RESUMO
Light plays a pivotal role in the regulation of affective behaviors. However, the precise circuits that mediate the impact of light on depressive-like behaviors are not well understood. Here, we show that light influences depressive-like behaviors through a disynaptic circuit linking the retina and the lateral habenula (LHb). Specifically, M4-type melanopsin-expressing retinal ganglion cells (RGCs) innervate GABA neurons in the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which in turn inhibit CaMKIIα neurons in the LHb. Specific activation of vLGN/IGL-projecting RGCs, activation of LHb-projecting vLGN/IGL neurons, or inhibition of postsynaptic LHb neurons is sufficient to decrease the depressive-like behaviors evoked by long-term exposure to aversive stimuli or chronic social defeat stress. Furthermore, we demonstrate that the antidepressive effects of light therapy require activation of the retina-vLGN/IGL-LHb pathway. These results reveal a dedicated retina-vLGN/IGL-LHb circuit that regulates depressive-like behaviors and provide a potential mechanistic explanation for light treatment of depression.
Assuntos
Depressão , Transtorno Depressivo/terapia , Neurônios GABAérgicos/fisiologia , Corpos Geniculados/fisiologia , Habenula/fisiologia , Fototerapia , Células Ganglionares da Retina/fisiologia , Vias Visuais/fisiologia , Animais , Comportamento Animal , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Modelos Animais de Doenças , Neurônios GABAérgicos/metabolismo , Masculino , Inibição Neural/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Retina/fisiologia , Opsinas de Bastonetes/metabolismo , Estresse Psicológico , Tálamo/fisiologiaRESUMO
Animals promote their survival by avoiding rapidly approaching objects that indicate threats. In mice, looming-evoked defensive responses are triggered by the superior colliculus (SC) which receives direct retinal inputs. However, the specific neural circuits that begin in the retina and mediate this important behaviour remain unclear. Here we identify a subset of retinal ganglion cells (RGCs) that controls mouse looming-evoked defensive responses through axonal collaterals to the dorsal raphe nucleus (DRN) and SC. Looming signals transmitted by DRN-projecting RGCs activate DRN GABAergic neurons that in turn inhibit serotoninergic neurons. Moreover, activation of DRN serotoninergic neurons reduces looming-evoked defensive behaviours. Thus, a dedicated population of RGCs signals rapidly approaching visual threats and their input to the DRN controls a serotonergic self-gating mechanism that regulates innate defensive responses. Our study provides new insights into how the DRN and SC work in concert to extract and translate visual threats into defensive behavioural responses.
Assuntos
Comportamento Animal/fisiologia , Núcleo Dorsal da Rafe/fisiologia , Defesa Perceptiva , Células Ganglionares da Retina/fisiologia , Serotonina/metabolismo , Tonsila do Cerebelo/fisiologia , Animais , Neurônios GABAérgicos/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-fos/metabolismo , Colículos Superiores , Tálamo/fisiologia , Ácido gama-Aminobutírico/metabolismoRESUMO
Lycium barbarum polysaccharides (LBP), extracts from the wolfberries, are protective to retina after ischemia-reperfusion (I/R). The antioxidant response element (ARE)-mediated antioxidant pathway plays an important role in maintaining the redox status of the retina. Heme oxygenase-1 (HO-1), combined with potent AREs in its promoter, is a highly effective therapeutic target for the protection against neurodegenerative diseases, including I/R-induced retinal damage. The aim of our present study was to investigate whether the protective effect of LBP after I/R damage was mediated via activation of the Nrf2/HO-1-antioxidant pathway in the retina. Retinal I/R was induced by an increase in intraocular pressure to 130 mm Hg for 60 minutes. Prior to the induction of ischemia, rats were orally treated with either vehicle (PBS) or LBP (1 mg/kg) once a day for 1 week. For specific experiments, zinc protoporphyrin (ZnPP, 20 mg/kg), an HO-1 inhibitor, was intraperitoneally administered at 24 h prior to ischemia. The protective effects of LBP were evaluated by quantifying ganglion cell and amacrine cell survival, and by measuring cell apoptosis in the retinal layers. In addition, HO-1 expression was examined using Western blotting and immunofluorescence analyses. Cytosolic and nuclear Nrf2 was measured using immunofluorescent staining. LBP treatment significantly increased Nrf2 nuclear accumulation and HO-1 expression in the retina after I/R injury. Increased apoptosis and a decrease in the number of viable cells were observed in the ganglion cell layer (GCL) and inner nuclear layer (INL) in the I/R retina, which were reversed by LBP treatment. The HO-1 inhibitor, ZnPP, diminished the LBP treatment-induced protective effects in the retina after I/R. Taken together, these results suggested that LBP partially exerted its beneficial neuroprotective effects via the activation of Nrf2 and an increase in HO-1 protein expression.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Heme Oxigenase-1/metabolismo , Lycium/química , Fator 2 Relacionado a NF-E2/metabolismo , Retina/efeitos dos fármacos , Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Amácrinas/efeitos dos fármacos , Células Amácrinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Masculino , Estresse Oxidativo/efeitos dos fármacos , Transporte Proteico , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão , Retina/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologiaRESUMO
PURPOSE: To investigate the effect of ginkgo biloba on the retinal ganglion cell survival in a rat optic nerve crush model. METHODS: Twenty-four Sprague-Dawley rats were divided randomly into a study group of 12 animals receiving intraperitoneal injections of ginkgo biloba and a control group of 12 animals receiving intraperitoneal saline injections. All injections were performed 1 hr before the optic nerve crush and daily afterwards. For each animal, the right optic nerve was crushed closely behind the globe for 60 seconds using a microclip with 40 g power. The left optic nerve was kept intact. At 23 days after the optic nerve crush, the retinal ganglion cells were labelled retrogradely by injecting 3% fluorogold into both sides of the superior colliculus of the brain. At 4 weeks after the optic nerve crush, the animals were killed. Photographs taken from retinal flat mounts were assessed for the number and density of the retinal ganglion cells. RESULTS: The survival rate, defined as the ratio of the retinal ganglion cell density in the right eye with the optic nerve crush divided by the retinal ganglion cell density in left eye without an optic nerve trauma, was significantly (p=0.035) higher in the study group with ginkgo biloba than in the control group (60.0+/-6.0% versus 53.5+/-8.0%). CONCLUSION: The results suggest that intraperitoneal injections of a ginkgo biloba extract given prior to and daily after an experimental and standardized optic nerve crush in rats were associated with a higher survival rate of retinal ganglion cells.