Gene Profiling Reveals a Role for Stress Hormones in the Molecular and Behavioral Response to Food Restriction

doi:10.1016/j.biopsych.2011.06.028

Biological Psychiatry

Volume 71, Issue 4, 15 February 2012, Pages 358-365

https://doi.org/10.1016/j.biopsych.2011.06.028 Get rights and content

Background

Food restriction is known to enhance learning and motivation. The neural mechanisms underlying these responses likely involve alterations in gene expression in brain regions mediating the motivation to feed.

Methods

Analysis of gene expression profiles in male C57BL/6J mice using whole-genome microarrays was completed in the medial prefrontal cortex, nucleus accumbens, ventral tegmental area, and the hypothalamus following a 5-day food restriction. Quantitative polymerase chain reaction was used to validate these findings and determine the time course of expression changes. Plasma levels of the stress hormone corticosterone (CORT) were measured by enzyme-linked immunosorbent assay. Expression changes were measured in adrenalectomized animals that underwent food restriction, as well as in animals receiving daily injections of CORT. Progressive ratio responding for food, a measure of motivated behavior, was assessed after CORT treatment in restricted and fed animals.

Results

Brief food restriction results in an upregulation of peripheral stress responsive genes in the mammalian brain. Time-course analysis demonstrated rapid and persistent expression changes in all four brain regions under study. Administration of CORT to nonrestricted animals was sufficient to induce a subset of the genes, and alterations in gene expression after food restriction were dependent on intact adrenal glands. CORT can increase the motivation to work for food only in the restricted state.

Conclusions

These data demonstrate a central role for CORT in mediating both molecular and behavioral responses to food restriction. The stress hormone-induced alterations in gene expression described here may be relevant for both adaptive and pathological responses to stress.

Section snippets

Mice

All experiments were performed on 8- to 9-week-old C57BL/6J male mice (Jackson Labs, Bar Harbor, Maine) later sacrificed at 10 to 12 weeks. Animals had ad libitum water and were on a 12-hour light–dark cycle beginning at 7 am. Four independent cohorts, fed Research Diets (New Brunswick, New Jersey) D12450B, were used in the microarray study (n = 4 arrays, n = 20 animals, pooled as discussed subsequently). Time course cohorts and the 5-day CORT cohort were fed Prolab RMH 3000 (LabDiet, St.

Food Restriction Paradigm

To investigate the gene expression changes found in selected brain regions associated with food restriction, 9-week-old C57BL/6J male mice were housed five per cage, and food intake was monitored for 7 days. Average food intake values were calculated and used to provide 75% of that amount each day to the FR group. All food manipulations occurred near the beginning of the dark cycle to minimize disruption of normal activity patterns. One cage was randomly assigned to the FR group, and the other

Discussion

These results demonstrate that brief food restriction evokes stress hormone-induced alterations in gene expression within mesocorticolimbic circuits. A microarray screen was conducted to elucidate the potential molecular mechanisms associated with food-restriction-induced behavioral plasticity. A group of genes were identified that are induced after 1 day of food restriction and were persistently upregulated after 10 days. Many of this novel set of upregulated genes were previously associated

Role of CORT

To test the role of stress hormones in mediating the observed expression changes, CORT production was ablated by removing the adrenal glands and then exposing these animals to the 5-day restriction paradigm. None of the genes identified after food restriction were upregulated in the absence of adrenal glands, suggesting that factors released from these glands are necessary to initiate these changes in gene expression. To determine further the specific role of CORT, the hormone was administered

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Archival ReportGene Profiling Reveals a Role for Stress Hormones in the Molecular and Behavioral Response to Food Restriction

Background

Methods

Results

Conclusions

Section snippets

Mice

Food Restriction Paradigm

Discussion

Role of CORT

Physiol Behav

Neuron

Neuron

Cell Metab

Physiol Behav

Brain Res Mol Brain Res

Physiol Behav

Methods

Biol Psychiatry

Immunity

J Biol Chem

J Biol Chem

J Biol Chem

Neurosci Lett

J Biol Chem

Physiol Behav

Prog Brain Res

Neuroscience

Eur J Pharmacol

Neuron

Trends Pharmacol Sci

Schedules of Reinforcement

The effect of deprivation and frequency of reinforcement on variable-interval responding

J Exp Anal Behav

Effects of hunger and male sex hormone on self-stimulation of the brain

J Comp Physiol Psychol

Food deprivation increases oral and intravenous drug intake in rats

Science

Food restriction enhances the central rewarding effect of abused drugs

J Neurosci

Leptin and the regulation of body weight in mammals

Nature

Hypothalamic response to starvation: Implications for the study of wasting disorders

Am J Physiol

Role of leptin in the neuroendocrine response to fasting

Nature

A role for melanin-concentrating hormone in the central regulation of feeding behaviour

Nature

Archival Report
Gene Profiling Reveals a Role for Stress Hormones in the Molecular and Behavioral Response to Food Restriction