Delta Frequency Optogenetic Stimulation of the Thalamic Nucleus Reuniens Is Sufficient to Produce Working Memory Deficits: Relevance to Schizophrenia
Background: Low-frequency (delta/theta) oscillations in the thalamocortical system are elevated in schizophrenia during wakefulness and are also induced in the N-methyl-D-asparate receptor hypofunction rat model. To determine whether abnormal delta oscillations might produce functional deficits, we...
| Main Authors: | , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier
2017
|
| Online Access: | http://hdl.handle.net/1721.1/110530 https://orcid.org/0000-0001-7149-3584 |
| _version_ | 1811077956443832320 |
|---|---|
| author | Duan, Aranda R. Varela, Carmen Zhang, Yuchun Lisman, John Shen, Yinghua Xiong, Lealia Li Wilson, Matthew A |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Duan, Aranda R. Varela, Carmen Zhang, Yuchun Lisman, John Shen, Yinghua Xiong, Lealia Li Wilson, Matthew A |
| author_sort | Duan, Aranda R. |
| collection | MIT |
| description | Background: Low-frequency (delta/theta) oscillations in the thalamocortical system are elevated in schizophrenia during wakefulness and are also induced in the N-methyl-D-asparate receptor hypofunction rat model. To determine whether abnormal delta oscillations might produce functional deficits, we used optogenetic methods in awake rats. We illuminated channelrhodopsin-2 in the thalamic nucleus reuniens (RE) at delta frequency and measured the effect on working memory (WM) performance (the RE is involved in WM, a process affected in schizophrenia [SZ]).
Methods: We injected RE with adeno-associated virus to transduce cells with channelrhodopsin-2. An optical fiber was implanted just dorsal to the hippocampus in order to illuminate RE axon terminals.
Results: During optogenetic delta frequency stimulation, rats displayed a strong WM deficit. On the following day, performance was normal if illumination was omitted.
Conclusions: The optogenetic experiments show that delta frequency stimulation of a thalamic nucleus is sufficient to produce deficits in WM. This result supports the hypothesis that delta frequency bursting in particular thalamic nuclei has a causal role in producing WM deficits in SZ. The action potentials in these bursts may “jam” communication through the thalamus, thereby interfering with behaviors dependent on WM. Studies in thalamic slices using the N-methyl-D-asparate receptor hypofunction model show that delta frequency bursting is dependent on T-type Ca2+ channels, a result that we confirmed here in vivo. These channels, which are strongly implicated in SZ by genome-wide association studies, may thus be a therapeutic target for treatment of SZ. |
| first_indexed | 2024-09-23T10:51:07Z |
| format | Article |
| id | mit-1721.1/110530 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:51:07Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1105302022-09-27T15:28:46Z Delta Frequency Optogenetic Stimulation of the Thalamic Nucleus Reuniens Is Sufficient to Produce Working Memory Deficits: Relevance to Schizophrenia Duan, Aranda R. Varela, Carmen Zhang, Yuchun Lisman, John Shen, Yinghua Xiong, Lealia Li Wilson, Matthew A Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Shen, Yinghua Xiong, Lealia Li Wilson, Matthew A Background: Low-frequency (delta/theta) oscillations in the thalamocortical system are elevated in schizophrenia during wakefulness and are also induced in the N-methyl-D-asparate receptor hypofunction rat model. To determine whether abnormal delta oscillations might produce functional deficits, we used optogenetic methods in awake rats. We illuminated channelrhodopsin-2 in the thalamic nucleus reuniens (RE) at delta frequency and measured the effect on working memory (WM) performance (the RE is involved in WM, a process affected in schizophrenia [SZ]). Methods: We injected RE with adeno-associated virus to transduce cells with channelrhodopsin-2. An optical fiber was implanted just dorsal to the hippocampus in order to illuminate RE