Neurochemical and electrophysiological deficits in the ventral hippocampus and selective behavioral alterations caused by high-fat diet in female C57BL/6 mice
Introduction
Overweight and obesity affect all societal segments, irrespective of age, gender and ethnicity (WHO, 2000, Wang and Beydoun, 2007). Besides genetics, which play an important, but a minor role, several environmental factors, with high-fat consumption being a major one, drive the obesity epidemic (Swinburn et al., 2004). Worldwide prevalence of overweight and obesity in adults is increasing in both genders (Stevens et al., 2012). Importantly, obesity prevalence in adult American females from certain ethnic groups, i.e., African and Mexican Americans, is higher than in their male counterparts (Terrell, 2002, Kanter and Caballero, 2012).
Epidemiological and animal data have demonstrated emotional disturbances, such as anxiety and/or depression, associated with high-fat consumption and subsequent weight gain/obesity (Petry et al., 2008, Gadalla, 2009, Mizunoya et al., 2013). As it is the case with research in the biomedical field in general, including in neuroscience (Beery and Zucker, 2011), male subjects in obesity-related laboratory animal research are over-represented, i.e., (Del Rosario et al., 2012, Cone et al., 2013); information on adverse neurological effects of high-fat diet (HFD) consumption and HFD-induced obesity in females is available, i.e., (Sato et al., 2010, Balasubramanian et al., 2012), but, compared to available data in males, is rather limited. Besides using mostly males, the majority of animal studies investigating the neurological effects of HFD have done so in advanced obese phenotypes induced by long-term (6–12 months) HFD consumption (Hwang et al., 2010, Heyward et al., 2012, Karimi et al., 2013); data regarding the relatively early impact of HFD in the likely continuum of neurological deficits/dysfunctions in the face of continued HFD feeding are scarce.
HFD consumption alters brain neurochemistry in a region-specific manner (Molteni et al., 2004, Sharma et al., 2013) and this alteration might be partially responsible for the HFD-induced behavioral impairments. For example, chronic (3 months) HFD intake alters striatal and mesolimbic dopamine (DA) signaling in rodents (Davis et al., 2008, Sharma and Fulton, 2013). Besides DA, the use of selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors as anti-obese/anti-depressant agents demonstrates their important roles in regulating obesity and associated behavioral deficits (Chudasama and Bhatt, 2009).
HFD and other palatable foods also affect the hypothalamus, the prefrontal cortex (PFC) and the hippocampus (Heyward et al., 2012, Rojo et al., 2013), with hypothalamic DA playing a key role in regulating food intake (Meguid et al., 2000). Several animal studies have reported HFD-induced hypothalamic DA dysfunction, characterized by decreased DA turnover (Levin et al., 1986), increased D4 receptor mRNA expression (Huang et al., 2005) and upregulation of genes involved in the synthesis and release of DA (Lee et al., 2010). While HFD’s effects on the hypothalamus are mainly related to food intake regulation, HFD consumption also targets the hippocampus and the PFC and it affects emotional and cognitive functions. Thus, in male rodents chronically fed HFD, compromised hippocampal synaptic plasticity and cognitive deficits are observed (Stranahan et al., 2008, Valladolid-Acebes et al., 2012, Karimi et al., 2013); however, female data are limited. Besides cognition, the hippocampus also modulates anxiety and preferential roles for the dorsal hippocampus (dHIP) in spatial memory and the ventral hippocampus (vHIP) in anxiety-related behaviors have been suggested (Bannerman et al., 2004, Fanselow and Dong, 2010).
In this study, we aimed to investigate the early neurological effects caused by relatively short-term HFD intake in female C57BL/6 mice using behavioral, neurochemical and electrophysiological measures. The C57BL/6 mouse strain is the most widely used strain in neuroscience research (Kalueff and Nguyen, 2014). Importantly, compared to other strains of mice, such as SWR/J, C57BL/6 is a good model for studying human obesity as it simulates the human metabolic abnormalities (hyperinsulinemia, hyperglycemia, and hypertension) when fed ad libitum with a HFD, while not showing metabolic irregularities when fed a low-fat diet (LFD; Collins et al., 2004). Behavioral tests were conducted to evaluate the effects of HFD on: (i) motor function (open field, pole and grip strength), (ii) emotional disturbances, such as anxiety or depression (marble burying and forced swim) and (iii) cognitive changes (novel object recognition (NOR)). To investigate the HFD-induced neurochemical alterations underlying the behavioral changes (if any), levels of DA, 5-HT, NE and their metabolites were determined in multiple brain regions, namely PFC, nucleus accumbens (NAc), striatum, dHIP and vHIP that are implicated in the regulation of locomotor, emotional and/or cognitive functions. The two hippocampal zones (dorsal and ventral) were analyzed separately due to their distinct roles in memory and anxiety (Bannerman et al., 2004, Fanselow and Dong, 2010). Additionally, based on the neurochemical and behavioral data gathered after 5–6 weeks on HFD, synaptic function was evaluated in the vHIP after additional 5–6 weeks of HFD consumption.
Section snippets
Animals
Young adult female C57BL/6 mice (6–7 weeks old, Harlan, Indianapolis, IN, USA) were housed (4–5 per cage) in an environmentally controlled room (22–24 °C) with food and water available ad libitum on a 12-h light/dark cycle in Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) accredited facility throughout the study. All procedures were in accord with the latest National Institutes of Health (NIH) guidelines and were approved in advance by the Institutional Animal
Body weight, body weight gain, food intake, food efficiency, and water intake
While the initial body weights of the LFD and HFD groups were not different (P = 0.63; Table 1), HFD feeding for six (t = 4.60, df = 14) or 11–12 (t = 5.07, df = 9) weeks resulted in significantly greater weights (P < 0.001; Table 1). Similarly, six (t = 3.47, df = 14) or 11–12 (t = 4.17, df = 9) weeks on HFD resulted in significantly greater weight gains (P < 0.01; Table 1). The amount of food consumed (g/mouse/day) was not significantly different between the LFD and HFD groups during the first 6 weeks (t = 0.88, P =
Discussion
Although multiple factors are implicated in obesity’s etiology, a clear role for the environment in its rapid rise has been established (Sallis and Glanz, 2009). Among the environmental factors, increased dietary fat consumption is considered a major contributor (Swinburn et al., 2004). As previous, largely done with males, rodent studies have focused mainly on the neurological consequences of chronic HFD intake, we evaluated the effects of HFD consumption at a relatively early time point in
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
This project was supported in part with funds from the University of Georgia’s Obesity Initiative (http://obesity.ovpr.uga.edu/), and by University of Georgia Research Foundation (UGARF) and Georgia Research Alliance (GRA) start-up funds provided to DAH.
Glossary
- High-fat diet
- A diet rich in fat, especially saturated fat.
- Hyperglycemia, Hyperinsulinemia and Hypertension
- Metabolic conditions that are associated with obesity, characterized by abnormally high circulating levels of glucose, insulin and increased blood pressure, respectively.
- Low-fat diet
- A diet that is low in saturated fat.
- Obesity
- A condition characterized by excess body adiposity and is measured in terms of body mass index (BMI, a measure of adiposity based on height and weight); a BMI score of
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