Volumetric MRI scans from 26 women with repeated episodes of childhood sexual abuse (CSA), and 17 healthy women (18-22 years) were analyzed for sensitive periods effects on hippocampal and amydgala volume, frontal cortex gray matter volume and corpus callosum area. Hipppocampal volume was reduced in association with CSA at 3-5 years (β=−0.69, p<0.0001) and 11-13 years (β=−0.25, p<0.05). Corpus callosum was reduced with CSA at 9-10 years (β= −0.44, p<0.005), and frontal cortex was attenuated in subjects with CSA at ages 14-16 (β=−0.48, p<0.005). Brain regions have unique windows of vulnerability to the effects of traumatic stress.

The accumulation of damaged mitochondria has been proposed as a key factor in aging and the pathogenesis of many common agerelated diseases, including Parkinson disease (PD). Recently, in vitro studies of the PD-related proteins Parkin and PINK1 have found that these factors act in a common pathway to promote the selective autophagic degradation of damaged mitochondria (mitophagy). However, whether Parkin and PINK1 promote mitophagy under normal physiological conditions in vivo is unknown. To address this question, we used a proteomic approach in Drosophila to compare the rates of mitochondrial protein turnover in parkin mutants, PINK1 mutants, and control flies. We found that parkin null mutants showed a significant overall slowing of mitochondrial protein turnover, similar to but less severe than the slowing seen in autophagydeficient Atg7 mutants, consistent with the model that Parkin acts upstream of Atg7 to promote mitophagy. By contrast, the turnover of many mitochondrial respiratory chain (RC) subunits showed greater impairment in parkin than Atg7 mutants, and RC turnover was also selectively impaired in PINK1 mutants. Our findings show that the PINK1-Parkin pathway promotes mitophagy in vivo and, unexpectedly, also promotes selective turnover of mitochondrial RC subunits. Failure to degrade damaged RC proteins could account for the RC deficits seen in many PD patients and may play an important role in PD pathogenesis. U nderstanding the mechanisms of mitochondrial quality control is a critical challenge in research on neurodegeneration and aging. The accumulation of damaged mitochondria has been linked to normal aging and multiple age-related disorders, including Alzheimer's disease, diabetes, and Parkinson disease (PD) (1, 2). Recent research points to two PD-associated proteins as essential mediators of selective autophagic mitochondrial degradation: phosphatase and tensin homolog-induced putative kinase 1 (PINK1), a mitochondrially targeted serine/threonine kinase, and Parkin, a cytosolic E3 ubiquitin ligase. Genetic studies in Drosophila determined that PINK1 acts upstream of Parkin in a common pathway to regulate mitochondrial morphology and integrity (3-8), and led to the hypothesis that this pathway promotes the selective degradation of damaged mitochondria (6, 9). Subsequent experiments, primarily in cultured cells, validated this hypothesis and described the mechanism of action of the pathway (10-12). These studies showed that loss of mitochondrial membrane potential (depolarization) leads to accumulation of PINK1 on the mitochondrial outer membrane, which triggers recruitment of Parkin to the mitochondria. Parkin then ubiquitinates proteins in the outer mitochondrial membrane (13-17), leading to autophagic degradation of the dysfunctional mitochondrion.Although there is substantial support for the role of the PINK1-Parkin pathway in selective mitochondrial degradation, it is still not clear that this pathway promotes mitochondrial degradation in vivo. PINK1-Parkin-dependent mitophagy has been d...

Loss-of-function mutations in the PINK1 or parkin genes result in recessive heritable forms of parkinsonism. Genetic studies of Drosophila orthologs of PINK1 and parkin indicate that PINK1, a mitochondrially targeted serine/threonine kinase, acts upstream of Parkin, a cytosolic ubiquitin-protein ligase, to promote mitochondrial fragmentation, although the molecular mechanisms by which the PINK1/Parkin pathway promotes mitochondrial fragmentation are unknown. We tested the hypothesis that PINK1 and Parkin promote mitochondrial fragmentation by targeting core components of the mitochondrial morphogenesis machinery for ubiquitination. We report that the steady-state abundance of the mitochondrial fusion-promoting factor Mitofusin (dMfn) is inversely correlated with the activity of PINK1 and Parkin in Drosophila. We further report that dMfn is ubiquitinated in a PINK1- and Parkin-dependent fashion and that dMfn co-immunoprecipitates with Parkin. By contrast, perturbations of PINK1 or Parkin did not influence the steady-state abundance of the mitochondrial fission-promoting factor Drp1 or the mitochondrial fusion-promoting factor Opa1, or the subcellular distribution of Drp1. Our findings suggest that dMfn is a direct substrate of the PINK1/Parkin pathway and that the mitochondrial morphological alterations and tissue degeneration phenotypes that derive from mutations in PINK1 and parkin result at least in part from reduced ubiquitin-mediated turnover of dMfn.

Volumetric MRI scans from 26 women with repeated episodes of childhood sexual abuse (CSA), and 17 healthy women (18-22 years) were analyzed for sensitive periods effects on hippocampal and amydgala volume, frontal cortex gray matter volume and corpus callosum area. Hipppocampal volume was reduced in association with CSA at 3-5 years (β=−0.69, p<0.0001) and 11-13 years (β=−0.25, p<0.05). Corpus callosum was reduced with CSA at 9-10 years (β= −0.44, p<0.005), and frontal cortex was attenuated in subjects with CSA at ages 14-16 (β=−0.48, p<0.005). Brain regions have unique windows of vulnerability to the effects of traumatic stress.

Although the effects of psychostimulants on brain dopamine systems are well recognized, the direct actions of cocaine on serotonin systems also appear to be important to its addictive properties. For example, serotonin actions at 5-HT1B receptors in the ventral tegmental area (VTA) modulate cocaine-induced dopamine release in the nucleus accumbens (NAcc) and alter the rewarding and stimulant properties of cocaine. However, the mechanisms of these effects have been unclear, because several neuron types in VTA express 5-HT1B receptors. One possibility is that 5-HT1B receptors on the terminals of GABAergic projections from NAcc to VTA inhibit local GABA release, thereby disinhibiting VTA neurons. We tested this hypothesis directly by using viral-mediated gene transfer to overexpress 5-HT1B receptors in NAcc projections to VTA. A viral vector containing either epitope hemagglutinin-tagged 5-HT1B and green fluorescent protein (HA1B-GFP) cassettes or green fluorescent protein cassette alone (GFP-only) was injected into the NAcc shell, which sends projections to the VTA. HA1B-GFP injection induced elevated expression of 5-HT1B receptors in neuronal fibers in VTA and increased cocaine-induced locomotor hyperactivity without affecting baseline locomotion. Overexpression of 5-HT1B receptors also shifted the dose-response curve for cocaine-conditioned place preference to the left, indicating alterations in the rewarding effects of cocaine. Thus, increased expression of 5-HT1B receptors in NAcc efferents, probably in the terminals of medium spiny neurons projecting to the VTA, may contribute to psychomotor sensitization and offer an important target for regulating the addictive effects of cocaine.