Elsevier

Psychoneuroendocrinology

Volume 38, Issue 9, September 2013, Pages 1553-1564
Psychoneuroendocrinology

Methylphenidate prevents high-fat diet (HFD)-induced learning/memory impairment in juvenile mice

https://doi.org/10.1016/j.psyneuen.2013.01.004Get rights and content

Summary

The prevalence of childhood obesity has risen dramatically and coincident with this upsurge is a growth in adverse childhood psychological conditions including impulsivity, depression, anxiety and attention deficit/hyperactive disorder (ADHD). Due to confounds that exist when determining causality of childhood behavioral perturbations, controversy remains as to whether overnutrition and/or childhood obesity is important. Therefore, we examined juvenile mice to determine if biobehaviors were impacted by a short-term feeding (1–3 wks) of a high-fat diet (HFD). After 1 wk of a HFD feeding, mouse burrowing and spontaneous wheel running were increased while mouse exploration of the open quadrants of a zero maze, perfect alternations in a Y-maze and recognition of a novel object were impaired. Examination of mouse cortex, hippocampus and hypothalamus for dopamine and its metabolites demonstrated increased homovanillic acid (HVA) concentrations in the hippocampus and cortex that were associated with decreased cortical BDNF gene expression. In contrast, pro-inflammatory cytokine gene transcripts and serum IL-1α, IL-1β, TNF-α and IL-6 were unaffected by the short-term HFD feeding. Administration to mice of the psychostimulant methylphenidate prevented HFD-dependent impairment of learning/memory. HFD learning/memory impairment was not inhibited by the anti-depressants desipramine or reboxetine nor was it blocked in IDO or IL-1R1 knockout mice. In sum, a HFD rapidly impacts dopamine metabolism in the brain appearing to trigger anxiety-like behaviors and learning/memory impairments prior to the onset of weight gain and/or pre-diabetes. Thus, overnutrition due to fats may be central to childhood psychological perturbations such as anxiety and ADHD.

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.

References (54)

  • M.D. Rapport et al.

    Attention deficit disorder and methylphenidate: normalization rates, clinical effectiveness, and response prediction in 76 children

    J. Am. Acad. Child Adolesc. Psychiatry

    (1994)
  • C.M. Sherwin et al.

    Studies on the motivation for burrowing by laboratory mice

    Appl. Anim. Behav. Sci.

    (2004)
  • G.J. Wang et al.

    Brain dopamine and obesity

    Lancet

    (2001)
  • R. Yirmiya et al.

    Immune modulation of learning, memory, neural plasticity and neurogenesis

    Brain Behav. Immun.

    (2011)
  • J.M. York et al.

    Individually ventilated cages cause chronic low-grade hypoxia impacting mice hematologically and behaviorally

    Brain Behav. Immun.

    (2012)
  • C.A. Altar et al.

    Brain-derived neurotrophic factor augments rotational behavior and nigrostriatal dopamine turnover in vivo

    Proc. Natl. Acad. Sci. U.S.A.

    (1992)
  • A.F. Arnsten et al.

    Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: relevance to therapeutic effects in attention deficit hyperactivity disorder

    Behav. Brain Funct.

    (2005)
  • Z. Arvanitakis et al.

    Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function

    Arch. Neurol.

    (2004)
  • A. Astrup

    Macronutrient balances and obesity: the role of diet and physical activity

    Public Health Nutr.

    (1999)
  • J.L. Bayer-Carter et al.

    Diet intervention and cerebrospinal fluid biomarkers in amnestic mild cognitive impairment

    Arch. Neurol.

    (2011)
  • G. Brandacher et al.

    Chronic immune activation underlies morbid obesity: is IDO a key player?

    Curr. Drug Metab.

    (2007)
  • N.J. Broadbent et al.

    Spatial memory, recognition memory, and the hippocampus

    Proc. Natl. Acad. Sci. U.S.A.

    (2004)
  • R. Buettner et al.

    High-fat diets: modeling the metabolic disorders of human obesity in rodents

    Obesity (Silver Spring)

    (2007)
  • S. Cortese et al.

    Comorbidity between ADHD and obesity: exploring shared mechanisms and clinical implications

    Postgrad. Med.

    (2010)
  • R. Dantzer et al.

    From inflammation to sickness and depression: when the immune system subjugates the brain

    Nat. Rev. Neurosci.

    (2008)
  • C. Davis

    Attention-deficit/hyperactivity disorder: associations with overeating and obesity

    Curr. Psychiatry Rep.

    (2010)
  • R.M. Deacon

    Burrowing in rodents: a sensitive method for detecting behavioral dysfunction

    Nat. Protoc.

    (2006)
  • Cited by (99)

    View all citing articles on Scopus
    View full text