ABSTRACT
The effects of ultraviolet (UV) radiation on brain function have previously been investigated; however, the specific neurotransmitter-mediated mechanisms responsible for UV radiation-induced neurobehavioral changes remain elusive. In this study, we aimed to explore the mechanisms underlying UV radiation-induced neurobehavioral changes. In a mouse model, we observed that UV irradiation of the skin induces deficits in hippocampal memory, synaptic plasticity, and adult neurogenesis, as well as increased dopamine levels in the skin, adrenal glands, and brain. Chronic UV exposure altered the expression of genes involved in dopaminergic neuron differentiation. Furthermore, chronic peripheral dopamine treatments resulted in memory deficits. Systemic administration of a dopamine D1/D5 receptor antagonist reversed changes in memory, synaptic plasticity, adult neurogenesis, and gene expression in UV-irradiated mice. Our findings provide converging evidence that chronic UV exposure alters dopamine levels in the central nervous system and peripheral organs, including the skin, which may underlie the observed neurobehavioral shifts, such as hippocampal memory deficits and impaired neurogenesis. This study underscores the importance of protection from UV exposure and introduces the potential of pharmacological approaches targeting dopamine receptors to counteract the adverse neurological impacts of UV exposure.
Subject(s)
Dopamine , Memory Disorders , Ultraviolet Rays , Animals , Dopamine/metabolism , Ultraviolet Rays/adverse effects , Memory Disorders/etiology , Memory Disorders/metabolism , Mice , Male , Neurogenesis/radiation effects , Neuronal Plasticity/radiation effects , Hippocampus/metabolism , Hippocampus/radiation effects , Skin/metabolism , Skin/radiation effects , Signal Transduction , Mice, Inbred C57BL , Receptors, Dopamine D1/metabolism , Brain/metabolism , Brain/radiation effects , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/radiation effectsABSTRACT
Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.
Subject(s)
GABAergic Neurons/physiology , Nucleus Accumbens/physiology , Stress, Physiological/physiology , Ventral Tegmental Area/physiology , gamma-Aminobutyric Acid/metabolism , Action Potentials/physiology , Animals , Anticipation, Psychological/physiology , Behavior, Animal , Biological Clocks/physiology , Dopamine/metabolism , Dopaminergic Neurons/physiology , Dopaminergic Neurons/radiation effects , Female , GABAergic Neurons/metabolism , GABAergic Neurons/radiation effects , Immunohistochemistry , Limbic System/physiology , Male , Mice , Mice, Inbred C57BL , Nucleus Accumbens/radiation effects , Optogenetics , Restraint, Physical/physiology , Restraint, Physical/psychology , Reward , Ventral Tegmental Area/radiation effectsABSTRACT
Ultrasound mediated neuromodulation has been demonstrated to a safe treatment strategy in the field of neuroscience. In this study, low-intensity pulsed ultrasound (LIPUS) was used to treat Parkinson's disease (PD) models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) to explore the possibility of ultrasound neuroprotective effect on PD. The results demonstrated that LIPUS treatment can attenuate the central neurotoxicity of MPTP in mice, reduce the loss of tyrosine hydroxylase positive neurons in the substantia nigra pars compacta and decrease the apoptosis in the section of substantia nigra. The movement and balance dysfunctions in PD mice were improved with LIPUS treatment. In addition, we demonstrated that LIPUS can inhibit the decreased activity and increased apoptosis of dopaminergic neurons induced by MPP+, restrain the accumulation of reactive oxygen species (ROS) and decrease of mitochondrial membrane potential caused by MPP+. Moreover, LIPUS stimulation alone did not cause any cytotoxicity and tissue damage in our study. Taken together, the protective and regulatory effects of LIPUS on dopaminergic neurons make it possible as a new, safe and noninvasive treatment for PD.
