RESUMO
PURPOSE: To investigate whether neonatal exposure to fractionated external gamma radiation and co-exposure to radiation and nicotine can affect/exacerbate developmental neurotoxic effects, including altered behavior/cognitive function and the susceptibility of the cholinergic system in adult male mice. MATERIALS AND METHODS: Neonatal male Naval Medical Research Institute (NMRI) mice were irradiated with one 200 mGy fraction/day and/or exposed to nicotine (66 µg/kg b.w.) twice daily on postnatal day (PND) 10, 10-11, 10-12 or 10-13 (nicotine only). At 2 months of age the animals were tested for spontaneous behavior in a novel home environment, habituation capacity and nicotine-induced behavior. RESULTS: Fractionated irradiation and co-exposure to radiation and nicotine on three consecutive days disrupted behavior and habituation and altered susceptibility of the cholinergic system. All observed effects were significantly more pronounced in mice co-exposed to both radiation and nicotine. CONCLUSIONS: The fractionated irradiation regime affects behavior/cognitive function in a similar manner as has previously been observed for single-dose exposures. Neonatal co-exposure to radiation and nicotine, during a critical period of brain development in general and cholinergic system development in particular, enhance these behavioral defects suggesting that the cholinergic system can be a target system for this type of developmental neurotoxic effects.
Assuntos
Sintomas Comportamentais/etiologia , Encéfalo/efeitos da radiação , Neurônios Colinérgicos/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Nicotina/toxicidade , Tolerância a Radiação/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Sintomas Comportamentais/fisiopatologia , Encéfalo/efeitos dos fármacos , Neurônios Colinérgicos/efeitos da radiação , Disfunção Cognitiva/fisiopatologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Raios gama/efeitos adversos , Masculino , CamundongosRESUMO
Optogenetic techniques are used widely to perturb and interrogate neural circuits in behaving animals, but illumination can have additional effects, such as the activation of endogenous opsins in the retina. We found that illumination, delivered deep into the brain via an optical fiber, evoked a behavioral artifact in mice performing a visually guided discrimination task. Compared with blue (473 nm) and yellow (589 nm) illumination, red (640 nm) illumination evoked a greater behavioral artifact and more activity in the retina, the latter measured with electrical recordings. In the mouse, the sensitivity of retinal opsins declines steeply with wavelength across the visible spectrum, but propagation of light through brain tissue increases with wavelength. Our results suggest that poor retinal sensitivity to red light was overcome by relatively robust propagation of red light through brain tissue and stronger illumination of the retina by red than by blue or yellow light. Light adaptation of the retina, via an external source of illumination, suppressed retinal activation and the behavioral artifact without otherwise impacting behavioral performance. In summary, long wavelength optogenetic stimuli are particularly prone to evoke behavioral artifacts via activation of retinal opsins in the mouse, but light adaptation of the retina can provide a simple and effective mitigation of the artifact.
Assuntos
Artefatos , Neurônios Colinérgicos/fisiologia , Discriminação Psicológica/efeitos da radiação , Potenciais Evocados Visuais/fisiologia , Optogenética , Reconhecimento Visual de Modelos/fisiologia , Retina/fisiologia , Adaptação Fisiológica , Animais , Channelrhodopsins , Neurônios Colinérgicos/citologia , Neurônios Colinérgicos/efeitos da radiação , Discriminação Psicológica/fisiologia , Potenciais Evocados Visuais/efeitos da radiação , Feminino , Expressão Gênica , Luz , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microeletrodos , Fibras Ópticas , Reconhecimento Visual de Modelos/efeitos da radiação , Estimulação Luminosa , Retina/citologia , Retina/efeitos da radiação , Técnicas Estereotáxicas , Análise e Desempenho de TarefasRESUMO
The basal forebrain (BF) plays a crucial role in cortical activation. Our previous study showed that activation of cholinergic BF neurons alone is sufficient to suppress slow-wave sleep (SWS) and promote wakefulness and rapid-eye-movement (REM) sleep. However, the exact role of silencing cholinergic BF neurons in the sleep-wake cycle remains unclear. We inhibitied the cholinergic BF neurons genetically targeted with archaerhodopsin (Arch) with yellow light to clarify the role of cholinergic BF neurons in the sleep-wake cycle. Bilateral inactivation of cholinergic BF neurons genetically targeted with archaerhodopsin prolonged SWS and decreased the probability of awakening from SWS in mice. However, silencing these neurons changed neither the duration of wakefulness or REM sleep, nor the probability of transitions to other sleep-wake episodes from wakefulness or REM sleep. Furthermore, silencing these neurons for 6 h within the inactive or active period increased the duration of SWS at the expense of the duration of wakefulness, as well as increasing the number of prolonged SWS episodes (120-240 s). The lost wakefulness was compensated by a delayed increase of wakefulness, so the total duration of SWS and wakefulness during 24 h was kept stable. Our results indicate that the main effect of these neurons is to terminate SWS, whereas wakefulness or REM sleep may be determined by co-operation of the cholinergic BF neurons with other arousal-sleep control systems.
Assuntos
Proteínas Arqueais/farmacologia , Prosencéfalo Basal/fisiopatologia , Neurônios Colinérgicos/efeitos dos fármacos , Fases do Sono/fisiologia , Animais , Neurônios Colinérgicos/fisiologia , Neurônios Colinérgicos/efeitos da radiação , Eletromiografia , Fenômenos Eletrofisiológicos , Imuno-Histoquímica , Luz , Camundongos , Camundongos Transgênicos , Sono REM/fisiologia , Vigília/fisiologiaRESUMO
Theta oscillations in the limbic system depend on the integrity of the medial septum. The different populations of medial septal neurons (cholinergic and GABAergic) are assumed to affect different aspects of theta oscillations. Using optogenetic stimulation of cholinergic neurons in ChAT-Cre mice, we investigated their effects on hippocampal local field potentials in both anesthetized and behaving mice. Cholinergic stimulation completely blocked sharp wave ripples and strongly suppressed the power of both slow oscillations (0.5-2 Hz in anesthetized, 0.5-4 Hz in behaving animals) and supratheta (6-10 Hz in anesthetized, 10-25 Hz in behaving animals) bands. The same stimulation robustly increased both the power and coherence of theta oscillations (2-6 Hz) in urethane-anesthetized mice. In behaving mice, cholinergic stimulation was less effective in the theta (4-10 Hz) band yet it also increased the ratio of theta/slow oscillation and theta coherence. The effects on gamma oscillations largely mirrored those of theta. These findings show that medial septal cholinergic activation can both enhance theta rhythm and suppress peri-theta frequency bands, allowing theta oscillations to dominate.