, average age 23.4 ± 3.96 years). Following a 12-hour overnight fast, study participants gave three timed blood draws after receiving either water or a drink containing sucralose or sucrose. Neural activity was evaluated with Functional Magnetic Resonance Imaging (fMRI), and blood samples were used to investigate plasma glucose, insulin, glucagon-like peptide (7-36), acyl-ghrelin, total peptide YY, and leptin. The results showed that sucrose ingestion induced higher circulating glucose levels, insulin, and glucagon-like peptide-1, and curbed acyl-ghrelin levels, compared to sucralose. Furthermore, participants with an obese BMI classification (BMI ≥ 30) displayed more predilection to savory food cues, seen through higher medial frontal and orbitofrontal cortical reactivity (MFC, OFC, respectively) after ingesting sucralose. Female participants in particular displayed greater MFC and OFC reactivity to high-caloric foods, sweet foods, and consumed more total calories after ingesting sucralose compared to male participants, who did not show any differences with either sucralose or sucrose. To conclude, the authors highlight that their findings demonstrate a marked vulnerability of obese and female populations to heterogeneous neural reactivity following sucralose ingestion compared to sucrose ingestion. [NPID: Obesity, sex differences, sucrose, sucralose, neural response, appetite, satiety]

This 2021 article highlights the importance of diet in maintaining health, particularly as people age. Specifically diets high in antioxidants and anti-inflammatory potential (those found in nuts, fruits, vegetables, and fish) have been implicated in the reduction of age-related cognitive decline and the risk of degenerative disease development. While there have been many studies published in the past decade that address the impact of diet on health, this present paper reviewed the data on the role of diet and nutrition in aging and age-related cognitive decline. The authors discuss the relevance of macronutrients and micronutrients in this area of research and provide an overview of how the gut microbiota-gut-brain axis (the connection between gut, its microbiota, and the brain) along with nutrition can influence brain function in general and cognitive processes. For enhancing cognitive functioning, the dietary interventions that show therapeutic potential include those designed to optimize macro- and micronutrient levels, as well as those that attempt to maximize functioning of the microbiota-gut-brain axis. [NPID: nutrition, diet, macronutrients, nutrients, micronutrients, aging, cognition, cognitive function, antioxidants, gut microbiota, brain]

This 2021 study investigated the possible correlation between green tea intake and annual rate of change of gray matter, white matter, and hippocampal volumes in middle-aged and older Japanese adults. There were a total of 1693 participants in this National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) project, all of whom were aged 40-89 years. The hippocampal volume changed at an average rate of 0.499% per year. When green tea consumption was added to the equation, it was found to negatively correlate with the annual rate of change of hippocampal volume. In fact, the rate of change in hippocampal volume decreased for each 1 ml/day increase in green tea ingestion. There was no other association involving grey and white matter volumes. To summarize, increased consumption of green tea was linked with less annual hippocampal deterioration among Japanese adults, particularly among older individuals and women. Each additional 100 milliliters per day of green tea was related to a reduction of approximately 5% in annual hippocampal atrophy. [NPID: green tea, Japanese, Japan, healthy, health, nutrition, diet, brain, aging, white matter, grey matter, hippocampus, older]

This 2017 article explains that adult neurogenesis, which is a process by which stem cells in the hippocampal brain region spread into new neurons and other resident brain cells, is influenced by factors such as diet. Neurogenesis is very important in the preservation of cognitive function and the repairing of damaged brain cells (including those affected by brain disorders and aging). But adult neurogenesis can be negatively affected by aging, neuroinflammation, oxidative stress, brain injury, diets rich in sugars and fats, and addiction to alcohol and opioids. On the other hand, there are several diets and dietary components, as well as caloric restriction, physical exercise, and learning, that may induce stem cell proliferation in adult brains. Although it is not yet fully understood how these nutrients and dietary factors can affect adult neurogenesis, nutritional approaches show promise with regards to protection from cognitive decline and neurodegenerative disease development. This present review summarizes the evidence supporting the influential role of nutritional approaches in the modification of adult neurogenesis, and their potential to preserve cognitive integrity during aging. [NPID: cognition, aging, hippocampus, brain, stem cells, diet, nutrition, stress, alcohol, opioids, addiction, neurogenesis]