Subject(s)
Dopaminergic Neurons/radiation effects , Parkinson Disease/therapy , Ultrasonic Therapy , Ultrasonic Waves , Animals , Disease Models, Animal , Male , Mice , Mice, Inbred C57BLABSTRACT
In recent times, photobiomodulation has been shown to be beneficial in animal models of Parkinson's disease, improving locomotive behavior and being neuroprotective. Early observations in people with Parkinson's disease have been positive also, with improvements in the non-motor symptoms of the disease being evident most consistently. Although the precise mechanisms behind these improvements are not clear, two have been proposed: direct stimulation, where light reaches and acts directly on the distressed neurons, and remote stimulation, where light influences cells and/or molecules that provide systemic protection, thereby acting indirectly on distressed neurons. In relation to Parkinson's disease, given that the major zone of pathology lies deep in the brain and that light from an extracranial or external photobiomodulation device would not reach these vulnerable regions, stimulating the distressed neurons directly would require intracranial delivery of light using a device implanted close to the vulnerable regions. For indirect systemic stimulation, photobiomodulation could be applied to either the head and scalp, using a transcranial helmet, or to a more remote body part (e.g., abdomen, leg). In this review, we discuss the evidence for both the direct and indirect neuroprotective effects of photobiomodulation in Parkinson's disease and propose that both types of treatment modality, when working together using both intracranial and extracranial devices, provide the best therapeutic option.
Subject(s)
Brain/radiation effects , Low-Level Light Therapy , Neuroprotective Agents/radiation effects , Parkinson Disease/therapy , Dopaminergic Neurons/radiation effects , Humans , MitochondriaABSTRACT
BACKGROUND: Parkinson's disease (PD) is one of the most common neurodegenerative disorders involving devastating loss of dopaminergic neurons in the substantia nigra. Early steps in PD pathogenesis include mitochondrial dysfunction, and mutations in mitochondrial genes have been linked to familial forms of the disease. However, low penetrance of mutations indicates a likely important role for environmental factors in PD risk through gene by environment interactions. Herein, we study how genetic deficiencies in mitochondrial dynamics processes including fission, fusion, and mitophagy interact with environmental exposures to impact neurodegeneration. METHODS: We utilized the powerful model organism Caenorhabditis elegans to study ultraviolet C radiation (UVC)- and 6-hydroxydopamine-induced degeneration of fluorescently-tagged dopaminergic neurons in the background of fusion deficiency (MFN1/2 homolog, fzo-1), fission deficiency (DMN1L homolog, drp-1), and mitochondria-specific autophagy (mitophagy) deficiency (PINK1 and PRKN homologs, pink-1 and pdr-1). RESULTS: Overall, we found that deficiency in either mitochondrial fusion or fission sensitizes nematodes to UVC exposure (used to model common environmental pollutants) but protects from 6-hydroxydopamine-induced neurodegeneration. By contrast, mitophagy deficiency makes animals more sensitive to these stressors with an interesting exception-pink-1 deficiency conferred remarkable protection from 6-hydroxydopamine. We found that this protection could not be explained by compensatory antioxidant gene expression in pink-1 mutants or by differences in mitochondrial morphology. CONCLUSIONS: Together, our results support a strong role for gene by environment interactions in driving dopaminergic neurodegeneration and suggest that genetic deficiency in mitochondrial processes can have complex effects on neurodegeneration.
Subject(s)
Dopaminergic Neurons/metabolism , Mitochondrial Dynamics , Parkinson Disease/genetics , Radiation Tolerance/genetics , Animals , Caenorhabditis elegans , Caenorhabditis elegans Proteins/genetics , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/radiation effects , Dynamins/genetics , GTP Phosphohydrolases/genetics , Mitophagy , Oxidopamine/toxicity , Parkinson Disease/etiology , Protein Serine-Threonine Kinases/genetics , Ubiquitin-Protein Ligases/genetics , Ultraviolet Rays/adverse effectsABSTRACT
Dopamine (DA) neuron projections to the striatum are functionally heterogeneous with diverse behavioral roles. We focus here on DA neuron projections to the nucleus accumbens (NAc) medial Shell, their distinct anatomical and functional connections, and discuss their role in motivated behavior. We first review rodent studies showing that a subpopulation of DA neurons in the medial ventral tegmental area (VTA) project to the NAc medial Shell. Using a combinatorial strategy, we show that the majority of DA neurons projecting to the NAc Shell express vesicular glutamate transporter 2 (VGLUT2) making them capable of glutamate co-transmission (DA-GLU neurons). In the NAc dorsal medial Shell, all of the DA neuron terminals arise from DA-GLU neurons, while in the lateral NAc Shell, DA neuron terminals arise from both DA-GLU neurons and DA-only neurons, without VGLUT2. DA-GLU neurons make excitatory connections to the three major cells types, spiny projection neurons, fast-spiking interneuron and cholinergic interneurons (ChIs). The strongest DA-GLU neuron excitatory connections are to ChIs. Photostimulation of DA-GLU neuron terminals in the slice drives ChIs to burst fire. Finally, we review studies that address specially the behavioral function of this subpopulation of DA neurons in extinction learning and latent inhibition. Taking into account findings from anatomical and functional connectome studies, we propose that DA-GLU neuron connections to ChIs in the medial Shell play a crucial role in switching behavioral responses under circumstances of altered cue-reinforcer contingencies.
