Dataset Information

Distinct gene alterations between Fos-expressing striatal and thalamic neurons after withdrawal from methamphetamine self-administration.

ABSTRACT:

Background

Methamphetamine (Meth) seeking progressively increases after withdrawal (incubation of Meth craving). We previously demonstrated a role of anterior intralaminar nucleus of thalamus (AIT) to dorsomedial striatum (DMS) projections in this incubation. Here, we examined molecular alterations in DMS and AIT neurons activated (identified by neuronal activity marker Fos) during "incubated" Meth-seeking relapse test after prolonged withdrawal.

Methods

We trained male rats to self-administer Meth or saline (control condition) for 10 days (6 hr/day). Using fluorescence-activated cell sorting, we examined gene expression in Fos-positive (activated during a 2-hr relapse test) and Fos-negative (nonactivated) DMS and AIT neurons.

Results

In DMS, we found increased mRNA expressions of immediate early genes (IEGs) (Arc, Egr1, Npas4, Fosb), Trkb, glutamate receptors subunits (Gria3, Grin1, Grin2b, Grm1), and epigenetic enzymes (Hdac3, Hdac5, Crebbp) in Fos-positive neurons, compared with Fos-negative neurons. In AIT, we found that fewer genes (Egr1, Fosb, TrkB, Grin1, and Hdac5) exhibited increased mRNA expression in Fos-positive neurons. Unexpectedly, in both brain regions, gene alterations described above also occurred in drug-naïve saline self-administration control rats.

Conclusions

These results demonstrated that transcriptional regulations in Fos-positive neurons activated during the relapse tests are brain region-specific but are not uniquely associated with drug exposure during the self-administration training.

SUBMITTER: Li X

PROVIDER: S-EPMC6749486 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

Distinct gene alterations between Fos-expressing striatal and thalamic neurons after withdrawal from methamphetamine self-administration.

Li Xuan X Davis Ian R IR Lofaro Olivia M OM Zhang Jianjun J Cimbro Raffaello R Rubio F Javier FJ

Brain and behavior 20190731 9

<h4>Background</h4>Methamphetamine (Meth) seeking progressively increases after withdrawal (incubation of Meth craving). We previously demonstrated a role of anterior intralaminar nucleus of thalamus (AIT) to dorsomedial striatum (DMS) projections in this incubation. Here, we examined molecular alterations in DMS and AIT neurons activated (identified by neuronal activity marker Fos) during "incubated" Meth-seeking relapse test after prolonged withdrawal.<h4>Methods</h4>We trained male rats to se ...[more]

PMID: 31364821

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Project description:Methamphetamine (mAMPH) is a psychostimulant drug that increases extracellular levels of monoamines throughout the brain. It has previously been observed that a single injection of mAMPH increases immediate early gene (IEG) expression in both the striatum and cerebral cortex. Moreover, this effect is modulated by dopamine and glutamate receptors since systemic administration of dopamine or glutamate antagonists has been found to alter mAMPH-induced striatal and cortical IEG expression. However, because dopamine and glutamate receptors are found in extra-striatal as well as striatal brain regions, studies employing systemic injection of dopamine or glutamate antagonists fail to localize the effects of mAMPH-induced activation. In the present experiments, the roles of striatal dopamine and glutamate receptors in mAMPH-induced gene expression in the striatum and cerebral cortex were examined. The nuclear expression of Fos, the protein product of the IEG c-fos, was quantified in both the striatum and the cortex of animals receiving intrastriatal dopamine or glutamate antagonist administration. Intrastriatal infusion of dopamine (D1 or D2) or glutamate [N-methyl-D-aspartic acid (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)] antagonists affected not only mAMPH-induced striatal, but also cortical, Fos expression. Overall, the effects of the antagonists occurred dose-dependently, in both the infused and non-infused hemispheres, with greater influences occurring in the infused hemisphere. Finally, unilateral intrastriatal infusion of dopamine or glutamate antagonists changed the behavior of the rats from characteristic mAMPH-induced stereotypy to rotation ipsilateral to the infusion. These results demonstrate that mAMPH's actions on striatal dopamine and glutamate receptors modulate the widespread cortical activation induced by mAMPH. It is hypothesized that dopamine release from nigrostriatal terminals modulates activity within striatal efferent pathways, thereby disinhibiting thalamo-cortical circuits. By extension, these results suggest processes through which repeated exposure to mAMPH might influence cortical function in mAMPH abusers.

Project description:Electrical and pharmacological stimulation methods are commonly used to study neuronal brain circuits in vivo, but are problematic, because electrical stimulation has limited specificity, while pharmacological activation has low temporal resolution. A recently developed alternative to these methods is the use of optogenetic techniques, based on the expression of light sensitive channel proteins in neurons. While optogenetics have been applied in in vitro preparations and in in vivo studies in rodents, their use to study brain function in nonhuman primates has been limited to the cerebral cortex. Here, we characterize the effects of channelrhodopsin-2 (ChR2) transfection in subcortical areas, i.e., the putamen, the external globus pallidus (GPe) and the ventrolateral thalamus (VL) of rhesus monkeys. Lentiviral vectors containing the ChR2 sequence under control of the elongation factor 1? promoter (pLenti-EF1? -hChR2(H134R)-eYFP-WPRE, titer 10? particles/ml) were deposited in GPe, putamen and VL. Four weeks later, a probe combining a conventional electrode and an optic fiber was introduced in the previously injected brain areas. We found light-evoked responses in 31.5% and 32.7% of all recorded neurons in the striatum and thalamus, respectively, but only in 2.5% of recorded GPe neurons. As expected, most responses were time-locked increases in firing, but decreases or mixed responses were also seen, presumably via ChR2-mediated activation of local inhibitory connections. Light and electron microscopic analyses revealed robust expression of ChR2 on the plasma membrane of cell somas, dendrites, spines and terminals in the striatum and VL. This study demonstrates that optogenetic experiments targeting the striatum and basal ganglia-related thalamic nuclei can be successfully achieved in monkeys. Our results indicate important differences of the type and magnitude of responses in each structure. Experimental conditions such as the vector used, the number and rate of injections, or the light stimulation conditions have to be optimized for each structure studied.

Dataset Information

Distinct gene alterations between Fos-expressing striatal and thalamic neurons after withdrawal from methamphetamine self-administration.

Background

Methods

Results

Conclusions

Publications

Distinct gene alterations between Fos-expressing striatal and thalamic neurons after withdrawal from methamphetamine self-administration.

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