6 research outputs found
Increased Vesicular Monoamine Transporter 2 (VMAT2; <i>Slc18a2</i>) Protects against Methamphetamine Toxicity
The
psychostimulant methamphetamine (METH) is highly addictive
and neurotoxic to dopamine terminals. METH toxicity has been suggested
to be due to the release and accumulation of dopamine in the cytosol
of these terminals. The vesicular monoamine transporter 2 (VMAT2; <i>SLC18A2</i>) is a critical mediator of dopamine handling. Mice
overexpressing VMAT2 (VMAT2-HI) have an increased vesicular capacity
to store dopamine, thus augmenting striatal dopamine levels and dopamine
release in the striatum. Based on the altered compartmentalization
of intracellular dopamine in the VMAT2-HI mice, we assessed whether
enhanced vesicular function was capable of reducing METH-induced damage
to the striatal dopamine system. While wildtype mice show significant
losses in striatal levels of the dopamine transporter (65% loss) and
tyrosine hydroxylase (46% loss) following a 4 × 10 mg/kg METH
dosing regimen, VMAT2-HI mice were protected from this damage. VMAT2-HI
mice were also spared from the inflammatory response that follows
METH treatment, showing an increase in astroglial markers that was
approximately one-third of that of wildtype animals (117% vs 36% increase
in GFAP, wildtype vs VMAT2-HI). Further analysis also showed that
elevated VMAT2 level does not alter the ability of METH to increase
core body temperature, a mechanism integral to the toxicity of the
drug. Finally, the VMAT2-HI mice showed no difference from wildtype
littermates on both METH-induced conditioned place preference and
in METH-induced locomotor activity (1 mg/kg METH). These results demonstrate
that elevated VMAT2 protects against METH toxicity without enhancing
the rewarding effects of the drug. Since the VMAT2-HI mice are protected
from METH despite higher basal dopamine levels, this study suggests
that METH toxicity depends more on the proper compartmentalization
of synaptic dopamine than on the absolute amount of dopamine in the
brain
Selective Enhancement of Dopamine Release in the Ventral Pallidum of Methamphetamine-Sensitized Mice
Drugs of abuse induce
sensitization, which is defined as enhanced
response to additional drug following a period of withdrawal. Sensitization
occurs in both humans and animal models of drug reinforcement and
contributes substantially to the addictive nature of drugs of abuse,
because it is thought to represent enhanced motivational wanting for
drug. The ventral pallidum, a key member of the reward pathway, contributes
to behaviors associated with reward, such as sensitization. Dopamine
inputs to the ventral pallidum have not been directly characterized.
Here we provide anatomical, neurochemical, and behavioral evidence
demonstrating that dopamine terminals in the ventral pallidum contribute
to reward in mice. We report subregional differences in dopamine release,
measured by <i>ex vivo</i> fast-scan cyclic voltammetry:
rostral ventral pallidum exhibits increased dopamine release and uptake
compared with caudal ventral pallidum, which is correlated with tissue
expression of dopaminergic proteins. We then subjected mice to a methamphetamine-sensitization
protocol to investigate the contribution of dopaminergic projections
to the region in reward related behavior. Methamphetamine-sensitized
animals displayed a 508% and 307% increase in baseline dopamine release
in the rostral and caudal ventral pallidum, respectively. Augmented
dopamine release in the rostral ventral pallidum was significantly
correlated with sensitized locomotor activity. Moreover, this presynaptic
dopaminergic plasticity occurred only in the ventral pallidum and
not in the ventral or dorsal striatum, suggesting that dopamine release
in the ventral pallidum may be integrally important to drug-induced
sensitization
Image_1_Genetic background influences the 5XFAD Alzheimer's disease mouse model brain proteome.pdf
There is an urgent need to improve the translational validity of Alzheimer's disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable the discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. In this study, we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in the hippocampus and cortex (n = 3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across the hippocampus and cortex in 5XFAD and non-transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress responses and neuronal synapse/signaling. The modules with the strongest relationship to human disease—neuronal synapse/signaling and lysosome/stress response—were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated with AD genotype in the hippocampus compared with the cortex. Our findings suggest that the genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD.</p
Table_1_Genetic background influences the 5XFAD Alzheimer's disease mouse model brain proteome.XLSX
There is an urgent need to improve the translational validity of Alzheimer's disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable the discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. In this study, we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in the hippocampus and cortex (n = 3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across the hippocampus and cortex in 5XFAD and non-transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress responses and neuronal synapse/signaling. The modules with the strongest relationship to human disease—neuronal synapse/signaling and lysosome/stress response—were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated with AD genotype in the hippocampus compared with the cortex. Our findings suggest that the genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD.</p
Dryad-Lohr-etal-excelFSCV
This is an excel spreadsheet that shows all of the raw data collected for the fast scan cyclic voltammetry experiments. Tabs are used to delineate the various experiments
Dryad-Lohr-etal-westerns
These are all of the original images of the western blots in this manuscript. They are in a powerpoint file