Does activation of midbrain dopamine neurons promote or reduce feeding?

BACKGROUND: Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced DA activity. On the other hand, psychostimulant drugs that increase DA signalling suppress food intake. This poses the questions of how endogenous DA neuronal activity regulates feeding, and whether enhancing DA neuronal activity would either promote or reduce food intake. METHODS: Here, we used designer receptors exclusively activated by designer drugs (DREADD) technology to determine the effects of enhancing DA neuronal activity on feeding behaviour. We chemogenetically activated selective midbrain DA neuronal subpopulations and assessed the effects on feeding microstructure in rats. RESULTS: Treatment with the psychostimulant drug amphetamine or the selective DA reuptake inhibitor GBR 12909 significantly suppressed food intake. Selective chemogenetic activation of DA neurons in the ventral tegmental area (VTA) was found to reduce meal size, but had less impact on total food intake. Targeting distinct VTA neuronal pathways revealed that specific activation of the mesolimbic pathway towards nucleus accumbens (NAc) resulted in smaller and shorter meals. In addition, the meal frequency was increased, rendering total food intake unaffected. The disrupted feeding patterns following activation of VTA DA neurons or VTA to NAc projection neurons were accompanied by locomotor hyperactivity. Activation of VTA neurons projecting towards prefrontal cortex or amygdala, or of DA neurons in the substantia nigra, did not affect feeding behaviour. CONCLUSIONS: Chemogenetic activation of VTA DA neurons or VTA to NAc pathway disrupts feeding patterns. Increased activity of mesolimbic DA neurons appears to both promote and reduce food intake, by facilitating both the initiation and cessation of feeding behaviou

Expression Profiling after Prolonged Experimental Febrile Seizures in Mice Suggests Structural Remodeling in the Hippocampus

Febrile seizures are the most prevalent type of seizures among children up to 5 years of age (2-4% of Western-European children). Complex febrile seizures are associated with an increased risk to develop temporal lobe epilepsy. To investigate short- and long-term effects of experimental febrile seizures (eFS), we induced eFS in highly febrile convulsion-susceptible C57BL/6J mice at post-natal day 10 by exposure to hyperthermia (HT) and compared them to normotherm-exposed (NT) mice. We detected structural re-organization in the hippocampus 14 days after eFS. To identify molecular candidates, which entrain this structural re-organization, we investigated temporal changes in mRNA expression profiles eFS 1 hour to 56 days after eFS. We identified 931 regulated genes and profiled several candidates using in situ hybridization and histology at 3 and 14 days after eFS. This is the first study to report genome-wide transcriptome analysis after eFS in mice. We identify temporal regulation of multiple processes, such as stress-, immune- and inflammatory responses, glia activation, glutamate-glutamine cycle and myelination. Identification of the short- and long-term changes after eFS is important to elucidate the mechanisms contributing to epileptogenesis

Timed regulation of biological processes after eFS.

<p>Bar blackness indicates the peak effect of the process. P10: postnatal day 10, 1H: 1 hour post-eFS, 3D: 3 days post-eFS, 14D: 14 days post-eFS, 56D: 56 days post-eFS, Glu/Gln cycle: glutamate/glutamine cycle.</p

Hierarchical clustering analysis of mRNA expression after eFS.

<p>Hierarchical clustering analysis of differentially expressed genes (930) in all experimental littermate couples (1 hour, 3 and 14 days post-eFS). Rows depict differential expression levels per HT/NT littermate couple, per time-point after eFS. Clustering was performed based on gene and sample clustering using Pearson correlation on average linkage. Tree cluster, right from heat-map, shows hierarchical distance between samples from the different time points. Differential gene expression (log2(Fc) between HT/NT littermate couples is shown in the heatmap as upregulated (red), downregulated (green), or no change (white) according to colored-scale bar.</p

Expression of candidate genes mRNA related to structural reorganization.

<p>(A, C, E, G) Representative images of <i>Nrxn1</i>, <i>Dpysl3</i>, <i>Ptprd</i>, and <i>Slit2</i> gene expression in the hippocampus of NT (left panel) and HT (right panel) animals three days after eFS. (B, D, F, H) Comparison of <i>Nrxn1</i>, <i>Dpysl3</i>, <i>Ptprd</i>, and <i>Slit2</i> gene expression levels in subfields of the hippocampus in HT (<i>n</i> = 9, red bars) animals compared to NT (<i>n</i> = 9, blue bars) littermates. <i>Ptprd</i> is upregulated in the CA2 subfield of the hippocampus of HT animals, * indicates a significant difference of <i>P</i> = 0.0097, littermate-paired Student’s t-test. Bars represents mean ± standard error of the mean. Scalebars in panel A, C, E, and G: 500μm.</p

Validation of microarray results by qPCR analysis.

<p>Gene expression levels as determined by qPCR (Rn) in normothermic (NT) and hyperthermic (HT) animals compared to fold-change in expression of 5 genes as detected by microarray analysis (Rm). <i>P</i> < 0.05 was considered significant (one-tailed Student’s t-test). Indicated are mean ± standard error of the mean.</p

Hyperthermia induces upregulation of neurofilament protein-expression.

<p>(A) Neurofilament (NF) immunostaining in the hippocampus of a normothermic (NT) control animal, 14 days post-hyperthermia exposure. Square marks subfield enlargement; panel B. (B) Immunostaining for NF in the stratum lucidum of NT control animal (left panel) and in hyperthermia-exposed (HT) littermate (right panel). (C) Comparison of NF-based DAB staining in the stratum lucidum between NT and HT littermates. All HT (<i>n</i> = 10) animals showed increased DAB-staining in the stratum lucidum. Pair-wise comparison of DAB-staining intensities showed increased NF expression in HT animals compared to NT littermates (<i>n</i> = 10), Wilcoxon signed-rank test, * indicates a significance of <i>P</i> = 0.0049. Tukey-style box plots. Scalebars: 100 μm.</p