RESUMEN
Besides generating vision, light modulates various physiological functions, including mood. While light therapy applied in the daytime is known to have anti-depressive properties, excessive light exposure at night has been reportedly associated with depressive symptoms. The neural mechanisms underlying this day-night difference in the effects of light are unknown. Using a light-at-night (LAN) paradigm in mice, we showed that LAN induced depressive-like behaviors without disturbing the circadian rhythm. This effect was mediated by a neural pathway from retinal melanopsin-expressing ganglion cells to the dorsal perihabenular nucleus (dpHb) to the nucleus accumbens (NAc). Importantly, the dpHb was gated by the circadian rhythm, being more excitable at night than during the day. This indicates that the ipRGCâdpHbâNAc pathway preferentially conducts light signals at night, thereby mediating LAN-induced depressive-like behaviors. These findings may be relevant when considering the mental health effects of the prevalent nighttime illumination in the industrial world.
Asunto(s)
Ritmo Circadiano/fisiología , Ritmo Circadiano/efectos de la radiación , Depresión/fisiopatología , Luz/efectos adversos , Vías Visuales/fisiología , Animales , Depresión/etiología , Habénula/fisiología , Habénula/efectos de la radiación , Ratones , Núcleo Accumbens/fisiología , Núcleo Accumbens/efectos de la radiación , Células Ganglionares de la Retina/fisiología , Células Ganglionares de la Retina/efectos de la radiación , Vías Visuales/efectos de la radiaciónRESUMEN
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.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Habénula/efectos de los fármacos , Habénula/metabolismo , Ketamina/farmacología , Ketamina/uso terapéutico , Afecto/efectos de los fármacos , Anhedonia/efectos de los fármacos , Animales , Antidepresivos/administración & dosificación , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio/metabolismo , Modelos Animales de Enfermedad , Habénula/patología , Habénula/efectos de la radiación , Ketamina/administración & dosificación , Masculino , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Recompensa , Ritmo Teta/efectos de los fármacosRESUMEN
Bipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain's primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks in mood disorders.
Asunto(s)
Trastorno Bipolar/fisiopatología , Relojes Circadianos/genética , Trastorno Depresivo Mayor/fisiopatología , Núcleo Supraquiasmático/fisiopatología , Amígdala del Cerebelo/efectos de la radiación , Animales , Antidepresivos/farmacología , Trastorno Bipolar/genética , Proteínas CLOCK/genética , Relojes Circadianos/efectos de los fármacos , Trastorno Depresivo Mayor/genética , Estudio de Asociación del Genoma Completo , Giro del Cíngulo/efectos de la radiación , Habénula/efectos de la radiación , Hipocampo/efectos de la radiación , Humanos , Luz , Compuestos de Litio/farmacología , Ratones , Modelos Animales , Sustancia Gris Periacueductal/efectos de la radiaciónRESUMEN
The localization of calcium and calcium-activated ATPases was investigated electron microscopically in the medial habenula of mice after whole body irradiation with modulated microwaves. In non-irradiated animals calcium-containing precipitates were seen in different subcellular compartments and were often localized on the luminal side of membranes of synaptic vesicles in nerve terminals. At 1 h after 16-Hz modulated microwave irradiation, the number of synaptic vesicles containing calcium precipitates decreased, and reaction products appeared at new locations: in the synaptic clefts and on non-synaptic surfaces of the neuronal plasma membrane. This modified calcium distribution remained unchanged for 24 h following irradiation. Calcium-activated "ecto"-localized ATPase was detected as a punctuated-linear distribution of the reaction product outlining whole areas of glial and neuronal plasma membrane in the habenula of control animals. This pattern did not change on microwave irradiation. However, a quercetin-sensitive "endo"-localized Ca(2+)-ATPase activity appeared in some nerve terminals 24 h after irradiation. Thus, microwave irradiation can influence neuronal calcium homeostasis by inducing Ca2+ redistribution across the plasma membrane and by modifying Ca(2+)-ATPase activity. However, no direct correlation between these effects could be demonstrated by the present study.