Using Optogenetics and Place Preference to Study the Influence of Drugs of Abuse on Environmental Associations

Dr. Steidl’s research and those in the department of Pharmacology at the University of Oxford and Department of Neuroscience at Tufts University’s School of Medicine (Stephanie Trouche, Pavel Perestenko, Gido can de Ven, Claire Brately, Colin McNamara, Natalia Campo-Urriza, S Lucas Black, Leon Reijmers, and David Dupret) both utilized place preference and optogenetics to study the effects drugs of abuse in relation to spatial memory on the ventral tegmental area (VTA) and hippocampus respectively. Optogenetics were employed in both experiments in order to selectively activate specific brain areas associated with chambers of the place preference apparatus.

Place Preference Maze with two unique chambers (left and right)
and center common chamber

Dr. Steidl excited two populations of laterodorsal tegmental nuclei (LDTg), one glutamatergic and the other cholinergic, to increase dopamine levels in the VTA. Optogenetics was used to selectively activate these LDTg populations in order to pair dopamine release with one of the chambers in the place preference apparatus. During the final place preference task, the mice showed significantly more light-paired chamber entries than unpaired chamber entries when LDTg-glutamatergic pathways were activated and an increased amount of time spent in the light-paired chamber when LDTg-cholinergic pathways were activated (Steidl et. al, 2017). This indicated that LDTg-glutamatergic pathways were more important for the reinforcement of chamber entries, while LDTg-cholinergic pathways were more important for the reinforcement of time spent in the chamber (Steidl et. al, 2017).

Oxford and Tufts University used c-fos-based approach to optogenetics to silence hippocampal neurons when the mouse is in specific environments. The optogenetic virus was injected bilaterally into the dorsal hippocampal CA1 of the c-fos-tTA transgenic mice. CA1 principle cells “contribute to adaptive memories by providing the brain with neuronal engrams that represent the spatial context of life events” (Trouche et. al, 2016). They then paired a drug of abuse, cocaine, with a specific environment and found that when mice were reintroduced to the cocaine-paired environment, without recent drug administration, the same CA1 neurons were recruited when the mouse was under the drug’s influence and when not. This created a cocaine-place preference; however, when the CA1 was silenced, the mice no longer showed a cocaine-place preference. This absence of cocaine-place preference was caused by “shifted neuronal activity from [the cocaine-paired environment] to the alternative [neuronal] subset” that was previously conditioned in the mice (Trouche et. al, 2016). “This intervention neutralized an otherwise long-lasting drug-place preference… by disengaging the initially recruited neurons while enabling previously quiet neurons to emerge and provide an alternative representation (Trouche et. al, 2016). The results are not reversed by drug-priming, as would happen in regular extinction, and therefore is an effective method to “reset spatial strategies” and eliminate maladaptive behavior (Trouche et. al, 2016).

Both Dr. Steidl and the research done by Oxford and Tufts University illustrated the usefulness of optogenetics as a tool in neuroscientific research. Its ability to selectively activate brain processes, such as neurotransmitter-specific axon pathways and specific cell groups, allows for the manipulation of living tissue in real-time. The linking of optogenetic laser activation to the neurological experience of drugs of abuse allowed for both experiments to create drug-place preference. In Dr. Steidl’s research this allowed him to distinguish between the synaptic pathways he was testing and the Oxford and Tufts University research used it to pair the activation of specific neuronal group with an environment strong enough to override the drug-place preference. These techniques have allowed neuroscientists to conduct research with increased temporal and spatial resolution and increased precision.

Works Cited

“Place Preference Maze.” Www.mazeengineers.com, 2017, mazeengineer-mazeengillc.netdna-ssl.com/wp-content/uploads/2015/01/wall_model_sociability_02_3.png.

Steidl, S., Wang, H., Ordonez, M., Zhang, S., & Morales, M. (2017). Optogenetic excitation in the ventral tegmental area of glutamatergic or cholinergic inputs from the laterodorsal tegmental area drives reward. European Journal of Neuroscience,45, 559-571.

Trouche, S., Perestenko, P. V., Van de Ven, G. M., Brately, C. T., McNamara, C. G., Campo-Urriza, N., . . . Dupret, D. (2016). Recoding a cocaine-place memory engram to a neutral engram in the hippocampus. Nature Neuroscience,19, 564-567. Retrieved October 1, 2017, from www.nature.com.