Subject(s)
Dopaminergic Neurons/physiology , Glutamic Acid/physiology , Nucleus Accumbens/cytology , Action Potentials , Animals , Brain Mapping , Cholinergic Neurons/physiology , Connectome , Cues , Dopaminergic Neurons/radiation effects , Dopaminergic Neurons/ultrastructure , Extinction, Psychological/physiology , Fear/physiology , Humans , Interneurons/physiology , Mice , Nerve Endings/physiology , Nerve Endings/radiation effects , Nerve Tissue Proteins/metabolism , Neural Pathways/anatomy & histology , Nucleus Accumbens/physiology , Reinforcement, Psychology , Ventral Tegmental Area/anatomy & histology , Ventral Tegmental Area/physiology , Vesicular Glutamate Transport Protein 2/metabolismABSTRACT
Subtypes of nucleus accumbens medium spiny neurons (MSNs) promote dichotomous outcomes in motivated behaviors. However, recent reports indicate enhancing activity of either nucleus accumbens (NAc) core MSN subtype augments reward, suggesting coincident MSN activity may underlie this outcome. Here, we report a collateral excitation mechanism in which high-frequency, NAc core dopamine 1 (D1)-MSN activation causes long-lasting potentiation of excitatory transmission (LLP) on dopamine receptor 2 (D2)-MSNs. Our mechanistic investigation demonstrates that this form of plasticity requires release of the excitatory peptide substance P from D1-MSNs and robust cholinergic interneuron activation through neurokinin receptor stimulation. We also reveal that D2-MSN LLP requires muscarinic 1 receptor activation, intracellular calcium signaling, and GluR2-lacking AMPAR insertion. This study uncovers a mechanism for shaping NAc core activity through the transfer of excitatory information from D1-MSNs to D2-MSNs and may provide a means for altering goal-directed behavior through coordinated MSN activity.
Subject(s)
Dopaminergic Neurons/physiology , Long-Term Potentiation/physiology , Nucleus Accumbens/physiology , Substance P/metabolism , Action Potentials/physiology , Animals , Aprepitant/pharmacology , Calcium Signaling/physiology , Cholinergic Neurons/physiology , Dopaminergic Neurons/radiation effects , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Interneurons/physiology , Mice , Mice, Inbred C57BL , Motivation , Neurokinin-1 Receptor Antagonists/pharmacology , Nucleus Accumbens/cytology , Photic Stimulation , Piperidines/pharmacology , Receptor, Muscarinic M1/physiology , Receptors, AMPA/physiology , Receptors, Dopamine D1/analysis , Receptors, Dopamine D2/analysis , Receptors, Neurokinin-1/physiologyABSTRACT
Transcranial photobiomodulation (PBM), which involves the application of low-intensity red to near-infrared light (600-1100â¯nm) to the head, provides neuroprotection in animal models of various neurodegenerative diseases. However, the absorption of light energy by the human scalp and skull may limit the utility of transcranial PBM in clinical contexts. We have previously shown that targeting light at peripheral tissues (i.e. "remote PBM") also provides protection of the brain in an MPTP mouse model of Parkinson's disease, suggesting remote PBM might be a viable alternative strategy for overcoming penetration issues associated with transcranial PBM. This present study aimed to determine an effective pre-conditioning regimen of remote PBM for inducing neuroprotection and elucidate the molecular mechanisms by which remote PBM enhances the resilience of brain tissue. Balb/c mice were irradiated with 670-nm light (4â¯J/cm2 per day) targeting dorsum and hindlimbs for 2, 5 or 10â¯days, followed by injection of the parkinsonian neurotoxin MPTP (50â¯mg/kg) over two consecutive days. Despite no direct irradiation of the head, 10â¯days of pre-conditioning with remote PBM significantly attenuated MPTP-induced loss of midbrain tyrosine hydroxylase-positive dopaminergic cells and mitigated the increase in FOS-positive neurons in the caudate-putamen complex. Interrogation of the midbrain transcriptome by RNA microarray and pathway enrichment analysis suggested upregulation of cell signaling and migration (including CXCR4+ stem cell and adipocytokine signaling), oxidative stress response pathways and modulation of the blood-brain barrier following remote PBM. These findings establish remote PBM preconditioning as a viable neuroprotective intervention and provide insights into the mechanisms underlying this phenomenon.
