RESUMO
The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the 'anti-reward center', the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Habenula/efeitos dos fármacos , Habenula/metabolismo , Ketamina/farmacologia , Ketamina/uso terapêutico , Afeto/efeitos dos fármacos , Anedonia/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/metabolismo , Modelos Animais de Doenças , Habenula/patologia , Habenula/efeitos da radiação , Ketamina/administração & dosagem , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Recompensa , Ritmo Teta/efeitos dos fármacosRESUMO
Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia-neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.
Assuntos
Astrócitos/metabolismo , Depressão/metabolismo , Habenula/metabolismo , Neurônios/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/patologia , Habenula/efeitos dos fármacos , Habenula/patologia , Masculino , Terapia de Alvo Molecular , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , RecompensaRESUMO
Clinical studies show that anxiety and chronic pain are concomitant. The neural basis for the comorbidity is unclear. The prefrontal cortex (PFC) has been recognized as a critical area for affective disorders and chronic pain modulation. In this study, we examined the role of the PFC in the pathogenesis of anxiety associated with chronic pain in a rat model of neuropathic pain with spare nerve injury (SNI). The SNI rats showed apparent anxiety-like behaviors in both open field (OF) test and elevated-plus maze (EPM) test eight weeks after surgery. Thus, the number of entries to the central area in the OF decreased to 45% (±5%, n = 15) of sham control (n = 17), while the overall motor activity (i.e., total distance) was unaffected. In the EPM, the percentage of entries into the open arms significantly (p < 0.001) decreased in SNI rats (SNI: 12.58 ± 2.7%, n = 15; sham: 30.75 ± 2.82%, n = 17), so did the time spent in the open arms (SNI: 4.35 ± 1.45%, n = 15; Sham: 11.65 ± 2.18%, n = 17). To explore the neural basis for the association between anxiety and chronic pain, local field potentials (LFPs) were recorded from the medial PFC (mPFC) and ventral hippocampus. In SNI rats, there were significantly greater increases in both theta-frequency power in the mPFC and theta-frequency synchronization between the mPFC and ventral hippocampus, when animals were displaying elevated anxiety-like behaviors in avoiding anxiogenic regions in EPM and OF chamber. Western blot analyses showed a significant elevation of serotonin transporter expression in the anxious SNI rats. Inhibition of serotonin transporter effectively alleviated anxiety-like behaviors following sub-chronic (15 days) treatment with systemic citalopram (10 mg/kg/day, intraperitoneally). Moreover, the anxiety-like behaviors in the SNI rats were also suppressed by direct mPFC application of serotonin. Taken together, we conclude that the plasticity of serotonin transmission in the mPFC likely contribute to the promotion of anxiety state associated with neuropathic pain.
Assuntos
Ansiedade/fisiopatologia , Comportamento Animal , Dor Crônica/fisiopatologia , Neuralgia/fisiopatologia , Plasticidade Neuronal , Córtex Pré-Frontal/fisiopatologia , Potenciais de Ação , Animais , Ansiedade/complicações , Ansiedade/patologia , Dor Crônica/complicações , Dor Crônica/patologia , Hipocampo/fisiopatologia , Masculino , Tecido Nervoso/lesões , Tecido Nervoso/patologia , Tecido Nervoso/cirurgia , Neuralgia/complicações , Neuralgia/patologia , Córtex Pré-Frontal/patologia , Ratos Wistar , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Ritmo TetaRESUMO
BACKGROUND: Although the interaction between pain and cognition has been recognized for decades, the neural substrates underlying their association remain unclear. The prefrontal cortex (PFC) is known as a critical brain area for higher cognitive functions, as well as for pain perception and modulation. The objective of the present study was to explore the role of the PFC in the interaction between chronic pain and cognitive functions by examining the relationship between spontaneous activity in the frontal lobe and pain intensity reported by postherpetic neuralgia (PHN) patients. METHODS: Resting-state functional magnetic resonance imaging data from 16 PHN patients were collected, and regional homogeneity and related functional connectivity were analyzed. RESULTS: The results showed negative correlations between patients' pain scores and regional homogeneity values in several prefrontal areas, including the left lateral PFC, left medial PFC, and right lateral orbitofrontal cortex (P<0.05, AlphaSim-corrected). Further analysis revealed that the functional connectivity of some of these prefrontal areas with other cortical regions was also modulated by pain intensity. Therefore, functional connections of the left lateral PFC with both the left parietal cortex and the left occipital cortex were correlated with patients' pain ratings (P<0.05, AlphaSim-corrected). Similarly, functional connectivity between the right lateral orbitofrontal cortex and bilateral postcentral/precentral gyri was also correlated with pain intensity in the patients (P<0.05, AlphaSim-corrected). CONCLUSION: Our findings indicate that activity in the PFC is modulated by chronic pain in PHN patients. The pain-related modulation of prefrontal activity may serve as the neural basis for interactions between chronic pain and cognitive functions, which may link to cognitive impairments observed in chronic pain patients.