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

Abstract

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 (1-3wks) of a high-fat diet (HFD). After 1wk 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.

Keywords: ADHD; BDNF; COMT; Catechol-O-methyltransferase; DA; DOPAC; Depressive-like behavior; Forced swim test; HFD; HPLC; HVA; IDO; IP; Indoleamine 2,3 dioxygenase; KO; LFD; MAO; Monoamine oxidase; NGF; PBS; Type 2 diabetes; WT; attention deficit/hyperactive disorder; brain derived neurotrophic factor; catechol-O-methyltransferase; dihydroxyphenylacetic acid; dopamine; high-fat diet; high-performance liquid chromatography; homovanillic acid; indoleamine 2,3 dioxygenase; intraperitoneal; knockout; low-fat diet; monoamine oxidase; nerve growth factor; phosphate buffered saline; wild type.

Figure.1. HFD feeding for 1 wk causes anxiety-like behaviors and impaired memory

Wild type mice were fed a LFD or HFD for 1 or 3 wks. (A) Burrowing behavior was measured for 30 min. Results are expressed as amount of material removed from the burrow, means ± SEM; n = 8–11. *P ≤ 0.01, **P ≤ 0.03. (B) Voluntary wheel running was measured for 24 h. Results are expressed as wheel turns, means ± SEM; n = 16. *P ≤ 0.001. (C) Exploration of an elevated zero maze was measured for 5 min. Results are expressed as time spent in the open areas of the maze, means ± SEM; n = 15–16. *P ≤ 0.05. (D) Movement during the forced swim test was measured for 5 min. Results are expressed as time spent immobile, means ± SEM; n = 16. *P ≤ 0.02. (E) Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 16. *P ≤ 0.001. (F) Exploration in a Y maze was measured for 5 min. Results are expressed as perfect alternation, means ± SEM; n = 16. *P ≤ 0.02.

Figure.1. HFD feeding for 1 wk causes anxiety-like behaviors and impaired memory

Wild type mice were fed a LFD or HFD for 1 or 3 wks. (A) Burrowing behavior was measured for 30 min. Results are expressed as amount of material removed from the burrow, means ± SEM; n = 8–11. *P ≤ 0.01, **P ≤ 0.03. (B) Voluntary wheel running was measured for 24 h. Results are expressed as wheel turns, means ± SEM; n = 16. *P ≤ 0.001. (C) Exploration of an elevated zero maze was measured for 5 min. Results are expressed as time spent in the open areas of the maze, means ± SEM; n = 15–16. *P ≤ 0.05. (D) Movement during the forced swim test was measured for 5 min. Results are expressed as time spent immobile, means ± SEM; n = 16. *P ≤ 0.02. (E) Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 16. *P ≤ 0.001. (F) Exploration in a Y maze was measured for 5 min. Results are expressed as perfect alternation, means ± SEM; n = 16. *P ≤ 0.02.

Figure.1. HFD feeding for 1 wk causes anxiety-like behaviors and impaired memory

Wild type mice were fed a LFD or HFD for 1 or 3 wks. (A) Burrowing behavior was measured for 30 min. Results are expressed as amount of material removed from the burrow, means ± SEM; n = 8–11. *P ≤ 0.01, **P ≤ 0.03. (B) Voluntary wheel running was measured for 24 h. Results are expressed as wheel turns, means ± SEM; n = 16. *P ≤ 0.001. (C) Exploration of an elevated zero maze was measured for 5 min. Results are expressed as time spent in the open areas of the maze, means ± SEM; n = 15–16. *P ≤ 0.05. (D) Movement during the forced swim test was measured for 5 min. Results are expressed as time spent immobile, means ± SEM; n = 16. *P ≤ 0.02. (E) Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 16. *P ≤ 0.001. (F) Exploration in a Y maze was measured for 5 min. Results are expressed as perfect alternation, means ± SEM; n = 16. *P ≤ 0.02.

Figure.1. HFD feeding for 1 wk causes anxiety-like behaviors and impaired memory

Wild type mice were fed a LFD or HFD for 1 or 3 wks. (A) Burrowing behavior was measured for 30 min. Results are expressed as amount of material removed from the burrow, means ± SEM; n = 8–11. *P ≤ 0.01, **P ≤ 0.03. (B) Voluntary wheel running was measured for 24 h. Results are expressed as wheel turns, means ± SEM; n = 16. *P ≤ 0.001. (C) Exploration of an elevated zero maze was measured for 5 min. Results are expressed as time spent in the open areas of the maze, means ± SEM; n = 15–16. *P ≤ 0.05. (D) Movement during the forced swim test was measured for 5 min. Results are expressed as time spent immobile, means ± SEM; n = 16. *P ≤ 0.02. (E) Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 16. *P ≤ 0.001. (F) Exploration in a Y maze was measured for 5 min. Results are expressed as perfect alternation, means ± SEM; n = 16. *P ≤ 0.02.

