Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits
The lateral habenula (LHb) and the ventral tegmental area (VTA), which form interconnected circuits, have important roles in the crucial control of sensory and cognitive motifs. Signaling in the LHb-VTA pathway can be exacerbated during pain conditions by a hyperactivity of LHb glutamatergic neurons...
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MDPI AG
2023-03-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/3/820 |
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| author | Mobina Alemi Ana Raquel Pereira Mariana Cerqueira-Nunes Clara Monteiro Vasco Galhardo Helder Cardoso-Cruz |
| author_facet | Mobina Alemi Ana Raquel Pereira Mariana Cerqueira-Nunes Clara Monteiro Vasco Galhardo Helder Cardoso-Cruz |
| author_sort | Mobina Alemi |
| collection | DOAJ |
| description | The lateral habenula (LHb) and the ventral tegmental area (VTA), which form interconnected circuits, have important roles in the crucial control of sensory and cognitive motifs. Signaling in the LHb-VTA pathway can be exacerbated during pain conditions by a hyperactivity of LHb glutamatergic neurons to inhibit local VTA DAergic cells. However, it is still unclear whether and how this circuit is endogenously engaged in pain-related cognitive dysfunctions. To answer this question, we modulated this pathway by expressing halorhodopsin in LHb neurons of adult male rats, and then selectively inhibited the axonal projections from these neurons to the VTA during a working memory (WM) task. Behavioral performance was assessed after the onset of an inflammatory pain model. We evaluated the impact of the inflammatory pain in the VTA synapses by performing immunohistochemical characterization of specific markers for GABAergic (GAD65/67) and dopaminergic neurons (dopamine transporter (DAT), dopamine D2 receptor (D2r) and tyrosine hydroxylase (TH)). Our results revealed that inhibition of LHb terminals in the VTA during the WM delay-period elicits a partial recovery of the performance of pain animals (in higher complexity challenges); this performance was not accompanied by a reduction of nociceptive responses. Finally, we found evidence that the pain-affected animals exhibit VTA structural changes, namely with an upregulation of GAD65/67, and a downregulation of DAT and D2r. These results demonstrate a role of LHb neurons and highlight their responsibility in the stability of the local VTA network, which regulates signaling in frontal areas necessary to support WM processes. |
| first_indexed | 2024-03-11T06:53:35Z |
| format | Article |
| id | doaj.art-70c96201420a4b6587e83014ede47ef6 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T06:53:35Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-70c96201420a4b6587e83014ede47ef62023-11-17T09:46:06ZengMDPI AGBiomedicines2227-90592023-03-0111382010.3390/biomedicines11030820Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory DeficitsMobina Alemi0Ana Raquel Pereira1Mariana Cerqueira-Nunes2Clara Monteiro3Vasco Galhardo4Helder Cardoso-Cruz5Instituto de Investigação e Inovação em Saúde—Pain Neurobiology Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde—Pain Neurobiology Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde—Pain Neurobiology Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde—Pain Neurobiology Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde—Pain Neurobiology Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde—Pain Neurobiology Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, PortugalThe lateral habenula (LHb) and the ventral tegmental area (VTA), which form interconnected circuits, have important roles in the crucial control of sensory and cognitive motifs. Signaling in the LHb-VTA pathway can be exacerbated during pain conditions by a hyperactivity of LHb glutamatergic neurons to inhibit local VTA DAergic cells. However, it is still unclear whether and how this circuit is endogenously engaged in pain-related cognitive dysfunctions. To answer this question, we modulated this pathway by expressing halorhodopsin in LHb neurons of adult male rats, and then selectively inhibited the axonal projections from these neurons to the VTA during a working memory (WM) task. Behavioral performance was assessed after the onset of an inflammatory pain model. We evaluated the impact of the inflammatory pain in the VTA synapses by performing immunohistochemical characterization of specific markers for GABAergic (GAD65/67) and dopaminergic neurons (dopamine transporter (DAT), dopamine D2 receptor (D2r) and tyrosine hydroxylase (TH)). Our results revealed that inhibition of LHb terminals in the VTA during the WM delay-period elicits a partial recovery of the performance of pain animals (in higher complexity challenges); this performance was not accompanied by a reduction of nociceptive responses. Finally, we found evidence that the pain-affected animals exhibit VTA structural changes, namely with an upregulation of GAD65/67, and a downregulation of DAT and D2r. These results demonstrate a role of LHb neurons and highlight their responsibility in the stability of the local VTA network, which regulates signaling in frontal areas necessary to support WM processes.https://www.mdpi.com/2227-9059/11/3/820lateral habenulaglutamatergic projectionsventral tegmental areaoptogenetic inhibitionworking memory deficitsinflammatory pain |
| spellingShingle | Mobina Alemi Ana Raquel Pereira Mariana Cerqueira-Nunes Clara Monteiro Vasco Galhardo Helder Cardoso-Cruz Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits Biomedicines lateral habenula glutamatergic projections ventral tegmental area optogenetic inhibition working memory deficits inflammatory pain |
| title | Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits |
| title_full | Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits |
| title_fullStr | Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits |
| title_full_unstemmed | Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits |
| title_short | Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits |
| title_sort | role of glutamatergic projections from lateral habenula to ventral tegmental area in inflammatory pain related spatial working memory deficits |
| topic | lateral habenula glutamatergic projections ventral tegmental area optogenetic inhibition working memory deficits inflammatory pain |
| url | https://www.mdpi.com/2227-9059/11/3/820 |
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