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Alachkar, A.

Publications and source records attributed to Alachkar, A..

2 recordsLinked to original sources
bioRxiv2021

Intergenerational Stress Transmission is Associated with Brain Metabotranscriptome Remodeling andMitochondrial Dysfunction

Intergenerational stress increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational stress transmission is a consequence of in utero neurodevelopmental disruptions vs early-life mother-infant interaction is largely unknown. Here, we demonstrated that exposure to traumatic stress in mice during pregnancy, through predator scent exposure, induces in the offspring social deficits and depressive-like behavior. We found, through cross-fostering experiments, that raising of normal pups by traumatized mothers produced a similar behavioral phenotype to that induced in pups raised by their biological traumatized mothers. Good caregiving (by non-traumatized mothers), however, did not completely protect against the prenatal trauma-induced behavioral deficits. These findings support a two-hit stress mechanism of both in utero and early-life parenting (poor caregiving by the traumatized mothers) environments. Associated with the behavioral deficits, we found profound changes in brain metabolomics and transcriptomic (metabotranscriptome). Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid, in the brains of neonatal and adult pups whose mothers were exposed to stress during pregnancy, indicated mitochondrial metabolism dysfunctions and epigenetic mechanisms. Bioinformatic analyses revealed mechanisms involving stress- and hypoxia-response metabolic pathways in the brains of the neonatal mice, which appear to lead to long-lasting alterations in mitochondrial-energy metabolism, and epigenetic processes pertaining to DNA and chromatin modifications. Most strikingly, we demonstrated that an early pharmacological intervention that can correct mitochondria metabolism - lipid metabolism and epigenetic modifications with acetyl-L-carnitine (ALCAR) supplementation - produces long-lasting protection against the behavioral deficits associated with intergenerational transmission of traumatic stress. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/438868v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1fb2500org.highwire.dtl.DTLVardef@13a5c6forg.highwire.dtl.DTLVardef@8aa512org.highwire.dtl.DTLVardef@5b6906_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗
bioRxiv2021

Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic and Chemogenic Manipulations

The melanin concentrating hormone (MCH) system is involved in numerous functions including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. MCH acts on a G protein-coupled receptor MCHR1, which expresses ubiquitously in the brain and localizes to neuronal primary cilia. Cilia act as cells antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in-vivo. In the current work, we examined the effects of the activation and inactivation of MCH system on cilia lengths by using different methodologies, including pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation, or indirectly through optogenetic and chemogenetic- mediated excitation of MCH neurons, causes cilia shortening. Contrarily, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induces cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions, and implicate cilia MCHR1 as a potential therapeutic target for the treatment of pathological conditions characterized by impaired cilia function.

molecular biology↗