Intermittent access to palatable foods may promote compulsive eating, cognitive impairments and reduced hippocampal plasticity, but this 2020 preclinical study explores its effects on hippocampal function and neurogenesis. The male Wistar rats were fed either chow for 7 days/week (named the Chow/Chow group) or fed chow intermittently for 5 days/week with the remaining 2 days on a palatable diet (Chow/Palatable Group). Ferragud et al. (2020) assessed hippocampal function and neurogenesis either during withdrawal or following the reintroduction of palatable foods. Additionally, the study determined if the uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist memantine can prevent the diet-induced memory deficits and inhibit the maladaptive feeding. The chow/palatable group of rats showed bias in opting for a “novel cue” over a “novel place” and performed poorer in terms of contextual spatial processing, compared with control. The study also revealed reduced expression of immature neurons in the dentate gyrus of the hippocampus and a withdrawal-dependent drop in proliferating cells among the chow/palatable group. When these rats were treated with memantine, their excessive consumption of palatable foods dropped, the memory deficits were reversed, and the withdrawal-induced hypophagia were reduced. These findings demonstrate that withdrawal from palatable foods may cause NMDAR-dependent deficits in hippocampal function and a reduction in hippocampal neurogenesis. [NPID: brain, compulsive eating, cognitive impairments, hippocampus, neurogenesis, memory, palatable foods]

The purpose of this 2018 study was to determine if a western diet changes brain metabolism, increases blood-brain barrier (BBB) transport and inflammation, and induces cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice (a model of hyperlipidemia and cognitive decline). Cognitive processes (assessed by Y-maze and radial arm water maze) were influenced moderately by the western diet and LDLr -/-. The western diet induced increases in BBB transport, microvessel factor VIII levels (in the LDLr -/- mice) and microglia IBA1 staining (in WT mice), both indicating activation and neuroinflammation. The LDLr -/- mice had a significant increase in 18F- fluorodeoxyglucose uptake irrespective of diet, while brain 1H-magnetic resonance spectroscopy revealed increased lactate and lipid moieties. Rutkowsky et al. (2018) also discovered that a western diet altered brain TCA cycle and β-oxidation intermediates, levels of amino acids, and complex lipid levels and elevated proinflammatory lipid mediators, shown by the GC/MS and LC/MS/MS metabolic assessments of whole mouse brain. This study thus uncovered evidence that the western diet has multiple effects on brain metabolism, physiology, and altered cognitive function that likely manifest via multiple cellular pathways. [NPID: brain, inflammation, cognition, cognitive decline, neuroinflammation]

This 2020 study explains that while it is the brain’s responsibility to maintain whole-body homeostasis, it is the hypothalamus’ and dorsal vagal complex (DVC)’s role to regulate metabolic processes whilst sensing both hormones and nutrients. Haigh et al. (2020) highlight that the mitochondria contribute to the maintenance of energy homeostasis by responding to the level of nutrient availability, and metabolic diseases e.g. obesity and type 2 diabetes (T2D) disturb these processes. Mitochondria also plays a role in regulating glucose, and controlling whole-body metabolism, and therefore are pivotal in the development and maintenance of obesity and T2D. [NPID: brain, homeostasis, hypothalamus, hormones, mitochondria, obesity, type 2 diabetes, diabetes, glucose]

