Inactivation of the melanin concentrating hormone system impairs maternal behavior

Zhiwei Wang,Olivier Civelli,Nayna Sanathara,Kara Onouye,Lamees Alhassen,Amal Alachkar,Lien Wang

doi:10.1016/j.euroneuro.2016.08.014

Zhiwei Wang, Olivier Civelli + Show 5 more

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https://doi.org/10.1016/j.euroneuro.2016.08.014

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Abstract

In order to prepare the mother for the demands of pregnancy and lactation, the maternal brain is subjected to a number of adaptations. Maternal behaviors are regulated by complex neuronal interactions. Here, we show that the melanin concentrating hormone (MCH) system is an important regulator of maternal behaviors.First, we report that melanin concentrating hormone receptor 1 knockout (MCHR1 KO) mice display a disruption of maternal behavior. Early postpartum MCHR1 KO females exhibit poor nesting, deficits in pup retrieval and maternal aggression. In addition, ablation of MCH receptors results in decreased milk production and prolactin mRNA levels. Then we show that these results are in line with those obtained in wild type mice (WT) treated with the specific MCHR1 antagonist GW803430. Furthermore, following pups retrieval, MCHR1 KO mice display a lower level of Fos expression than WT mice in the ventral tegmental area, and nucleus accumbens. With the progression of the lactation period, however, the MCHR1 KO mice improve maternal care towards their pups. This is manifested by an increase in the pups׳ survival rate and the decrease in pups׳ retrieval time beyond the second day after parturition.In conclusion, we show that the MCH system plays a significant role in the initiation of maternal behavior. In this context, MCH may play a role in integrating information from multiple sources, and connecting brain reward, homeostatic and regulatory systems.

Highlights

Introduction lMethionine, an essential amino acid, is required for the generation of S-adenosylmethionine (SAM), the primary methyl donor in almost all methylation reactions
Positive Symptoms MET-treated mice exhibited a 2-fold increase in their locomotor activity, indicated by the increase in total distance that they travelled (P < .01; Figure 2A). They displayed a greater level of stereotypic behaviors (P < .05; Figure 2B). These results suggest that MET-treated mice are hyperactive and display behavioral phenotypes that are related to the positive symptoms of schizophrenia
The transmethylation hypothesis of schizophrenia had proposed that abnormal methylated metabolites of dopamine, noradrenaline, and serotonin might be responsible for the psychotic symptoms (Osmond and Smythies, 1952)

Summary

Introduction

Introduction lMethionine, an essential amino acid, is required for the generation of S-adenosylmethionine (SAM), the primary methyl donor in almost all methylation reactions. A chronic dietary deficit of methionine lowers the concentration of SAM and reduces methylation of DNA cytosine in Received: March 2, 2015; Revised: May 1, 2015; Accepted: May 11, 2015 Results:We found that this treatment induces behavioral responses that reflect the 3 types of schizophrenia-like symptoms (positive, negative, or cognitive deficits) as monitored in a battery of behavioral assays (locomotion, stereotypy, social interaction, forced swimming, prepulse inhibition, novel object recognition, and inhibitory avoidance). These responses were differentially reversed by typical haloperidol and atypical clozapine antipsychotics in ways that parallel their effects in schizophrenics. Our model relies on an essential natural amino acid and on an intervention that is relatively simple and time effective and may offer an additional tool for assessing novel antipsychotics

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