Subject(s)
Brain/metabolism , Brain/radiation effects , Low-Level Light Therapy/methods , Parkinsonian Disorders/radiotherapy , Transcriptome/radiation effects , Animals , Caudate Nucleus/metabolism , Caudate Nucleus/radiation effects , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/radiation effects , Male , Mice, Inbred BALB C , Parkinsonian Disorders/metabolism , Pars Compacta/metabolism , Pars Compacta/radiation effects , Putamen/metabolism , Putamen/radiation effectsABSTRACT
Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here, we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in living mice. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through ß2-containing (ß2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders.
Subject(s)
Dopaminergic Neurons/metabolism , Light , Mesencephalon/cytology , Receptors, Nicotinic/metabolism , Reward , Action Potentials/drug effects , Action Potentials/physiology , Action Potentials/radiation effects , Animals , Cell Line , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/radiation effects , Mice, Inbred C57BL , Nicotine/pharmacology , Signal Transduction/radiation effects , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/metabolism , Ventral Tegmental Area/radiation effectsABSTRACT
The ventral tegmental area (VTA) receives phenotypically distinct innervations from the pedunculopontine tegmental nucleus (PPTg). While PPTg-to-VTA inputs are thought to play a critical role in stimulus-reward learning, direct evidence linking PPTg-to-VTA phenotypically distinct inputs in the learning process remains lacking. Here, we used optogenetic approaches to investigate the functional contribution of PPTg excitatory and inhibitory inputs to the VTA in appetitive Pavlovian conditioning. We show that photoinhibition of PPTg-to-VTA cholinergic or glutamatergic inputs during cue presentation dampens the development of anticipatory approach responding to the food receptacle during the cue. Furthermore, we employed in vivo optetrode recordings to show that photoinhibition of PPTg cholinergic or glutamatergic inputs significantly decreases VTA non-dopamine (non-DA) neural activity. Consistently, photoinhibition of VTA non-DA neurons disrupts the development of cue-elicited anticipatory approach responding. Taken together, our study reveals a crucial regulatory mechanism by PPTg excitatory inputs onto VTA non-DA neurons during appetitive Pavlovian conditioning.
Subject(s)
Appetite/physiology , Conditioning, Classical/physiology , Dopaminergic Neurons/physiology , Learning , Pedunculopontine Tegmental Nucleus/physiology , Ventral Tegmental Area/physiology , Animals , Appetite/radiation effects , Conditioning, Classical/radiation effects , Cues , Dopaminergic Neurons/radiation effects , Glutamates/metabolism , Light , Male , Mice, Inbred C57BL , Pedunculopontine Tegmental Nucleus/radiation effects , Reward , Ventral Tegmental Area/radiation effectsABSTRACT
Cell replacement therapy holds great promise for Parkinson's disease (PD), but residual undifferentiated cells and immature neural progenitors in the therapy may cause tumor formation. Although cell sorting could effectively exclude these proliferative cells, from the viewpoint of clinical application, there exists no adequate coping strategy in the case of their contamination. In this study, we analyzed a component of proliferative cells in the grafts of human-induced pluripotent stem cell-derived neural progenitors and investigated the effect of radiation therapy on tumor formation. In our differentiating protocol, analyses of neural progenitors (day 19) revealed that the proliferating cells expressed early neural markers (SOX1, PAX6) or a dopaminergic neuron progenitor marker (FOXA2). When grafted into the rat striatum, these immature neurons gradually became postmitotic in the brain, and the rosette structures disappeared at 14 weeks. However, at 4-8 weeks, the SOX1(+)PAX6(+) cells formed rosette structures in the grafts, suggesting their tumorigenic potential. Therefore, to develop a fail-safe therapy against tumor formation, we investigated the effect of radiation therapy. At 4 weeks posttransplantation, when KI67(+) cells comprised the highest ratio, radiation therapy with (137)Cs Gammacell Exactor for tumor-bearing immunodeficient rats showed a significant decrease in graft volume and percentage of SOX1(+)KI67(+) cells in the graft, thus demonstrating the preventive effect of gamma-ray irradiation against tumorigenicity. These results give us critical criteria for the safety of future cell replacement therapy for PD.