This 2018 review examined the literature on “old” and “newly” discovered influencing factors of reward-inducing overeating and eating addiction, analysing for instance high-fat palatable foods and dietary lipids on endocannabinoid formation and their potential to derange the feeding homeostasis. Other topics discussed include endocannabinoid signaling as a key mechanism acting both at hypothalamic and mesolimbic circuits and affecting both dopamine function and interplay between leptin and ghrelin signaling. Coccurello & Maccarrone (2018) covered the lateral hypothalamus, and specifically the lateral hypothalamus-ventral tegmental area-nucleus accumbens neural circuitry, since the former is capable of responding to the food-associated homeostatic information transferred (e.g. with food salience, motivation to eat, reward-seeking, and development of compulsive eating), and in order to study the functional interplay between ghrelin, dopamine, orexin, and endocannabinoid signaling. The endocannabinoids were identified to be potentially crucial in food reward processing within the lateral hypothalamus, as were orexin neurons in the integration of endocrine signals with food reinforcement and hedonic eating. Furthermore, the role played by different stressors in the reinstatement of preference for palatable food and food-seeking behavior were considered in the light of endocannabinoid production, activation of orexin receptors and disinhibition of dopamine neurons. The authors also have linked the type-1 cannabinoid receptor-dependent inhibition of GABA-ergic release and relapse to reward-associated stimuli to ghrelin and orexin signaling in the lateral hypothalamus-ventral tegmental area-nucleus accumbens network to mark its pathological potential for food addiction-like habits. [NPID: brain, hippocampus, reward, eating addiction, addiction, high-fat, homeostasis, mesolimbic circuits, endocannabinoids, dopamine, ghrelin, hedonic eating, pleasure, GABA, Gaba, food addiction]

May et al. (2020) investigated the neural mechanisms by which the reduced taste sensation and modulated food choices affect one’s diet, by using the genetically tractable organism D. melanogaster and examining protocerebral anterior medial dopaminergic neurons (PAM DANs) that responds to sweet taste (it also innervates the β'2 compartment of the mushroom body). In animals fed a high-sugar diet, a relatively small and delayed reaction was observed at the PAM-β'2 to sweet stimuli, and the response was sensitive to the strength of the signal transmission out of the sensory neurons. Interestingly, closed-loop optogenetic activation of β'2 DANs restored normal eating in animals fed high sucrose, which indicates that feeding rate and satiation are controlled by PAM-β'2 DANs activity. This could mean that diet-dependent alterations in taste can impair the central processing of sensory signals and cause less satiation. [NPID: brain, taste sensation, high-sugar, sensory neurons, satiety, taste, sensory signals]

Since few human studies had explored the brain structures potentially affected by long-term diet quality, Akbaraly et al. (2018) tested whether there is an association between cumulative average Alternative Healthy Eating Index 2010 (AHEI-2010) score during adult life, with hippocampal volume. The researchers gathered data on the 459 participants of the Whitehall II imaging sub-study (average age 59.6) including structural images of the brain obtained from the multimodal magnetic resonance imaging examination performed at the end of the follow-up. The results showed an increase of 92.5 mm3 (standard error = 42.0 mm3) in total hippocampal volume for each 1 SD (SD = 8.7 points) increment in AHEI-2010 score. Higher AHEI-2010 cumulative average score was associated with a larger total hippocampal volume among the sample population. This association was independent of sociodemographic factors, smoking habits, physical activity, cardiometabolic health factors, cognitive impairment, and depressive symptoms, and was more pronounced in the left hippocampus than in the right hippocampus. Interestingly, one of the AHEI-2010 components that was independently associated with larger hippocampal volume was no or light alcohol consumption. Given the importance of hippocampal structures in several neuropsychiatric diseases, Akbaraly et al. (2018) have reaffirmed the necessity to take into account adherence to healthy dietary recommendation in multi-interventional programs to promote healthy brain aging. [NPID: brain, hippocampus, alcohol]

Molteni et al. (2002) carried out this study investigating a potential mechanism by which a high fat and sugar (HFS) diet can influence brain structure and function via regulation of neurotrophins. The team of researchers demonstrated that animals that learn a spatial task faster possess more brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus. The results showed reductions in hippocampal BDNF levels and spatial learning performance after 2 months of consuming a HFS diet. Moreover, the downstream effectors for the action of BDNF on synaptic plasticity were reduced proportionally to BDNF levels in the hippocampus of rats maintained on the HFS diet for between 2 and 24 months. This study also marked that the rats maintained on this diet had less synapsin I mRNA and protein (which are important for neurotransmitter release) and lower concentrations of cyclic AMP-response element-binding protein (CREB) mRNA and protein (CREB is also required for various forms of memory and is under regulatory control of BDNF). Thirdly, growth-associated protein 43 mRNA levels, which are important for neurite outgrowth, neurotransmitter release, learning and memory) were lower in the rats kept on the high-fat and high-sugar diet. Molteni et al. (2002) discovered that this HFS diet, typically consumed in most industrialised western societies, can influence aspects of neuronal and behavioral plasticity associated with the function of BDNF. [NPID: brain, HFS, neurotrophins, spatial task, BDNF, brain-derived neurotrophic factor, spatial learning, neurotransmitter release]