axon terminals. Results: During optogenetic delta frequency stimulation, rats displayed a strong WM deficit. On the following day, performance was normal if illumination was omitted. Conclusions: The optogenetic experiments show that delta frequency stimulation of a thalamic nucleus is sufficient to produce deficits in WM. This result supports the hypothesis that delta frequency bursting in particular thalamic nuclei has a causal role in producing WM deficits in SZ. The action potentials in these bursts may “jam” communication through the thalamus, thereby interfering with behaviors dependent on WM. Studies in thalamic slices using the N-methyl-D-asparate receptor hypofunction model show that delta frequency bursting is dependent on T-type Ca2+ channels, a result that we confirmed here in vivo. These channels, which are strongly implicated in SZ by genome-wide association studies, may thus be a therapeutic target for treatment of SZ. National Institutes of Health (U.S.) (Grant R01MH086518-05) National Institutes of Health (U.S.) (T32NS007292-28) National Institutes of Health (U.S.) (R01-GM104948-02) 2017-07-07T15:10:20Z 2017-07-07T15:10:20Z 2015-02 Article http://purl.org/eprint/type/JournalArticle 0006-3223 http://hdl.handle.net/1721.1/110530 Duan, Aranda R. et al. “Delta Frequency Optogenetic Stimulation of the Thalamic Nucleus Reuniens Is Sufficient to Produce Working Memory Deficits: Relevance to Schizophrenia.” Biological Psychiatry 77.12 (2015): 1098–1107. https://orcid.org/0000-0001-7149-3584 en_US http://dx.doi.org/10.1016/j.biopsych.2015.01.020 Biological Psychiatry Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Duan, Aranda R. Varela, Carmen Zhang, Yuchun Lisman, John Shen, Yinghua Xiong, Lealia Li Wilson, Matthew A Delta Frequency Optogenetic Stimulation of the Thalamic Nucleus Reuniens Is Sufficient to Produce Working Memory Deficits: Relevance to Schizophrenia |
| title | Delta Frequency Optogenetic Stimulation of the Thalamic Nucleus Reuniens Is Sufficient to Produce Working Memory Deficits: Relevance to Schizophrenia |
| title_full | Delta Frequency Optogenetic Stimulation of the Thalamic Nucleus Reuniens Is Sufficient to Produce Working Memory Deficits: Relevance to Schizophrenia |
| title_fullStr | Delta Frequency Optogenetic Stimulation of the Thalamic Nucleus Reuniens Is Sufficient to Produce Working Memory Deficits: Relevance to Schizophrenia |
| title_full_unstemmed | Delta Frequency Optogenetic Stimulation of the Thalamic Nucleus Reuniens Is Sufficient to Produce Working Memory Deficits: Relevance to Schizophrenia |
| title_short | Delta Frequency Optogenetic Stimulation of the Thalamic Nucleus Reuniens Is Sufficient to Produce Working Memory Deficits: Relevance to Schizophrenia |
| title_sort | delta frequency optogenetic stimulation of the thalamic nucleus reuniens is sufficient to produce working memory deficits relevance to schizophrenia |
| url | http://hdl.handle.net/1721.1/110530 https://orcid.org/0000-0001-7149-3584 |
| work_keys_str_mv | AT duanarandar deltafrequencyoptogeneticstimulationofthethalamicnucleusreuniensissufficienttoproduceworkingmemorydeficitsrelevancetoschizophrenia AT varelacarmen deltafrequencyoptogeneticstimulationofthethalamicnucleusreuniensissufficienttoproduceworkingmemorydeficitsrelevancetoschizophrenia AT zhangyuchun deltafrequencyoptogeneticstimulationofthethalamicnucleusreuniensissufficienttoproduceworkingmemorydeficitsrelevancetoschizophrenia AT lismanjohn deltafrequencyoptogeneticstimulationofthethalamicnucleusreuniensissufficienttoproduceworkingmemorydeficitsrelevancetoschizophrenia AT shenyinghua deltafrequencyoptogeneticstimulationofthethalamicnucleusreuniensissufficienttoproduceworkingmemorydeficitsrelevancetoschizophrenia AT xionglealiali deltafrequencyoptogeneticstimulationofthethalamicnucleusreuniensissufficienttoproduceworkingmemorydeficitsrelevancetoschizophrenia AT wilsonmatthewa deltafrequencyoptogeneticstimulationofthethalamicnucleusreuniensissufficienttoproduceworkingmemorydeficitsrelevancetoschizophrenia |