An excessive intake of sugar affect brain function


There has been a remarkable increase in intake of simple sugar (sucrose, isomerized sugar (corn syrup) from beverages and diets in modern society. The intake of simple sugars in adolescents, in whom mental disorders frequently occur, is higher than any other generations.

Moreover, patients with mental disorders consume approximately 2-fold more sugar than age-matched healthy individuals, and patients with schizophrenia who consume more sucrose exhibit more severe symptoms.

Despite accumulating evidence, it is still unproven that excessive sugar intake contributes to the pathogenesis of psychiatric disorders among susceptible individuals. Doesn’t an excessive intake of simple sugar affect higher brain function? Researchers have attempted to elucidate this causal relationship.

As a susceptibility gene for psychiatric disorder, the researchers selected Glyoxylase-1 and Disrupted-in-schizophrenia-1. By combining the heterozygous mice with environmental factors of excessive sugar intake at the age of puberty, they successfully created a novel mouse model exhibiting various mental disorder-like symptoms, including decreased sensorimotor gating function, decreased working memory, hyperactivity, abnormal gamma-band component in EEG.

In other words, this demonstrates a possibility that the excessive intake of simple sugar at the age of puberty could be an environmental risk factor of psychiatric disorders.

Furthermore, by analyzing this model mouse, the team aimed to identify the new phenotypes and mechanisms of developing mental disorder. They found “cerebral microvascular angiopathy.”

In order to verify the generality of this finding, they used a post-mortem brain from patients with schizophrenia and bipolar disorder, and identified angiopathy similar to the one seen in the model mice. They also found that the angiopathy was accompanied by an impaired glucose incorporation to brain parenchyma in their mice model.

These phenotypes were prevented by continuous administration of non-steroidal anti-inflammatory drugs (NSAIDs) before the onset of the disease, and some psychiatric-like symptoms were also suppressed. Notably, the patients used in this study did not necessarily have a record of excessive sucrose intake.

They developed psychiatric disorders under various stress circumstances, suggesting that psychiatric disorders are associated with angiopathy in the brain caused by various environmental stresses, including metabolic stress.

The concept of “sugar addiction” and the classification of sugar as a substance of abuse are still debated. There is, however, increasing evidence of overlap in the brain circuitry and molecular signaling pathways involved in sugar consumption and drug abuse (for recent review see Jacques et al., 2019). Humans consume sugar and food to regulate homeostatic energy balance, but also for pleasure and comfort.

This hedonistic desire for palatable food is reward-driven and overeating may result in maladaptive/negative neuroplasticity that overrides homeostatic regulation (Kenny, 2011). In humans, sugar and sweetness can induce dopamine release, reward and craving that are comparable in magnitude to those induced by addictive drugs, suggesting that sugar changes brain reward signaling and circuitry similar to other drugs of abuse (Avena and Hoebel, 2003b; Rada et al., 2005; Lenoir et al., 2007; Klenowski et al., 2016; Shariff et al., 2016, 2017).

High sugar and/or high fat diets have been shown to precipitate addiction-like psychiatric phenotypes in a number of rodent studies (Avena et al., 2009; Avena, 2010; Criscitelli and Avena, 2016). In rats, intermittent consumption of 10% (w/v) sucrose or 25% (w/v) glucose solution) elicits hallmark signs of addictive behavior such as binging, tolerance, craving (Rada et al., 2005), cross-sensitization (Avena and Hoebel, 2003b) and symptoms of withdrawal (Colantuoni et al., 2002; Avena et al., 2008) such as anxiety-(Colantuoni et al., 2002; Avena et al., 2008; Parylak et al., 2012; Eudave et al., 2018; Gueye et al., 2018; Xu and Reichelt, 2018) and depressive-like behaviors (Vollmayr et al., 2004; Iemolo et al., 2012; Harrell et al., 2015; Santos et al., 2018).

In addition, sugar consumption has been shown to increase reward seeking, impulsivity to feed and compulsivity in rats willing to endure noxious stimuli such as extreme cold, heat and foot-shock to procure sugar and highly palatable foods (Cabanac and Johnson, 1983; Avena et al., 2005; Foo and Mason, 2005; Oswald et al., 2011). Interestingly, rats are also more resilient to foot shock punishments when seeking for palatable food compared to methamphetamine (Krasnova et al., 2014).

Increasing evidence shows that unrestricted consumption of high-sugar food and beverages within the Western Diet might be linked to the increased obesity epidemic (Stanhope, 2016; Johnson et al., 2017; Freeman et al., 2018; Yoshida and Simoes, 2018; Sigala and Stanhope, 2021). A strong association between attention-deficits/hyperactivity disorders (ADHD) and overweight/obesity have further been revealed (Altfas, 2002; Strimas et al., 2008; Cortese et al., 2016; Cortese, 2019).

Taken together, these data suggest that sugar-induced obesity may participate to the developing pathogenesis of ADHD-like symptoms in western countries. In children, high sugar consumption correlates with hyperactivity (Kim and Chang, 2011) and in adults, with inattention and impulsivity (Li et al., 2020). However, some inconsistencies remain regarding the potential correlation (Yu et al., 2016; Farsad-Naeimi et al., 2020) or not (Del-Ponte et al., 2019) with ADHD (Johnson et al., 2011; Paglia, 2019).

In rodents, high-sucrose consumption also impairs neurocognitive functions such as spatial learning, object recognition, behavioral inhibition and fear-memory (Kendig, 2014; Reichelt et al., 2015; Kruse et al., 2019; Spoelma and Boakes, 2021). Interestingly, high sucrose intake during pregnancy elicits ADHD-like behavioral phenotypes in mice offspring, with increased locomotor activity, reduced attention/learning and impulsivity (Choi et al., 2015).

Anxiety, depression, and cognitive deficits are strongly associated with impaired hippocampal neurogenesis in animal models, although evidence for a causative relationship is often lacking. Indeed, anxiety and spatial memory deficits elicited by long-term consumption of sucrose are accompanied by alterations in hippocampal neurogenesis and physiology (Molteni et al., 2002; Stranahan et al., 2008; van der Borght et al., 2011; Lemos et al., 2016; Reichelt et al., 2016). While drugs of abuse such as ethanol are known to negatively affect neurogenesis, the effect of high levels of sugar consumption requires further characterization since link between neurogenesis to anxiety and depression has not been fully explored (Xu and Reichelt, 2018).

Sucrose became embedded in modern food and beverages, and the aforementioned studies suggest that sugar overconsumption satisfies all criteria for the classification of sugar as a drug of abuse, with its chronic abuse proposed to produce overweight, locomotor, emotional and cognitive impairments.

However, it remains unclear whether a lifetime of chronic overconsumption of sucrose, starting at adolescence, affects locomotor behavior, emotions and cognition through adulthood. Therefore, we used a mouse model of long-term intake of sucrose to determine the effects on locomotion, anxiety, memory, and hippocampal neurogenesis.

Our results show for the first time that long-term consumption of sucrose leads to significant weight gain and produces persistent hyperactivity and learning impairments, correlated to reduced hippocampal neurogenesis in adult mice. These results suggest that long-term sugar intake in the Western Diet might play a role in the pathogenesis of attention deficits and hyperactivity-related disorders.

reference link :

More information: Shinobu Hirai et al, High-sucrose diets contribute to brain angiopathy with impaired glucose uptake and psychosis-related higher brain dysfunctions in mice, Science Advances (2021). DOI: 10.1126/sciadv.abl6077


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