Since microglia in the hippocampus are vulnerable to the effects of ageing, Spencer et al. (2019) assesses if the morphological and functional changes in microglia explain the findings from their previous studies showing short-term high-fat diets (HFD) significantly impairing hippocampal- and amygdala- based cognitive function only in the ageing and not in the young rats. As with the former study, young and ageing rats were fed a HFD for 3 days and their hippocampus and amygdala were analysed. This study found that ageing came with the expected priming of hippocampal microglia (demonstrated by less branching and greater microglial numbers in the region). Ageing was accompanied by increased microglial phagocytosis of microbeads in the hippocampus. The only effect induced by the HFD was the increase in synaptophysin boutons in the aged - an indication of neurodegeneration. In the amygdala, the HFD worsened the effects of ageing on microglial priming and markedly suppressed phagocytosis without notably affecting synaptophysin. To summarise this data, both the hippocampus and the amygdala displayed age-related microglial priming, but the microglia in the amygdala are especially vulnerable to the detrimental impact of short-term high-fat dieting in aging. [NPID: brain, microglia, hippocampus, short-term high-fat, HFD, amygdala, cognitive function, HFD, aging]

Reichelt et al. (2019) states that the high-fat and high-sugar (HFHS) diet is associated with changes in brain plasticity and emotional behaviors in humans. Since perineuronal nets [(PNNs) specialized extracellular matrix structures] are central to regulation of neuroplasticity in the medial prefrontal cortex (mPFC), this rat-based study examined the underlying involvement of PNNs and cortical plasticity in the mPFC in diet-evoked social behavior deficits (social recognition). Adolescent rats (28-56 days old) were started on a HFHS-supplemented diet, before being euthanized at 56 days old (along with the controls fed standard chow). Using dual fluorescence immunohistochemistry, co-localization of PNNs with PV neurons in the prelimbic (PrL) and infralimbic (IL) and anterior cingulate (ACC) subregions of the PFCs in the rats were examined. The results showed consumption of the HFHS diet led to a reduction in PV+ neurons and PNNs in the infralimbic (IL) region of the mPFC by -21.9% and -16.5%, respectively. While PV+ neurons and PNNs were not significantly decreased in the ACC or PrL, the percentage of PV+ and PNN co-expressing neurons was higher in all assessed regions of the mPFC in HFHS-fed rats (+33.7% to +41.3%). This finding showcases that the population of PV neurons remaining are those surrounded by PNNs, which may afford some protection against HFHS diet-induced mPFC-dysregulation. ΔFosB expression (also assessed as a measure of chronic activity and behavioral addiction marker) increased 5-10-fold (p < 0.001) in each mPFC region, supporting the hypothesis that a HFHS diet induces mPFC dysfunction and subsequent behavioural deficits. Reichelt et al. (2019) here revealed a potential neurophysiological mechanism and response to specific diet-evoked social recognition deficits as a result of hypercaloric intake in adolescence. [NPID: brain, Western-style diet, WS diet, brain plasticity, neuroplasticity, animal, animal study, HFHS]

Although there have been many studies analysing the effect of maternal consumption of a Western Diet (WD) on DNA methylation in the offspring, Yokoyama et al. (2018) point out that the impact of a WD to an individual’s DNA methylation has rarely been probed. The aim of this study was to examine how chronic dieting with WD affects DNA methylation in the frontal cortex of mice. This study explains that the frontal cortex is involved in the regulation of cognitive function and is often affected in cases of cognitive decline. This experiment fed eight-week old mice with either a control diet (CD) or a WD for 12 weeks, before they were analysed for DNA methylation. The dot blot analysis indicated there was less global DNA methylation in the WD-fed mice than the control diet mice. Bioinformatic analysis also identified several networks and pathways containing genes displaying differential methylation, particularly those involved in metabolism, cell adhesion and cytoskeleton integrity, inflammation and neurological function. To conclude, Yokoyama and her team (2018) repeated that DNA methylation in the frontal cortex of mice were altered by consuming a WD, suggesting these findings could provide possible mechanisms by which WD consumption weakens cognitive function. [NPID: brain, Western-style diet, WS diet, saturated fat, DNA methylation, frontal cortex, cognitive decline, inflammation, neurological function, cognitive function]