Subject(s)
Carcinogenesis/pathology , Carcinogenesis/radiation effects , Gamma Rays , Induced Pluripotent Stem Cells/pathology , Neural Stem Cells/pathology , Cell Differentiation/radiation effects , Cell Line , Cell Proliferation/radiation effects , Dopaminergic Neurons/cytology , Dopaminergic Neurons/radiation effects , Humans , Immunohistochemistry , Induced Pluripotent Stem Cells/radiation effects , Mesencephalon/cytology , Neural Stem Cells/radiation effects , Spheroids, Cellular/cytology , Spheroids, Cellular/radiation effects , Stem Cell TransplantationABSTRACT
Optogenetic techniques enable one to target specific neurons with light-sensitive proteins, e.g., ion channels, ion pumps, or enzymes, and to manipulate their physiological state through illumination. Such artificial interference with selected elements of complex neuronal circuits can help to determine causal relationships between neuronal activity and the effect on the functioning of neuronal circuits controlling animal behavior. The advantages of optogenetics can best be exploited in genetically tractable animals whose nervous systems are, on the one hand, small enough in terms of cell numbers and to a certain degree stereotypically organized, such that distinct and identifiable neurons can be targeted reproducibly. On the other hand, the neuronal circuitry and the behavioral repertoire should be complex enough to enable one to address interesting questions. The fruit fly Drosophila melanogaster is a favorable model organism in this regard. However, the application of optogenetic tools to depolarize or hyperpolarize neurons through light-induced ionic currents has been difficult in adult flies. Only recently, several variants of Channelrhodopsin-2 (ChR2) have been introduced that provide sufficient light sensitivity, expression, and stability to depolarize central brain neurons efficiently in adult Drosophila. Here, we focus on the version currently providing highest photostimulation efficiency, ChR2-XXL. We exemplify the use of this optogenetic tool by applying it to a widely used aversive olfactory learning paradigm. Optogenetic activation of a population of dopamine-releasing neurons mimics the reinforcing properties of a punitive electric shock typically used as an unconditioned stimulus. In temporal coincidence with an odor stimulus this artificially induced neuronal activity causes learning of the odor signal, thereby creating a light-induced memory.
Subject(s)
Drosophila melanogaster/physiology , Optogenetics/methods , Photic Stimulation/methods , Animals , Animals, Genetically Modified/genetics , Animals, Genetically Modified/physiology , Brain/physiology , Channelrhodopsins , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/radiation effects , Drosophila melanogaster/genetics , Drosophila melanogaster/radiation effects , Gene Expression , Memory/radiation effects , Neurosciences/methodsABSTRACT
We have used the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model to explore whether (i) the neuroprotective effect of near infrared light (NIr) treatment in the SNc is dose-dependent and (ii) the relationship between tyrosine hydroxylase (TH)+ terminal density and glial cells in the caudate-putamen complex (CPu). Mice received MPTP injections (50 mg/kg) and 2 J/cm2 NIr dose with either 2 d or 7 d survival period. In another series, with a longer 14 d survival period, mice had a stronger MPTP regime (100 mg/kg) and either 2 J/cm2 or 4 J/cm2 NIr dose. Brains were processed for routine immunohistochemistry and cell counts were made using stereology. Our findings were that in the 2 d series, no change in SNc TH+ cell number was evident after any treatment. In the 7 d series however, MPTP insult resulted in â¼45% reduction in TH+ cell number; after NIr (2 J/cm2) treatment, many cells were protected from the toxic insult. In the 14 d series, MPTP induced a similar reduction in TH+ cell number. NIr mitigated the loss of TH+ cells, but only at the higher dose of 4 J/cm2; the lower dose of 2 J/cm2 had no neuroprotective effect in this series. The higher dose of NIr, unlike the lower dose, also mitigated the MPTP- induced increase in CPu astrocytes after 14 d; these changes were independent of TH+ terminal density, of which, did not vary across the different experimental groups. In summary, we showed that neuroprotection by NIr irradiation in MPTP-treated mice was dose-dependent; with increasing MPTP toxicity, higher doses of NIr were required to protect cells and reduce astrogliosis.
