Methylphenidate prevents high-fat diet (HFD)-induced learning/memory impairment in juvenile mice
Introduction
In humans, obesity impacts a variety of biobehaviors especially mood and cognition (Elias et al., 2003, Elias et al., 2005, Bruce-Keller et al., 2009, Cserjesi et al., 2009) but how obesity impairs these brain-based functions remains unclear. What is known is that intake of excess dietary fat is coupled to overnutrition which predisposes to the development of obesity and its complications (Lissner and Heitmann, 1995, Astrup, 1999). In mice, high fat diet (HFD) feeding has been extensively used to model the human diet-induced obese state (Surwit et al., 1988, Buettner et al., 2007) and, as in humans, a key outcome of mouse HFD feeding is inflammation in liver and adipose tissue (Li et al., 2008). This HFD-dependent pro-inflammatory state has been postulated to cause many of the adverse biobehaviors seen in obesity/diabesity, but brain-based inflammation caused by a HFD has been very difficult to demonstrate outside of the hypothalamus (Soczynska et al., 2011). Furthermore, cytokine-related sickness symptoms like reduced social exploration, loss of appetite with weight loss and depressive-like behaviors are not clearly seen in obese/diabese humans or rodents (Lavin et al., 2011, Soczynska et al., 2011). Therefore, mechanisms distinct from the brain-cytokine system may be responsible for the mood and cognitive dysfunctions associated with the obese state.
Previously, obesity-associated brain-based disorders were thought to be a consequence of type 2 diabetes (T2D) and, as with T2D-linked cognitive decline, take significant time to manifest often blending with age-related and/or Alzheimer-like neurodegeneration (Arvanitakis et al., 2004, Hassing et al., 2004). However, very recent studies in human adults indicate that short-term feedings of a HFD can impair attention (Edwards et al., 2011) and visual memory (Bayer-Carter et al., 2011). Furthermore, epidemiologic studies have identified childhood obesity as a risk factor for psychological maladies such as, attention deficit hyperactivity disorder (ADHD), impulsivity, depression and anxiety (Bazar et al., 2006, Cortese and Morcillo Penalver, 2010, Davis, 2010, Puder and Munsch, 2010, Smith et al., 2011). These studies have also found a negative association between childhood obesity and performance on tests of executive function and attention (Smith et al., 2011).
Common to both ADHD and the overweight/obese state is altered dopaminergic signaling in the brain. In general, brain biochemistry associated with overeating is not well understood, but in humans body mass index inversely correlates with brain dopamine 2 receptor (D2R) availability (Wang et al., 2001). In rats, a down-regulation of striatal DR2s is linked to compulsive eating and generates a phenotype similar to addiction-like neuroadaptation (Johnson and Kenny, 2010). Similarly, ADHD is allied with perturbed brain-based dopaminergic signaling in children (Nieoullon, 2002, Guxens et al., 2009). Thus, stimulants like methylphenidate which increase catecholamines in the brainstem, midbrain and cortex appear critical to the increased attention span and concentration afforded children treated for ADHD (Rapport et al., 1994, Wolraich et al., 2001). Due to the epidemiologic overlap between ADHD and the development of the childhood obese state, we examined the short-term behavioral impact of a HFD on young mice and explored the mechanism by which a HFD perturbed behavior.
Section snippets
Materials
All reagents and chemicals were purchased from Sigma–Aldrich (St. Louis, MO) except as noted. All primers were purchased from Applied Biosystems (Foster City, CA).
Animals
Animal use was conducted in accordance with Institutional Animal Care and Use Committee approved protocols at the University of Illinois. C57BL/6J male mice (3-wk old) were purchased from Jackson Laboratories (Bar Harbor, ME). IL1R1 knockout (KO) and indoleamine 2,3 dioxygenase (IDO) KO male mice were bred in house and weaned at 3 wks
HFD feeding for 1 wk causes anxiety-like behaviors and impaired memory without impacting blood glucose or body weight
Table 1 demonstrates that mice fed a HFD vs. a LFD for 2 and 3 wks had, respectively, a 35% and 54% increase in fasting blood glucose. HFD feeding for 1 wk did not impact blood glucose. After 3 wks of a HFD, mice body weights were increased 13%. At 1 wk and 2 wks, body weight was not significantly different between HFD- and LFD-fed mice. Fig. 1A shows that mice fed a HFD vs. a LFD for 1 and 3 wks had, respectively, a 200% (45.61 ± 9.04 g vs. 14.91 ± 7.15 g, p ≤ 0.01) and 86% (87.19 ± 6.35 g vs. 46.83 ± 11.12 g, p ≤
Discussion
The main findings of the study were that a 1 wk HFD feeding increased anxiety like behavior and impaired memory and learning as evidenced by increased mouse burrowing and spontaneous wheel running and decreased mouse exploration of the open quadrants of a zero maze, perfect alternations in a Y-maze and recognition of a novel object. After a 3 wk HFD feeding, mouse burrowing and novel object recognition remained increased and impaired, respectively, while immobility in the forced swim test
Role of the funding sources
This research was supported by the National Institutes of Health (DK064862, NS058525 and AA019357 to GGF) and Kraft Human Nutrition Endowed Fellowship to the Division of Nutritional Sciences (to M.M.K.).
Conflicts of interest
None declared.
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