Li et al. had previously demonstrated that a high-fructose diet causes a hippocampal neuroinflammatory response and neuronal loss in animals, but in this study Li and the team (2019) explored the changes in gut microbiota and intestinal epithelial barrier that accompany hippocampal neuroinflammation due to the high-fructose diet. The hippocampal neuroinflammatory response, reactive gliosis and neuronal loss were all observed in the C57BL/6N mice due to the consumption of a high-fructose diet. Broad-spectrum antibiotics were used to deplete gut microbiota and suppress the inflammatory response in the hippocampus but neuronal loss was still observed. Also seen in the fructose-fed mice were gut microbiota compositional alterations, reductions in short-chain fatty acids (SCFAs), intestinal epithelial barrier impairment, NOD-like receptor family pyrin domain-containing 6 (NLRP6) inflammasome dysfunction, high levels of serum endotoxin, and FITC-dextran. The scientists noted SCFAs and pioglitazone (a selective peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist) shaped the gut microbiota and ameliorated intestinal epithelial barrier impairment and NLRP6 inflammasome dysfunction in the mice. Although SCFAs-mediated NLRP6 inflammasome activation was inhibited by histamine (a bacterial metabolite) in ex vivo colonic explants and suppressed in murine CT26 colon carcinoma cells transfected with NLRP6 siRNA, pioglitazone and GW9662 (a PPAR-γ antagonist) exerted no impact on SCFAs-mediated NLRP6 inflammasome activation in ex vivo colonic explants. This suggests SCFAs may stimulate NLRP6 inflammasome independently of PPAR-γ activation. Incidentally, SCFAs and pioglitazone prevented fructose-induced hippocampal neuroinflammatory response and neuronal loss in mice, as well as activated colonic NLRP6 inflammasome and increased DCX+ newborn neurons in the hippocampal DG of control mice. In this study Li et al. (2019) discovered that gut dysbiosis is a critical factor for a high-fructose diet-induced hippocampal neuroinflammation in C57BL/6N mice and may be mediated by impairing intestinal epithelial barrier. Moreover, SCFAs can stimulate NLRP6 inflammasome and ameliorate the impairment of intestinal epithelial barrier, resulting in the protection against a high-fructose diet-induced hippocampal neuroinflammation and neuronal loss. To conclude, the team of researchers highlighted a new intervention strategy for reducing the risk of neurodegenerative diseases through supplementation of SCFAs or dietary fiber consumption. [NPID: brain, Western-style diet, WS diet, high fructose, gut health, short-chain fatty acids, inflammation, gut microbiota, neurodegenerative disease, dietary fiber]

Stevenson et. al (2020) randomly assorted a sample of 110 healthy lean adults to either a one week western-style (WS) diet intervention or a habitual-diet control group, to examine if the rapid impairments in hippocampal function and poorer appetite control seen when animals were fed with a WS diet can be replicated in humans. Measures of hippocampal-dependent learning and memory (HDLM) and of appetitive control were obtained pre- and post-intervention, as well as at the 3-week follow up for HDLM. HDLM performance and appetite control were lower in the WS-diet group compared to the control but HDLM was indifferent at the follow up and the appetite control was found to be strongly correlated with the HDLM decline. The findings from this study indicate a WS diet can rapidly impair appetite control which could ultimately promote overeating, and also suggests a functional role of the hippocampus in appetite control in addition to providing new evidence for the adverse neurocognitive effects of a Western-Style Diet. [NPID: brain, Western-style diet, WS diet, hippocampus, appetite control, learning, memory, HDLM, hippocampal-dependent learning and memory, overeating]