Subject(s)
Dopaminergic Neurons/radiation effects , Gliosis/radiotherapy , Infrared Rays/therapeutic use , MPTP Poisoning/radiotherapy , Parkinsonian Disorders/radiotherapy , Pars Compacta/radiation effects , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/administration & dosage , Animals , Astrocytes/pathology , Astrocytes/radiation effects , Caudate Nucleus/pathology , Caudate Nucleus/radiation effects , Cell Count , Cell Survival/radiation effects , Dopaminergic Neurons/drug effects , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Gliosis/pathology , Low-Level Light Therapy , MPTP Poisoning/pathology , Male , Mice , Mice, Inbred BALB C , Nerve Tissue Proteins/analysis , Parkinsonian Disorders/pathology , Pars Compacta/pathology , Putamen/pathology , Putamen/radiation effects , Tyrosine 3-Monooxygenase/analysisABSTRACT
OBJECT The authors of this study used a newly developed intracranial optical fiber device to deliver near-infrared light (NIr) to the midbrain of 6-hydroxydopamine (6-OHDA)-lesioned rats, a model of Parkinson's disease. The authors explored whether NIr had any impact on apomorphine-induced turning behavior and whether it was neuroprotective. METHODS Two NIr powers (333 nW and 0.16 mW), modes of delivery (pulse and continuous), and total doses (634 mJ and 304 J) were tested, together with the feasibility of a midbrain implant site, one considered for later use in primates. Following a striatal 6-OHDA injection, the NIr optical fiber device was implanted surgically into the midline midbrain area of Wistar rats. Animals were tested for apomorphine-induced rotations, and then, 23 days later, their brains were aldehyde fixed for routine immunohistochemical analysis. RESULTS The results showed that there was no evidence of tissue toxicity by NIr in the midbrain. After 6-OHDA lesion, regardless of mode of delivery or total dose, NIr reduced apomorphine-induced rotations at the stronger, but not at the weaker, power. The authors found that neuroprotection, as assessed by tyrosine hydroxylase expression in midbrain dopaminergic cells, could account for some, but not all, of the observed behavioral improvements; the groups that were associated with fewer rotations did not all necessarily have a greater number of surviving cells. There may have been other "symptomatic" elements contributing to behavioral improvements in these rats. CONCLUSIONS In summary, when delivered at the appropriate power, delivery mode, and dosage, NIr treatment provided both improved behavior and neuroprotection in 6-OHDA-lesioned rats.
Subject(s)
Mesencephalon/physiopathology , Mesencephalon/radiation effects , Parkinsonian Disorders/physiopathology , Parkinsonian Disorders/therapy , Phototherapy/methods , Animals , Apomorphine/pharmacology , Cell Survival/physiology , Cell Survival/radiation effects , Dopamine Agonists/pharmacology , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/pathology , Dopaminergic Neurons/physiology , Dopaminergic Neurons/radiation effects , Dose-Response Relationship, Radiation , Feasibility Studies , Immunohistochemistry , Low-Level Light Therapy , Male , Mesencephalon/drug effects , Mesencephalon/pathology , Movement/drug effects , Movement/radiation effects , Optical Fibers/adverse effects , Oxidopamine , Parkinsonian Disorders/pathology , Phototherapy/adverse effects , Phototherapy/instrumentation , Prostheses and Implants/adverse effects , Rats, Wistar , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Converging lines of evidence indicate that near-infrared light treatment, also known as photobiomodulation (PBM), may exert beneficial effects and protect against cellular toxicity and degeneration in several animal models of human pathologies, including neurodegenerative disorders. In the present study, we report that chronic PMB treatment mitigates dopaminergic loss induced by unilateral overexpression of human α-synuclein (α-syn) in the substantia nigra of an AAV-based rat genetic model of Parkinson's disease (PD). In this model, daily exposure of both sides of the rat's head to 808-nm near-infrared light for 28 consecutive days alleviated α-syn-induced motor impairment, as assessed using the cylinder test. This treatment also significantly reduced dopaminergic neuronal loss in the injected substantia nigra and preserved dopaminergic fibers in the ipsilateral striatum. These beneficial effects were sustained for at least 6 weeks after discontinuing the treatment. Together, our data point to PBM as a possible therapeutic strategy for the treatment of PD and other related synucleinopathies.