Figure.1. HFD feeding for 1 wk causes anxiety-like behaviors and impaired memory

Wild type mice were fed a LFD or HFD for 1 or 3 wks. (A) Burrowing behavior was measured for 30 min. Results are expressed as amount of material removed from the burrow, means ± SEM; n = 8–11. *P ≤ 0.01, **P ≤ 0.03. (B) Voluntary wheel running was measured for 24 h. Results are expressed as wheel turns, means ± SEM; n = 16. *P ≤ 0.001. (C) Exploration of an elevated zero maze was measured for 5 min. Results are expressed as time spent in the open areas of the maze, means ± SEM; n = 15–16. *P ≤ 0.05. (D) Movement during the forced swim test was measured for 5 min. Results are expressed as time spent immobile, means ± SEM; n = 16. *P ≤ 0.02. (E) Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 16. *P ≤ 0.001. (F) Exploration in a Y maze was measured for 5 min. Results are expressed as perfect alternation, means ± SEM; n = 16. *P ≤ 0.02.

Figure.1. HFD feeding for 1 wk causes anxiety-like behaviors and impaired memory

Wild type mice were fed a LFD or HFD for 1 or 3 wks. (A) Burrowing behavior was measured for 30 min. Results are expressed as amount of material removed from the burrow, means ± SEM; n = 8–11. *P ≤ 0.01, **P ≤ 0.03. (B) Voluntary wheel running was measured for 24 h. Results are expressed as wheel turns, means ± SEM; n = 16. *P ≤ 0.001. (C) Exploration of an elevated zero maze was measured for 5 min. Results are expressed as time spent in the open areas of the maze, means ± SEM; n = 15–16. *P ≤ 0.05. (D) Movement during the forced swim test was measured for 5 min. Results are expressed as time spent immobile, means ± SEM; n = 16. *P ≤ 0.02. (E) Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 16. *P ≤ 0.001. (F) Exploration in a Y maze was measured for 5 min. Results are expressed as perfect alternation, means ± SEM; n = 16. *P ≤ 0.02.

Figure.2. Switching HFD-fed mice to a LFD restores memory

Wild type mice were fed a LFD or HFD for 1 wk. After 1 wk, HFD-fed mice were switched to a LFD for 1 wk. Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 16. *P ≤ 0.001.

Figure.3. HFD-fed IDO KO mice have impaired memory

IDO KO and wild type (WT) mice were fed a LFD or HFD for 1 wk. Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 12. Bars without a common superscript are different (P < 0.05).

Figure.4. Methylphenidate corrects 1 wk HFD-dependent memory impairment

(A) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or methylphenidate (Mphen). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (B) Wild type mice were fed a LFD or HFD for 3 wks. Mice were treated with vehicle (V) or methylphenidate (Mphen). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (C) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or reboxetine (rebox). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (D) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or desipramine (desip). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05).

Figure.4. Methylphenidate corrects 1 wk HFD-dependent memory impairment

(A) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or methylphenidate (Mphen). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (B) Wild type mice were fed a LFD or HFD for 3 wks. Mice were treated with vehicle (V) or methylphenidate (Mphen). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (C) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or reboxetine (rebox). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (D) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or desipramine (desip). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05).

Figure.4. Methylphenidate corrects 1 wk HFD-dependent memory impairment

(A) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or methylphenidate (Mphen). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (B) Wild type mice were fed a LFD or HFD for 3 wks. Mice were treated with vehicle (V) or methylphenidate (Mphen). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (C) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or reboxetine (rebox). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (D) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or desipramine (desip). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05).

Figure.4. Methylphenidate corrects 1 wk HFD-dependent memory impairment

(A) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or methylphenidate (Mphen). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (B) Wild type mice were fed a LFD or HFD for 3 wks. Mice were treated with vehicle (V) or methylphenidate (Mphen). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (C) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or reboxetine (rebox). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05). (D) Wild type mice were fed a LFD or HFD for 1 wk. Mice were treated with vehicle (V) or desipramine (desip). Exploration of a familiar and novel object were measured for 5 min. Results are expressed as % investigation of the novel object compared to the familiar object, means ± SEM; n = 8. Bars without a common superscript are different (P < 0.05).