Chronic high fat diet consumption impairs sensorimotor gating in mice

Summary

Chronic intake of high fat diets (HFD) has been long recognized to induce neuronal adaptations and impair elementary cognitive functions. Yet, the consequences of chronic HFD consumption on central information processing remain elusive. The present study thus explored the impact of chronic HFD consumption on pre-attentive central information processing using the paradigm of prepulse inhibition (PPI) of the acoustic startle reflex in mice. Animals were fed an experimental diet with 60% of its calories derived from fat, and were compared to control low fat diet (LFD, 10% calories from fat) fed animals. A first experimental series demonstrated that adult mice exposed to chronic HFD throughout adolescent development displayed significant deficits in PPI compared to LFD-fed mice. Identical chronic HFD treatment further led to presynaptic dopaminergic abnormalities in the form of increased tyrosine hydroxylase density in the nucleus accumbens core and shell subregions. Moreover, we found that tyrosine hydroxylase density in the nucleus accumbens shell negatively correlated with the mean PPI scores, suggesting a potential contribution of the accumbal dopamine system to HFD-induced PPI deficits. This impression was further supported by an additional series of experiments showing that the HFD-induced attenuation of PPI can be mitigated by systemic administration of the dopamine receptor antagonist haloperidol. Finally, HFD feeding was sufficient to disrupt PPI when its exposure was restricted to the peripubertal period, whilst the same manipulation failed to affect PPI when limited to adulthood. In conclusion, our findings emphasize that pre-attentive information processing as assessed by the PPI paradigm is highly sensitive to nutritional factors in the form of chronic HFD consumption, especially when initiated during peripubertal maturation. It is likely that the disrupting effects of HFD on sensorimotor gating involve, at least in part, dopaminergic mechanisms.

Introduction

Chronic intake of high fat diets (HFD) is strongly associated with the development of a number of metabolic disturbances, including obesity, type-2 diabetes, and cardiovascular disease (Hu et al., 2001). Converging evidence from experimental work in animals and clinical investigations in humans indicates that excessive consumption of such “Western diets” can also lead to neuronal adaptations and impair elementary cognitive functions (Francis and Stevenson, 2013). Dietary effects on the hippocampus and prefrontal cortex have received wide appreciation in this context because cognitive performance critically depends on the integrity of these brain areas (Kanoski et al., 2007, Kanoski and Davidson, 2011). Owing to its negative impact on brain functions, chronic HFD intake has also been associated with an elevated risk of neurological disorders that are characterized by (progressive) cognitive impairments, most notably Alzheimer's Disease (AD) and other forms of dementias in aging (Hildreth et al., 2012).

In the present study, we set out to explore the impact of chronic HFD consumption on pre-attentive central information processing using the paradigm of prepulse inhibition (PPI) of the acoustic startle reflex. PPI refers to the reduction of the startle reaction to a startle-eliciting stimulus (pulse) when it is shortly preceded by a weak stimulus (prepulse) (Hoffman and Searle, 1965, Graham, 1975). PPI is an operational measure of sensorimotor gating, in which central gating mechanisms protect the processing of the information contained in the initial prepulse from distraction by the subsequent pulse stimulus (Swerdlow et al., 2000). PPI thus reflects the ability to filter or gate intrusive sensory-motor information, and this phenomenon can be readily demonstrated in a variety of species, including humans and rodents (Swerdlow et al., 1999).

A direct association between excessive intake of dietary fat and abnormalities in sensorimotor gating has thus far not been established. However, this possibility seems likely given some findings linking metabolic disturbances to PPI attenuation. First, significant PPI deficits have been reported in db/db mice, which harbor an autosomal recessive point mutation in the leptin receptor gene and are characterized by multiple metabolic dysfunctions, including hyperphagia, progressive hyperglycemia, and obesity (Sharma et al., 2010). Second, an indirect link between hyperphagia, excess fat deposition, and emergence of PPI deficits has also been established in an inflammation-mediated developmental pathogenesis model in mice (Pacheco-López et al., 2013). Deficits in PPI are also commonly (but not exclusively) observed in patients with schizophrenia (Braff et al., 2001), a chronic mental illness characterized by widespread psychopathological symptoms. Schizophrenic patients often display metabolic disturbances even prior to the initiation of chronic antipsychotic medication (Thakore et al., 2002, Verma et al., 2009, Kirkpatrick et al., 2012) and are frequently reported to consume saturated fat diets more excessively than healthy controls (reviewed in Dipasquale et al., 2013). Yet, the extent to which excessive HFD intake in this clinical population may actually contribute to the emergence of psychopathological symptoms such as PPI deficiency remains elusive.

These considerations prompted us to seek evidence for a possible causal relationship between chronic HFD consumption and sensorimotor gating dysfunctions in mice. To mimic chronic HFD intake, animals were fed an experimental diet with 60% of its calories derived from fat, whereas control low fat diet (LFD) animals were fed a diet with only 10% of its calories from fat. First, we compared the effects of chronic HFD or LFD feeding given throughout adolescent development on PPI in adulthood. In animal models, cognitive effects of chronic HFD exposure have mostly been studied following a dietary intervention restricted to adulthood (Winocur and Greenwood, 2005). Recent findings suggest that chronic HFD exposure during peripubertal development may exert a more extensive negative impact on cognitive functions compared to identical dietary exposure in adulthood (Boitard et al., 2012). To target both (and perhaps equally important) stages of maturation, our first series of investigations included HFD exposure throughout adolescent development covering both peripubertal and adult stages. We also correlated PPI scores in HFD and LFD animals with presynaptic dopamine-related changes in dorsal and ventral striatal regions based on the well-established functional role of the striatal dopamine system in sensorimotor gating (Swerdlow et al., 1992, Swerdlow et al., 1994). In addition, we determined whether the dopamine receptor antagonist haloperidol (HAL) might be effective in mitigating the anticipated disrupting effects of HFD on PPI. Finally, we also performed a direct examination of whether the impact of chronic HFD consumption on sensorimotor gating might be influenced by the precise timing of post-weaning diet exposures (Boitard et al., 2012). This was achieved by exposing mice to HFD or LFD diets specifically during the peri-pubertal or the adult period before assessment of sensorimotor gating functions.