Subject(s)
Dopaminergic Neurons/radiation effects , Low-Level Light Therapy , Parkinson Disease/radiotherapy , Substantia Nigra/radiation effects , Animals , Corpus Striatum/metabolism , Corpus Striatum/pathology , Corpus Striatum/radiation effects , Disease Models, Animal , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Female , Parkinson Disease/genetics , Parkinson Disease/metabolism , Parkinson Disease/pathology , Rats , Rats, Sprague-Dawley , Substantia Nigra/metabolism , Substantia Nigra/pathologyABSTRACT
We explored whether 810nm near-infrared light (NIr) offered neuroprotection and/or improvement in locomotor activity in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease. Mice received MPTP and 810nm NIr treatments, or not, and were tested for locomotive activity in an open-field test. Thereafter, brains were aldehyde-fixed and processed for tyrosine hydroxylase immunohistochemistry. Our results showed that MPTP-treated mice that were irradiated with 810nm NIr had both greater locomotor activity (â¼40%) and number of dopaminergic cells (â¼20%) than those that were not. In summary, 810nm (as with 670nm) NIr offered neuroprotection and improved locomotor activity in MPTP-treated mice.
Subject(s)
Dopaminergic Neurons/radiation effects , Infrared Rays , Motor Activity/radiation effects , Parkinsonian Disorders/radiotherapy , Pars Compacta/radiation effects , Animals , Cell Count , Dopaminergic Neurons/metabolism , Low-Level Light Therapy , Male , Mice , Mice, Inbred BALB C , Parkinsonian Disorders/metabolism , Pars Compacta/metabolism , Tyrosine 3-Monooxygenase/analysisABSTRACT
Pulsed electromagnetic fields (PEMF) exert biological effects and are in clinical use to facilitate bone repair and wound healing. Research has demonstrated that PEMF can induce signaling molecules and growth factors, molecules that play important roles in neuronal differentiation. Here, we tested the effects of a low-amplitude, nonthermal, pulsed radiofrequency signal on morphological neuronal differentiation in MN9D, a dopaminergic cell line. Cells were plated in medium with 10% fetal calf serum. After 1 day, medium was replaced with serum-containing medium, serum-free medium, or medium supplemented with dibutyryl cyclic adenosine monophosphate (Bt2 cAMP), a cAMP analog known to induce neurite outgrowth. Cultures were divided into groups and treated with PEMF signals for either 30 min per day or continuously for 15 min every hour for 3 days. Both serum withdrawal and Bt2 cAMP significantly increased neurite length. PEMF treatment similarly increased neurite length under both serum-free and serum-supplemented conditions, although to a lesser degree in the presence of serum, when continuous treatments had greater effects. PEMF signals also increased cell body width, indicating neuronal maturation, and decreased protein content, suggesting that this treatment was antimitotic, an effect reversed by the inhibitor of cAMP formation dideoxyadenosine. Bt2 cAMP and PEMF effects were not additive, suggesting that neurite elongation was achieved through a common pathway. PEMF signals increased cAMP levels from 3 to 5 hr after treatment, supporting this mechanism of action. Although neuritogenesis is considered a developmental process, it may also represent the plasticity required to form and maintain synaptic connections throughout life.
Subject(s)
Cell Differentiation/radiation effects , Dopaminergic Neurons/radiation effects , Electromagnetic Fields , Neurites/radiation effects , Neurogenesis/radiation effects , Animals , Cell Line , MiceABSTRACT
OBJECT: Previous experimental studies have documented the neuroprotection of damaged or diseased cells after applying, from outside the brain, near-infrared light (NIr) to the brain by using external light-emitting diodes (LEDs) or laser devices. In the present study, the authors describe an effective and reliable surgical method of applying to the brain, from inside the brain, NIr to the brain. They developed a novel internal surgical device that delivers the NIr to brain regions very close to target damaged or diseased cells. They suggest that this device will be useful in applying NIr within the large human brain, particularly if the target cells have a very deep location. METHODS: An optical fiber linked to an LED or laser device was surgically implanted into the lateral ventricle of BALB/c mice or Sprague-Dawley rats. The authors explored the feasibility of the internal device, measured the NIr signal through living tissue, looked for evidence of toxicity at doses higher than those required for neuroprotection, and confirmed the neuroprotective effect of NIr on dopaminergic cells in the substantia nigra pars compacta (SNc) in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson disease in mice. RESULTS: The device was stable in freely moving animals, and the NIr filled the cranial cavity. Measurements showed that the NIr intensity declined as distance from the source increased across the brain (65% per mm) but was detectable up to 10 mm away. At neuroprotective (0.16 mW) and much higher (67 mW) intensities, the NIr caused no observable behavioral deficits, nor was there evidence of tissue necrosis at the fiber tip, where radiation was most intense. Finally, the intracranially delivered NIr protected SNc cells against MPTP insult; there were consistently more dopaminergic cells in MPTP-treated mice irradiated with NIr than in those that were not irradiated. CONCLUSIONS: In summary, the authors showed that NIr can be applied intracranially, does not have toxic side effects, and is neuroprotective.
Subject(s)
Dopaminergic Neurons/radiation effects , Light , Parkinsonian Disorders/therapy , Phototherapy/methods , Animals , Cell Survival/radiation effects , Disease Models, Animal , Dopaminergic Neurons/cytology , Feasibility Studies , Infrared Rays , Male , Mice , Mice, Inbred BALB C , Neurosurgical Procedures/methods , Optical Fibers , Parkinsonian Disorders/pathology , Parkinsonian Disorders/surgery , Phototherapy/adverse effects , Phototherapy/instrumentation , Rats , Rats, Sprague-DawleyABSTRACT
We have examined whether near-infrared light (NIr) treatment mitigates oxidative stress and increased expression of hyperphosphorylated tau in a tau transgenic mouse strain (K3) that has a progressive degeneration of dopaminergic cells in the substantia nigra pars compacta (SNc). The brains of wild-type (WT), untreated K3 and NIr-treated K3 mice, aged five months (thus after the onset of parkinsonian signs and neuropathology), were labelled immunohistochemically for the oxidative stress markers 4-hydroxynonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHDG), hyperphosphorylated tau (using the AT8 antibody) and tyrosine hydroxylase (TH). The average intensity and area of 4-HNE, 8-OHDG and AT8 immunoreactivity were measured using the MetaMorph software and TH⺠cell number was estimated using stereology. Our results showed immunoreactivity for 4-HNE, 8-OHDG and AT8 within the SNc was increased in K3 mice compared to WT, and that this increase was mitigated by NIr. Results further showed that TH⺠cell number was lower in K3 mice than in WT, and that this loss was mitigated by NIr. In summary, NIr treatment reduced the oxidative stress caused by the tau transgene in the SNc of K3 mice and saved SNc cells from degeneration. Our results, when taken together with those in other models, strengthen the notion that NIr treatment saves dopaminergic cells in the parkinsonian condition.
Subject(s)
Brain/radiation effects , Cell Survival/radiation effects , Dopaminergic Neurons/radiation effects , Infrared Rays , Parkinsonian Disorders/pathology , Animals , Brain/metabolism , Brain/pathology , Disease Models, Animal , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Low-Level Light Therapy , Mice , Mice, Transgenic , Oxidative Stress/radiation effects , Parkinsonian Disorders/metabolism , Phosphorylation/radiation effects , tau Proteins/metabolismABSTRACT
BACKGROUND: We have shown previously that near-infrared light (NIr) treatment or photobiomodulation neuroprotects dopaminergic cells in substantia nigra pars compacta (SNc) from degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Balb/c albino mice, a well-known model for Parkinson's disease. The present study explores whether NIr treatment offers neuroprotection to these cells in C57BL/6 pigmented mice. In addition, we examine whether NIr influences behavioural activity in both strains after MPTP treatment. We tested for various locomotive parameters in an open-field test, namely velocity, high mobility and immobility. RESULTS: Balb/c (albino) and C57BL/6 (pigmented) mice received injections of MPTP (total of 50 mg/kg) or saline and NIr treatments (or not) over 48 hours. After each injection and/or NIr treatment, the locomotor activity of the mice was tested. After six days survival, brains were processed for TH (tyrosine hydroxylase) immunochemistry and the number of TH⺠cells in the substantia nigra pars compacta (SNc) was estimated using stereology. Results showed higher numbers of TH⺠cells in the MPTP-NIr groups of both strains, compared to the MPTP groups, with the protection greater in the Balb/c mice (30% vs 20%). The behavioural tests revealed strain differences also. For Balb/c mice, the MPTP-NIr group showed greater preservation of locomotor activity than the MPTP group. Behavioural preservation was less evident in the C57BL/6 strain however, with little effect of NIr being recorded in the MPTP-treated cases of this strain. Finally, there were differences between the two strains in terms of NIr penetration across the skin and fur. Our measurements indicated that NIr penetration was considerably less in the pigmented C57BL/6, compared to the albino Balb/c mice. CONCLUSIONS: In summary, our results revealed the neuroprotective benefits of NIr treatment after parkinsonian insult at both cellular and behavioural levels and suggest that Balb/c strain, due to greater penetration of NIr through skin and fur, provides a clearer model of protection than the C57BL/6 strain.